Metabolism

Metabolism (/məˈtæbəlɪzəm/, from Greek: μεταβολή metabolē, "change") is the set of life-sustaining chemical reactions in organisms. The three main purposes of metabolism are: the conversion of food to energy to run cellular processes; the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and some carbohydrates; and the elimination of nitrogenous wastes. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. (The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transport of substances into and between different cells, in which case the above described set of reactions within the cells is called intermediary metabolism or intermediate metabolism).

Metabolic reactions may be categorized as catabolic - the breaking down of compounds (for example, the breaking down of glucose to pyruvate by cellular respiration); or anabolic - the building up (synthesis) of compounds (such as proteins, carbohydrates, lipids, and nucleic acids). Usually, catabolism releases energy, and anabolism consumes energy.

The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step being facilitated by a specific enzyme. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy that will not occur by themselves, by coupling them to spontaneous reactions that release energy. Enzymes act as catalysts - they allow a reaction to proceed more rapidly - and they also allow the regulation of the rate of a metabolic reaction, for example in response to changes in the cell's environment or to signals from other cells.

The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals.[1] The basal metabolic rate of an organism is the measure of the amount of energy consumed by all of these chemical reactions.

A striking feature of metabolism is the similarity of the basic metabolic pathways among vastly different species.[2] For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacterium Escherichia coli and huge multicellular organisms like elephants.[3] These similarities in metabolic pathways are likely due to their early appearance in evolutionary history, and their retention because of their efficacy.[4][5]

Metabolism
Simplified view of the cellular metabolism
ATP-3D-vdW
Structure of adenosine triphosphate (ATP), a central intermediate in ENERGY metabolism

Key biochemicals

Trimyristin-3D-vdW
Structure of a triacylglycerol lipid
Human Metabolism - Pathways
This is a diagram depicting a large set of human metabolic pathways.

Most of the structures that make up animals, plants and microbes are made from three basic classes of molecule: amino acids, carbohydrates and lipids (often called fats). As these molecules are vital for life, metabolic reactions either focus on making these molecules during the construction of cells and tissues, or by breaking them down and using them as a source of energy, by their digestion. These biochemicals can be joined together to make polymers such as DNA and proteins, essential macromolecules of life.

Type of molecule Name of monomer forms Name of polymer forms Examples of polymer forms
Amino acids Amino acids Proteins (made of polypeptides) Fibrous proteins and globular proteins
Carbohydrates Monosaccharides Polysaccharides Starch, glycogen and cellulose
Nucleic acids Nucleotides Polynucleotides DNA and RNA

Amino acids and proteins

Proteins are made of amino acids arranged in a linear chain joined together by peptide bonds. Many proteins are enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as those that form the cytoskeleton, a system of scaffolding that maintains the cell shape.[6] Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle.[7] Amino acids also contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle (tricarboxylic acid cycle),[8] especially when a primary source of energy, such as glucose, is scarce, or when cells undergo metabolic stress.[9]

Lipids

Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes both internal and external, such as the cell membrane, or as a source of energy.[7] Lipids are usually defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as benzene or chloroform.[10] The fats are a large group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is called a triacylglyceride.[11] Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, and hydrophilic groups such as phosphate as in phospholipids. Steroids such as cholesterol are another major class of lipids.[12]

Carbohydrates

Glucose Fisher to Haworth
Glucose can exist in both a straight-chain and ring form.

Carbohydrates are aldehydes or ketones, with many hydroxyl groups attached, that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals).[7] The basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose. Monosaccharides can be linked together to form polysaccharides in almost limitless ways.[13]

Nucleotides

The two nucleic acids, DNA and RNA, are polymers of nucleotides. Each nucleotide is composed of a phosphate attached to a ribose or deoxyribose sugar group which is attached to a nitrogenous base. Nucleic acids are critical for the storage and use of genetic information, and its interpretation through the processes of transcription and protein biosynthesis.[7] This information is protected by DNA repair mechanisms and propagated through DNA replication. Many viruses have an RNA genome, such as HIV, which uses reverse transcription to create a DNA template from its viral RNA genome.[14] RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as coenzymes in metabolic-group-transfer reactions.[15]

Coenzymes

Acetyl-CoA-2D
Structure of the coenzyme acetyl-CoA.The transferable acetyl group is bonded to the sulfur atom at the extreme left.

Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups of atoms and their bonds within molecules.[16] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.[15] These group-transfer intermediates are called coenzymes. Each class of group-transfer reactions is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously made, consumed and then recycled.[17]

One central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day.[17] ATP acts as a bridge between catabolism and anabolism. Catabolism breaks down molecules, and anabolism puts them together. Catabolic reactions generate ATP, and anabolic reactions consume it. It also serves as a carrier of phosphate groups in phosphorylation reactions.

A vitamin is an organic compound needed in small quantities that cannot be made in cells. In human nutrition, most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells.[18] Nicotinamide adenine dinucleotide (NAD+), a derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD+ into NADH. This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.[19] Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD+/NADH form is more important in catabolic reactions, while NADP+/NADPH is used in anabolic reactions.

1GZX Haemoglobin
The structure of iron-containing hemoglobin. The protein subunits are in red and blue, and the iron-containing heme groups in green. From PDB: 1GZX​.

Minerals and cofactors

Inorganic elements play critical roles in metabolism; some are abundant (e.g. sodium and potassium) while others function at minute concentrations. About 99% of a mammal's mass is made up of the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, phosphorus, oxygen and sulfur.[20] Organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen; most of the oxygen and hydrogen is present as water.[20]

The abundant inorganic elements act as ionic electrolytes. The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate and the organic ion bicarbonate. The maintenance of precise ion gradients across cell membranes maintains osmotic pressure and pH.[21] Ions are also critical for nerve and muscle function, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cell's fluid, the cytosol.[22] Electrolytes enter and leave cells through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules.[23]

Transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant of those.[24][25] These metals are used in some proteins as cofactors and are essential for the activity of enzymes such as catalase and oxygen-carrier proteins such as hemoglobin.[26] Metal cofactors are bound tightly to specific sites in proteins; although enzyme cofactors can be modified during catalysis, they always return to their original state by the end of the reaction catalyzed. Metal micronutrients are taken up into organisms by specific transporters and bind to storage proteins such as ferritin or metallothionein when not in use.[27][28]

Catabolism

Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and oxidizing food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by anabolic reactions which build molecules. The exact nature of these catabolic reactions differ from organism to organism, and organisms can be classified based on their sources of energy and carbon (their primary nutritional groups), as shown in the table below. Organic molecules are used as a source of energy by organotrophs, while lithotrophs use inorganic substrates, and phototrophs capture sunlight as chemical energy. However, all these different forms of metabolism depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulfate.[29] In animals, these reactions involve complex organic molecules that are broken down to simpler molecules, such as carbon dioxide and water. In photosynthetic organisms, such as plants and cyanobacteria, these electron-transfer reactions do not release energy but are used as a way of storing energy absorbed from sunlight.[30]

Classification of organisms based on their metabolism
Energy source sunlight photo-   -troph
Preformed molecules chemo-
Electron donor organic compound   organo-  
inorganic compound litho-
Carbon source organic compound   hetero-
inorganic compound auto-

The most common set of catabolic reactions in animals can be separated into three main stages. In the first stage, large organic molecules, such as proteins, polysaccharides or lipids, are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to smaller molecules, usually acetyl coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by reducing the coenzyme nicotinamide adenine dinucleotide (NAD+) into NADH.

Digestion

Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and must be broken into their smaller units before they can be used in cell metabolism. Several common classes of enzymes digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into simple sugars known as monosaccharides.

Microbes simply secrete digestive enzymes into their surroundings,[31][32] while animals only secrete these enzymes from specialized cells in their guts, including the stomach and pancreas, and salivary glands.[33] The amino acids or sugars released by these extracellular enzymes are then pumped into cells by active transport proteins.[34][35]

Catabolism schematic
A simplified outline of the catabolism of proteins, carbohydrates and fats

Energy from organic compounds

Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into monosaccharides.[36] Once inside, the major route of breakdown is glycolysis, where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated.[37] Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA through aerobic (with oxygen) glycolysis and fed into the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD+ as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for re-use in glycolysis. An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.

Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their structures. Steroids are also broken down by some bacteria in a process similar to beta oxidation, and this breakdown process involves the release of significant amounts of acetyl-CoA, propionyl-CoA, and pyruvate, which can all be used by the cell for energy. M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis.[38]

Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy.[39] The oxidation pathway starts with the removal of the amino group by a transaminase. The amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms α-ketoglutarate.[40] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below).[41]

Energy transformations

Oxidative phosphorylation

In oxidative phosphorylation, the electrons removed from organic molecules in areas such as the protagon acid cycle are transferred to oxygen and the energy released is used to make ATP. This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are found in the cell's inner membrane.[42] These proteins use the energy released from passing electrons from reduced molecules like NADH onto oxygen to pump protons across a membrane.[43]

ATPsyn
Mechanism of ATP synthase. ATP is shown in red, ADP and phosphate in pink and the rotating stalk subunit in black.

Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates an electrochemical gradient.[44] This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase. The flow of protons makes the stalk subunit rotate, causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate – turning it into ATP.[17]

Energy from inorganic compounds

Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds. These organisms can use hydrogen,[45] reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate),[1] ferrous iron (FeII)[46] or ammonia[47] as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as oxygen or nitrite.[48] These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for soil fertility.[49][50]

Energy from light

The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists. This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can however operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching between carbon fixation and the fermentation of organic compounds.[51][52]

In many organisms the capture of solar energy is similar in principle to oxidative phosphorylation, as it involves the storage of energy as a proton concentration gradient. This proton motive force then drives ATP synthesis.[17] The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic reaction centres or rhodopsins. Reaction centers are classed into two types depending on the type of photosynthetic pigment present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have two.[53]

In plants, algae, and cyanobacteria, photosystem II uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump protons across the thylakoid membrane in the chloroplast.[30] These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through photosystem I and can then either be used to reduce the coenzyme NADP+, for use in the Calvin cycle, which is discussed below, or recycled for further ATP generation.[54]

Anabolism

Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed step-by-step from small and simple precursors. Anabolism involves three basic stages. First, the production of precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic acids.

Organisms differ according to the number of constructed molecules in their cells. Autotrophs such as plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions.

Carbon fixation

Plagiomnium affine laminazellen.jpeg
Plant cells (bounded by purple walls) filled with chloroplasts (green), which are the site of photosynthesis

Photosynthesis is the synthesis of carbohydrates from sunlight and carbon dioxide (CO2). In plants, cyanobacteria and algae, oxygenic photosynthesis splits water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the photosynthetic reaction centres, as described above, to convert CO2 into glycerate 3-phosphate, which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin – Benson cycle.[55] Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon fixation and CAM photosynthesis. These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and CAM photosynthesis incorporate the CO2 into other compounds first, as adaptations to deal with intense sunlight and dry conditions.[56]

In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a reversed citric acid cycle,[57] or the carboxylation of acetyl-CoA.[58][59] Prokaryotic chemoautotrophs also fix CO2 through the Calvin – Benson cycle, but use energy from inorganic compounds to drive the reaction.[60]

Carbohydrates and glycans

In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis.[37] However, this pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately, and prevents both pathways from running simultaneously in a futile cycle.[61][62]

Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate; plants do, but animals do not, have the necessary enzymatic machinery.[63] As a result, after long-term starvation, vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids.[64] In other organisms such as plants and bacteria, this metabolic problem is solved using the glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate, where it can be used for the production of glucose.[63][65]

Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-glucose) to an acceptor hydroxyl group on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures.[66] The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases.[67][68]

Fatty acids, isoprenoids and steroids

Sterol synthesis
Simplified version of the steroid synthesis pathway with the intermediates isopentenyl pyrophosphate (IPP), dimethylallyl pyrophosphate (DMAPP), geranyl pyrophosphate (GPP) and squalene shown. Some intermediates are omitted for clarity.

Fatty acids are made by fatty acid synthases that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the acyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups: in animals and fungi, all these fatty acid synthase reactions are carried out by a single multifunctional type I protein,[69] while in plant plastids and bacteria separate type II enzymes perform each step in the pathway.[70][71]

Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products.[72] These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate.[73] These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA,[74] while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.[73][75] One important reaction that uses these activated isoprene donors is steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.[76] Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.[76][77]

Proteins

Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can only synthesize eleven nonessential amino acids, so nine essential amino acids must be obtained from food.[7] Some simple parasites, such as the bacteria Mycoplasma pneumoniae, lack all amino acid synthesis and take their amino acids directly from their hosts.[78] All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid.[79]

Amino acids are made into proteins by being joined together in a chain of peptide bonds. Each different protein has a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase.[80] This aminoacyl-tRNA is then a substrate for the ribosome, which joins the amino acid onto the elongating protein chain, using the sequence information in a messenger RNA.[81]

Nucleotide synthesis and salvage

Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy.[82] Consequently, most organisms have efficient systems to salvage preformed nucleotides.[82][83] Purines are synthesized as nucleosides (bases attached to ribose).[84] Both adenine and guanine are made from the precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.[85]

Xenobiotics and redox metabolism

All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called xenobiotics.[86] Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases,[87] UDP-glucuronosyltransferases,[88] and glutathione S-transferases.[89] This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial biodegradation of pollutants and the bioremediation of contaminated land and oil spills.[90] Many of these microbial reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even persistent organic pollutants such as organochloride compounds.[91]

A related problem for aerobic organisms is oxidative stress.[92] Here, processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide.[93] These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases.[94][95]

Thermodynamics of living organisms

Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second law of thermodynamics states that in any closed system, the amount of entropy (disorder) cannot decrease. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are open systems that exchange matter and energy with their surroundings. Thus living systems are not in equilibrium, but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments.[96] The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder.[97]

Regulation and control

As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells, a condition called homeostasis.[98][99] Metabolic regulation also allows organisms to respond to signals and interact actively with their environments.[100] Two closely linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux through the pathway).[101] For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway.[102]

Insulin glucose metabolism ZP
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).

There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the flux through the pathway to compensate.[101] This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway.[103] Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface.[104] These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins.[105]

A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin.[106] Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen.[107] The metabolism of glycogen is controlled by activity of phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes.[108]

Evolution

Tree of life int
Evolutionary tree showing the common ancestry of organisms from all three domains of life. Bacteria are colored blue, eukaryotes red, and archaea green. Relative positions of some of the phyla included are shown around the tree.

The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all three domains of living things and were present in the last universal common ancestor.[3][109] This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism.[110][111] The retention of these ancient pathways during later evolution may be the result of these reactions having been an optimal solution to their particular metabolic problems, with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps.[4][5] The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, while previous metabolic pathways were a part of the ancient RNA world.[112]

Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway.[113] The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions created from pre-existing steps in the pathway.[114] An alternative model comes from studies that trace the evolution of proteins' structures in metabolic networks, this has suggested that enzymes are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident in the MANET database)[115] These recruitment processes result in an evolutionary enzymatic mosaic.[116] A third possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and perform similar functions on different molecules.[117]

As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the host.[118] Similar reduced metabolic capabilities are seen in endosymbiotic organisms.[119]

Investigation and manipulation

A thaliana metabolic network
Metabolic network of the Arabidopsis thaliana citric acid cycle. Enzymes and metabolites are shown as red squares and the interactions between them as black lines.

Classically, metabolism is studied by a reductionist approach that focuses on a single metabolic pathway. Particularly valuable is the use of radioactive tracers at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively labelled intermediates and products.[120] The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitors investigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called the metabolome. Overall, these studies give a good view of the structure and function of simple metabolic pathways, but are inadequate when applied to more complex systems such as the metabolism of a complete cell.[121]

An idea of the complexity of the metabolic networks in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide lists containing anything up to 45,000 genes.[122] However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more holistic mathematical models that may explain and predict their behavior.[123] These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on gene expression from proteomic and DNA microarray studies.[124] Using these techniques, a model of human metabolism has now been produced, which will guide future drug discovery and biochemical research.[125] These models are now used in network analysis, to classify human diseases into groups that share common proteins or metabolites.[126][127]

Bacterial metabolic networks are a striking example of bow-tie[128][129][130] organization, an architecture able to input a wide range of nutrients and produce a large variety of products and complex macromolecules using a relatively few intermediate common currencies.

A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants or bacteria are genetically modified to make them more useful in biotechnology and aid the production of drugs such as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid.[131] These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.[132]

History

The term metabolism is derived from the Greek Μεταβολισμός – "Metabolismos" for "change", or "overthrow".[133]

Aristotle's metabolism
Aristotle's metabolism as an open flow model

Greek philosophy

Aristotle's The Parts of Animals sets out enough details of his views on metabolism for an open flow model to be made. He believed that at each stage of the process, materials from food were transformed, with heat being released as the classical element of fire, and residual materials being excreted as urine, bile, or faeces.[134]

Islamic medicine

Ibn al-Nafis described metabolism in his 1260 AD work titled Al-Risalah al-Kamiliyyah fil Siera al-Nabawiyyah (The Treatise of Kamil on the Prophet's Biography) which included the following phrase "Both the body and its parts are in a continuous state of dissolution and nourishment, so they are inevitably undergoing permanent change."[135]

Application of the scientific method

The history of the scientific study of metabolism spans several centuries and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medicina.[136] He described how he weighed himself before and after eating, sleep, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called "insensible perspiration".

SantoriosMeal
Santorio Santorio in his steelyard balance, from Ars de statica medicina, first published 1614

In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue.[137] In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called "ferments". He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."[138] This discovery, along with the publication by Friedrich Wöhler in 1828 of a paper on the chemical synthesis of urea,[139] and is notable for being the first organic compound prepared from wholly inorganic precursors. This proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.

It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry.[140] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism.[141] He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle.[142][65] Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.

See also

References

  1. ^ a b Friedrich C (1998). Physiology and genetics of sulfur-oxidizing bacteria. Adv Microb Physiol. Advances in Microbial Physiology. 39. pp. 235–89. doi:10.1016/S0065-2911(08)60018-1. ISBN 978-0-12-027739-1. PMID 9328649.
  2. ^ Pace NR (January 2001). "The universal nature of biochemistry". Proc. Natl. Acad. Sci. U.S.A. 98 (3): 805–8. Bibcode:2001PNAS...98..805P. doi:10.1073/pnas.98.3.805. PMC 33372. PMID 11158550.
  3. ^ a b Smith E, Morowitz H (2004). "Universality in intermediary metabolism". Proc Natl Acad Sci USA. 101 (36): 13168–73. Bibcode:2004PNAS..10113168S. doi:10.1073/pnas.0404922101. PMC 516543. PMID 15340153.
  4. ^ a b Ebenhöh O, Heinrich R (2001). "Evolutionary optimization of metabolic pathways. Theoretical reconstruction of the stoichiometry of ATP and NADH producing systems". Bull Math Biol. 63 (1): 21–55. doi:10.1006/bulm.2000.0197. PMID 11146883.
  5. ^ a b Meléndez-Hevia E, Waddell T, Cascante M (1996). "The puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution". J Mol Evol. 43 (3): 293–303. Bibcode:1996JMolE..43..293M. doi:10.1007/BF02338838. PMID 8703096.
  6. ^ Michie K, Löwe J (2006). "Dynamic filaments of the bacterial cytoskeleton". Annu Rev Biochem. 75: 467–92. doi:10.1146/annurev.biochem.75.103004.142452. PMID 16756499.
  7. ^ a b c d e Nelson, David L.; Michael M. Cox (2005). Lehninger Principles of Biochemistry. New York: W. H. Freeman and company. p. 841. ISBN 978-0-7167-4339-2.
  8. ^ Kelleher J, Bryan 3rd, B, Mallet R, Holleran A, Murphy A, and Fiskum G (1987). "Analysis of tricarboxylic acid-cycle metabolism of hepatoma cells by comparison of 14CO2 ratios". Biochem J. 246 (3): 633–639. doi:10.1042/bj2460633. PMC 1148327. PMID 3120698.CS1 maint: Uses authors parameter (link)
  9. ^ Hothersall, J & Ahmed, A (2013). "Metabolic fate of the increased yeast amino acid uptake subsequent to catabolite derepression". J Amino Acids. 2013: 1–7. doi:10.1155/2013/461901. PMC 3575661. PMID 23431419.
  10. ^ Fahy E, Subramaniam S, Brown H, Glass C, Merrill A, Murphy R, Raetz C, Russell D, Seyama Y, Shaw W, Shimizu T, Spener F, van Meer G, VanNieuwenhze M, White S, Witztum J, Dennis E (2005). "A comprehensive classification system for lipids". J Lipid Res. 46 (5): 839–61. doi:10.1194/jlr.E400004-JLR200. PMID 15722563.
  11. ^ "Nomenclature of Lipids". IUPAC-IUB Commission on Biochemical Nomenclature (CBN). Retrieved 8 March 2007.
  12. ^ Hegardt F (1999). "Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis". Biochem J. 338 (Pt 3): 569–82. doi:10.1042/0264-6021:3380569. PMC 1220089. PMID 10051425.
  13. ^ Raman R, Raguram S, Venkataraman G, Paulson J, Sasisekharan R (2005). "Glycomics: an integrated systems approach to structure-function relationships of glycans". Nat Methods. 2 (11): 817–24. doi:10.1038/nmeth807. PMID 16278650.
  14. ^ Sierra S, Kupfer B, Kaiser R (2005). "Basics of the virology of HIV-1 and its replication". J Clin Virol. 34 (4): 233–44. doi:10.1016/j.jcv.2005.09.004. PMID 16198625.
  15. ^ a b Wimmer M, Rose I (1978). "Mechanisms of enzyme-catalyzed group transfer reactions". Annu Rev Biochem. 47: 1031–78. doi:10.1146/annurev.bi.47.070178.005123. PMID 354490.
  16. ^ Mitchell P (1979). "The Ninth Sir Hans Krebs Lecture. Compartmentation and communication in living systems. Ligand conduction: a general catalytic principle in chemical, osmotic and chemiosmotic reaction systems". Eur J Biochem. 95 (1): 1–20. doi:10.1111/j.1432-1033.1979.tb12934.x. PMID 378655.
  17. ^ a b c d Dimroth P, von Ballmoos C, Meier T (March 2006). "Catalytic and mechanical cycles in F-ATP synthases: Fourth in the Cycles Review Series". EMBO Rep. 7 (3): 276–82. doi:10.1038/sj.embor.7400646. PMC 1456893. PMID 16607397.
  18. ^ Coulston, Ann; Kerner, John; Hattner, JoAnn; Srivastava, Ashini (2006). "Nutrition Principles and Clinical Nutrition". Stanford School of Medicine Nutrition Courses. SUMMIT.
  19. ^ Pollak N, Dölle C, Ziegler M (2007). "The power to reduce: pyridine nucleotides – small molecules with a multitude of functions". Biochem J. 402 (2): 205–18. doi:10.1042/BJ20061638. PMC 1798440. PMID 17295611.
  20. ^ a b Heymsfield S, Waki M, Kehayias J, Lichtman S, Dilmanian F, Kamen Y, Wang J, Pierson R (1991). "Chemical and elemental analysis of humans in vivo using improved body composition models". Am J Physiol. 261 (2 Pt 1): E190–8. doi:10.1152/ajpendo.1991.261.2.E190. PMID 1872381.
  21. ^ Sychrová H (2004). "Yeast as a model organism to study transport and homeostasis of alkali metal cations" (PDF). Physiol Res. 53 Suppl 1: S91–8. PMID 15119939.
  22. ^ Levitan I (1988). "Modulation of ion channels in neurons and other cells". Annu Rev Neurosci. 11: 119–36. doi:10.1146/annurev.ne.11.030188.001003. PMID 2452594.
  23. ^ Dulhunty A (2006). "Excitation-contraction coupling from the 1950s into the new millennium". Clin Exp Pharmacol Physiol. 33 (9): 763–72. doi:10.1111/j.1440-1681.2006.04441.x. PMID 16922804.
  24. ^ Mahan D, Shields R (1998). "Macro- and micromineral composition of pigs from birth to 145 kilograms of body weight" (PDF). J Anim Sci. 76 (2): 506–12. doi:10.2527/1998.762506x. PMID 9498359.
  25. ^ Husted S, Mikkelsen B, Jensen J, Nielsen N (2004). "Elemental fingerprint analysis of barley (Hordeum vulgare) using inductively coupled plasma mass spectrometry, isotope-ratio mass spectrometry, and multivariate statistics". Anal Bioanal Chem. 378 (1): 171–82. doi:10.1007/s00216-003-2219-0. PMID 14551660.
  26. ^ Finney L, O'Halloran T (2003). "Transition metal speciation in the cell: insights from the chemistry of metal ion receptors". Science. 300 (5621): 931–6. Bibcode:2003Sci...300..931F. doi:10.1126/science.1085049. PMID 12738850.
  27. ^ Cousins R, Liuzzi J, Lichten L (2006). "Mammalian zinc transport, trafficking, and signals". J Biol Chem. 281 (34): 24085–9. doi:10.1074/jbc.R600011200. PMID 16793761.
  28. ^ Dunn L, Rahmanto Y, Richardson D (2007). "Iron uptake and metabolism in the new millennium". Trends Cell Biol. 17 (2): 93–100. doi:10.1016/j.tcb.2006.12.003. PMID 17194590.
  29. ^ Nealson K, Conrad P (1999). "Life: past, present and future". Philos Trans R Soc Lond B Biol Sci. 354 (1392): 1923–39. doi:10.1098/rstb.1999.0532. PMC 1692713. PMID 10670014.
  30. ^ a b Nelson N, Ben-Shem A (2004). "The complex architecture of oxygenic photosynthesis". Nat Rev Mol Cell Biol. 5 (12): 971–82. doi:10.1038/nrm1525. PMID 15573135.
  31. ^ Häse C, Finkelstein R (December 1993). "Bacterial extracellular zinc-containing metalloproteases". Microbiol Rev. 57 (4): 823–37. PMC 372940. PMID 8302217.
  32. ^ Gupta R, Gupta N, Rathi P (2004). "Bacterial lipases: an overview of production, purification and biochemical properties". Appl Microbiol Biotechnol. 64 (6): 763–81. doi:10.1007/s00253-004-1568-8. PMID 14966663.
  33. ^ Hoyle T (1997). "The digestive system: linking theory and practice". Br J Nurs. 6 (22): 1285–91. doi:10.12968/bjon.1997.6.22.1285. PMID 9470654.
  34. ^ Souba W, Pacitti A (1992). "How amino acids get into cells: mechanisms, models, menus, and mediators". JPEN J Parenter Enteral Nutr. 16 (6): 569–78. doi:10.1177/0148607192016006569. PMID 1494216.
  35. ^ Barrett M, Walmsley A, Gould G (1999). "Structure and function of facilitative sugar transporters". Curr Opin Cell Biol. 11 (4): 496–502. doi:10.1016/S0955-0674(99)80072-6. PMID 10449337.
  36. ^ Bell G, Burant C, Takeda J, Gould G (1993). "Structure and function of mammalian facilitative sugar transporters". J Biol Chem. 268 (26): 19161–4. PMID 8366068.
  37. ^ a b Bouché C, Serdy S, Kahn C, Goldfine A (2004). "The cellular fate of glucose and its relevance in type 2 diabetes". Endocr Rev. 25 (5): 807–30. doi:10.1210/er.2003-0026. PMID 15466941. Archived from the original on 4 December 2012. Retrieved 15 March 2007.
  38. ^ Wipperman, Matthew, F.; Thomas, Suzanne, T.; Sampson, Nicole, S. (2014). "Pathogen roid rage: Cholesterol utilization by Mycobacterium tuberculosis". Crit. Rev. Biochem. Mol. Biol. 49 (4): 269–93. doi:10.3109/10409238.2014.895700. PMC 4255906. PMID 24611808.
  39. ^ Sakami W, Harrington H (1963). "Amino acid metabolism". Annu Rev Biochem. 32: 355–98. doi:10.1146/annurev.bi.32.070163.002035. PMID 14144484.
  40. ^ Brosnan J (2000). "Glutamate, at the interface between amino acid and carbohydrate metabolism". J Nutr. 130 (4S Suppl): 988S–90S. doi:10.1093/jn/130.4.988S. PMID 10736367.
  41. ^ Young V, Ajami A (2001). "Glutamine: the emperor or his clothes?". J Nutr. 131 (9 Suppl): 2449S–59S, discussion 2486S–7S. doi:10.1093/jn/131.9.2449S. PMID 11533293.
  42. ^ Hosler J, Ferguson-Miller S, Mills D (2006). "Energy Transduction: Proton Transfer Through the Respiratory Complexes". Annu Rev Biochem. 75: 165–87. doi:10.1146/annurev.biochem.75.062003.101730. PMC 2659341. PMID 16756489.
  43. ^ Schultz B, Chan S (2001). "Structures and proton-pumping strategies of mitochondrial respiratory enzymes". Annu Rev Biophys Biomol Struct. 30: 23–65. doi:10.1146/annurev.biophys.30.1.23. PMID 11340051.
  44. ^ Capaldi R, Aggeler R (2002). "Mechanism of the F(1)F(0)-type ATP synthase, a biological rotary motor". Trends Biochem Sci. 27 (3): 154–60. doi:10.1016/S0968-0004(01)02051-5. PMID 11893513.
  45. ^ Friedrich B, Schwartz E (1993). "Molecular biology of hydrogen utilization in aerobic chemolithotrophs". Annu Rev Microbiol. 47: 351–83. doi:10.1146/annurev.mi.47.100193.002031. PMID 8257102.
  46. ^ Weber K, Achenbach L, Coates J (2006). "Microorganisms pumping iron: anaerobic microbial iron oxidation and reduction". Nat Rev Microbiol. 4 (10): 752–64. doi:10.1038/nrmicro1490. PMID 16980937.
  47. ^ Jetten M, Strous M, van de Pas-Schoonen K, Schalk J, van Dongen U, van de Graaf A, Logemann S, Muyzer G, van Loosdrecht M, Kuenen J (1998). "The anaerobic oxidation of ammonium". FEMS Microbiol Rev. 22 (5): 421–37. doi:10.1111/j.1574-6976.1998.tb00379.x. PMID 9990725.
  48. ^ Simon J (2002). "Enzymology and bioenergetics of respiratory nitrite ammonification". FEMS Microbiol Rev. 26 (3): 285–309. doi:10.1111/j.1574-6976.2002.tb00616.x. PMID 12165429.
  49. ^ Conrad R (1996). "Soil microorganisms as controllers of atmospheric trace gases (H2, CO, CH4, OCS, N2O, and NO)". Microbiol Rev. 60 (4): 609–40. PMC 239458. PMID 8987358.
  50. ^ Barea J, Pozo M, Azcón R, Azcón-Aguilar C (2005). "Microbial co-operation in the rhizosphere". J Exp Bot. 56 (417): 1761–78. doi:10.1093/jxb/eri197. PMID 15911555.
  51. ^ van der Meer M, Schouten S, Bateson M, Nübel U, Wieland A, Kühl M, de Leeuw J, Sinninghe Damsté J, Ward D (July 2005). "Diel Variations in Carbon Metabolism by Green Nonsulfur-Like Bacteria in Alkaline Siliceous Hot Spring Microbial Mats from Yellowstone National Park". Appl Environ Microbiol. 71 (7): 3978–86. doi:10.1128/AEM.71.7.3978-3986.2005. PMC 1168979. PMID 16000812.
  52. ^ Tichi M, Tabita F (2001). "Interactive Control of Rhodobacter capsulatus Redox-Balancing Systems during Phototrophic Metabolism". J Bacteriol. 183 (21): 6344–54. doi:10.1128/JB.183.21.6344-6354.2001. PMC 100130. PMID 11591679.
  53. ^ Allen J, Williams J (1998). "Photosynthetic reaction centers". FEBS Lett. 438 (1–2): 5–9. doi:10.1016/S0014-5793(98)01245-9. PMID 9821949.
  54. ^ Munekage Y, Hashimoto M, Miyake C, Tomizawa K, Endo T, Tasaka M, Shikanai T (2004). "Cyclic electron flow around photosystem I is essential for photosynthesis". Nature. 429 (6991): 579–82. Bibcode:2004Natur.429..579M. doi:10.1038/nature02598. PMID 15175756.
  55. ^ Miziorko H, Lorimer G (1983). "Ribulose-1,5-bisphosphate carboxylase-oxygenase". Annu Rev Biochem. 52: 507–35. doi:10.1146/annurev.bi.52.070183.002451. PMID 6351728.
  56. ^ Dodd A, Borland A, Haslam R, Griffiths H, Maxwell K (2002). "Crassulacean acid metabolism: plastic, fantastic". J Exp Bot. 53 (369): 569–80. doi:10.1093/jexbot/53.369.569. PMID 11886877.
  57. ^ Hügler M, Wirsen C, Fuchs G, Taylor C, Sievert S (May 2005). "Evidence for Autotrophic CO2 Fixation via the Reductive Tricarboxylic Acid Cycle by Members of the ɛ Subdivision of Proteobacteria". J Bacteriol. 187 (9): 3020–7. doi:10.1128/JB.187.9.3020-3027.2005. PMC 1082812. PMID 15838028.
  58. ^ Strauss G, Fuchs G (1993). "Enzymes of a novel autotrophic CO2 fixation pathway in the phototrophic bacterium Chloroflexus aurantiacus, the 3-hydroxypropionate cycle". Eur J Biochem. 215 (3): 633–43. doi:10.1111/j.1432-1033.1993.tb18074.x. PMID 8354269.
  59. ^ Wood H (1991). "Life with CO or CO2 and H2 as a source of carbon and energy". FASEB J. 5 (2): 156–63. doi:10.1096/fasebj.5.2.1900793. PMID 1900793.
  60. ^ Shively J, van Keulen G, Meijer W (1998). "Something from almost nothing: carbon dioxide fixation in chemoautotrophs". Annu Rev Microbiol. 52: 191–230. doi:10.1146/annurev.micro.52.1.191. PMID 9891798.
  61. ^ Boiteux A, Hess B (1981). "Design of glycolysis". Philos Trans R Soc Lond B Biol Sci. 293 (1063): 5–22. Bibcode:1981RSPTB.293....5B. doi:10.1098/rstb.1981.0056. PMID 6115423.
  62. ^ Pilkis S, el-Maghrabi M, Claus T (1990). "Fructose-2,6-bisphosphate in control of hepatic gluconeogenesis. From metabolites to molecular genetics". Diabetes Care. 13 (6): 582–99. doi:10.2337/diacare.13.6.582. PMID 2162755.
  63. ^ a b Ensign S (2006). "Revisiting the glyoxylate cycle: alternate pathways for microbial acetate assimilation". Mol Microbiol. 61 (2): 274–6. doi:10.1111/j.1365-2958.2006.05247.x. PMID 16856935.
  64. ^ Finn P, Dice J (2006). "Proteolytic and lipolytic responses to starvation". Nutrition. 22 (7–8): 830–44. doi:10.1016/j.nut.2006.04.008. PMID 16815497.
  65. ^ a b Kornberg H, Krebs H (1957). "Synthesis of cell constituents from C2-units by a modified tricarboxylic acid cycle". Nature. 179 (4568): 988–91. Bibcode:1957Natur.179..988K. doi:10.1038/179988a0. PMID 13430766.
  66. ^ Rademacher T, Parekh R, Dwek R (1988). "Glycobiology". Annu Rev Biochem. 57: 785–838. doi:10.1146/annurev.bi.57.070188.004033. PMID 3052290.
  67. ^ Opdenakker G, Rudd P, Ponting C, Dwek R (1993). "Concepts and principles of glycobiology". FASEB J. 7 (14): 1330–7. doi:10.1096/fasebj.7.14.8224606. PMID 8224606.
  68. ^ McConville M, Menon A (2000). "Recent developments in the cell biology and biochemistry of glycosylphosphatidylinositol lipids (review)". Mol Membr Biol. 17 (1): 1–16. doi:10.1080/096876800294443. PMID 10824734.
  69. ^ Chirala S, Wakil S (2004). "Structure and function of animal fatty acid synthase". Lipids. 39 (11): 1045–53. doi:10.1007/s11745-004-1329-9. PMID 15726818.
  70. ^ White S, Zheng J, Zhang Y (2005). "The structural biology of type II fatty acid biosynthesis". Annu Rev Biochem. 74: 791–831. doi:10.1146/annurev.biochem.74.082803.133524. PMID 15952903.
  71. ^ Ohlrogge J, Jaworski J (1997). "Regulation of fatty acid synthesis". Annu Rev Plant Physiol Plant Mol Biol. 48: 109–136. doi:10.1146/annurev.arplant.48.1.109. PMID 15012259.
  72. ^ Dubey V, Bhalla R, Luthra R (2003). "An overview of the non-mevalonate pathway for terpenoid biosynthesis in plants" (PDF). J Biosci. 28 (5): 637–46. doi:10.1007/BF02703339. PMID 14517367. Archived from the original (PDF) on 15 April 2007.
  73. ^ a b Kuzuyama T, Seto H (2003). "Diversity of the biosynthesis of the isoprene units". Nat Prod Rep. 20 (2): 171–83. doi:10.1039/b109860h. PMID 12735695.
  74. ^ Grochowski L, Xu H, White R (May 2006). "Methanocaldococcus jannaschii Uses a Modified Mevalonate Pathway for Biosynthesis of Isopentenyl Diphosphate". J Bacteriol. 188 (9): 3192–8. doi:10.1128/JB.188.9.3192-3198.2006. PMC 1447442. PMID 16621811.
  75. ^ Lichtenthaler H (1999). "The 1-Ddeoxy-D-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants". Annu Rev Plant Physiol Plant Mol Biol. 50: 47–65. doi:10.1146/annurev.arplant.50.1.47. PMID 15012203.
  76. ^ a b Schroepfer G (1981). "Sterol biosynthesis". Annu Rev Biochem. 50: 585–621. doi:10.1146/annurev.bi.50.070181.003101. PMID 7023367.
  77. ^ Lees N, Skaggs B, Kirsch D, Bard M (1995). "Cloning of the late genes in the ergosterol biosynthetic pathway of Saccharomyces cerevisiae—a review". Lipids. 30 (3): 221–6. doi:10.1007/BF02537824. PMID 7791529.
  78. ^ Himmelreich R, Hilbert H, Plagens H, Pirkl E, Li BC, Herrmann R (November 1996). "Complete sequence analysis of the genome of the bacterium Mycoplasma pneumoniae". Nucleic Acids Res. 24 (22): 4420–49. doi:10.1093/nar/24.22.4420. PMC 146264. PMID 8948633.
  79. ^ Guyton, Arthur C.; John E. Hall (2006). Textbook of Medical Physiology. Philadelphia: Elsevier. pp. 855–6. ISBN 978-0-7216-0240-0.
  80. ^ Ibba M, Söll D (2001). "The renaissance of aminoacyl-tRNA synthesis". EMBO Rep. 2 (5): 382–7. doi:10.1093/embo-reports/kve095. PMC 1083889. PMID 11375928. Archived from the original on 1 May 2011.
  81. ^ Lengyel P, Söll D (1969). "Mechanism of protein biosynthesis". Bacteriol Rev. 33 (2): 264–301. PMC 378322. PMID 4896351.
  82. ^ a b Rudolph F (1994). "The biochemistry and physiology of nucleotides". J Nutr. 124 (1 Suppl): 124S–127S. doi:10.1093/jn/124.suppl_1.124S. PMID 8283301. Zrenner R, Stitt M, Sonnewald U, Boldt R (2006). "Pyrimidine and purine biosynthesis and degradation in plants". Annu Rev Plant Biol. 57: 805–36. doi:10.1146/annurev.arplant.57.032905.105421. PMID 16669783.
  83. ^ Stasolla C, Katahira R, Thorpe T, Ashihara H (2003). "Purine and pyrimidine nucleotide metabolism in higher plants". J Plant Physiol. 160 (11): 1271–95. doi:10.1078/0176-1617-01169. PMID 14658380.
  84. ^ Davies O, Mendes P, Smallbone K, Malys N (2012). "Characterisation of multiple substrate-specific (d)ITP/(d)XTPase and modelling of deaminated purine nucleotide metabolism". BMB Reports. 45 (4): 259–64. doi:10.5483/BMBRep.2012.45.4.259. PMID 22531138.
  85. ^ Smith J (1995). "Enzymes of nucleotide synthesis". Curr Opin Struct Biol. 5 (6): 752–7. doi:10.1016/0959-440X(95)80007-7. PMID 8749362.
  86. ^ Testa B, Krämer S (2006). "The biochemistry of drug metabolism—an introduction: part 1. Principles and overview". Chem Biodivers. 3 (10): 1053–101. doi:10.1002/cbdv.200690111. PMID 17193224.
  87. ^ Danielson P (2002). "The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans". Curr Drug Metab. 3 (6): 561–97. doi:10.2174/1389200023337054. PMID 12369887.
  88. ^ King C, Rios G, Green M, Tephly T (2000). "UDP-glucuronosyltransferases". Curr Drug Metab. 1 (2): 143–61. doi:10.2174/1389200003339171. PMID 11465080.
  89. ^ Sheehan D, Meade G, Foley V, Dowd C (November 2001). "Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily". Biochem J. 360 (Pt 1): 1–16. doi:10.1042/0264-6021:3600001. PMC 1222196. PMID 11695986.
  90. ^ Galvão T, Mohn W, de Lorenzo V (2005). "Exploring the microbial biodegradation and biotransformation gene pool". Trends Biotechnol. 23 (10): 497–506. doi:10.1016/j.tibtech.2005.08.002. PMID 16125262.
  91. ^ Janssen D, Dinkla I, Poelarends G, Terpstra P (2005). "Bacterial degradation of xenobiotic compounds: evolution and distribution of novel enzyme activities". Environ Microbiol. 7 (12): 1868–82. doi:10.1111/j.1462-2920.2005.00966.x. PMID 16309386.
  92. ^ Davies K (1995). "Oxidative stress: the paradox of aerobic life". Biochem Soc Symp. 61: 1–31. doi:10.1042/bss0610001. PMID 8660387.
  93. ^ Tu B, Weissman J (2004). "Oxidative protein folding in eukaryotes: mechanisms and consequences". J Cell Biol. 164 (3): 341–6. doi:10.1083/jcb.200311055. PMC 2172237. PMID 14757749.
  94. ^ Sies H (1997). "Oxidative stress: oxidants and antioxidants" (PDF). Exp Physiol. 82 (2): 291–5. doi:10.1113/expphysiol.1997.sp004024. PMID 9129943.
  95. ^ Vertuani S, Angusti A, Manfredini S (2004). "The antioxidants and pro-antioxidants network: an overview". Curr Pharm Des. 10 (14): 1677–94. doi:10.2174/1381612043384655. PMID 15134565.
  96. ^ von Stockar U, Liu J (1999). "Does microbial life always feed on negative entropy? Thermodynamic analysis of microbial growth". Biochim Biophys Acta. 1412 (3): 191–211. doi:10.1016/S0005-2728(99)00065-1. PMID 10482783.
  97. ^ Demirel Y, Sandler S (2002). "Thermodynamics and bioenergetics". Biophys Chem. 97 (2–3): 87–111. doi:10.1016/S0301-4622(02)00069-8. PMID 12050002.
  98. ^ Albert R (2005). "Scale-free networks in cell biology". J Cell Sci. 118 (Pt 21): 4947–57. arXiv:q-bio/0510054. doi:10.1242/jcs.02714. PMID 16254242.
  99. ^ Brand M (1997). "Regulation analysis of energy metabolism". J Exp Biol. 200 (Pt 2): 193–202. PMID 9050227.
  100. ^ Soyer O, Salathé M, Bonhoeffer S (2006). "Signal transduction networks: topology, response and biochemical processes". J Theor Biol. 238 (2): 416–25. doi:10.1016/j.jtbi.2005.05.030. PMID 16045939.
  101. ^ a b Salter M, Knowles R, Pogson C (1994). "Metabolic control". Essays Biochem. 28: 1–12. PMID 7925313.
  102. ^ Westerhoff H, Groen A, Wanders R (1984). "Modern theories of metabolic control and their applications (review)". Biosci Rep. 4 (1): 1–22. doi:10.1007/BF01120819. PMID 6365197.
  103. ^ Fell D, Thomas S (1995). "Physiological control of metabolic flux: the requirement for multisite modulation". Biochem J. 311 (Pt 1): 35–9. doi:10.1042/bj3110035. PMC 1136115. PMID 7575476.
  104. ^ Hendrickson W (2005). "Transduction of biochemical signals across cell membranes". Q Rev Biophys. 38 (4): 321–30. doi:10.1017/S0033583506004136. PMID 16600054.
  105. ^ Cohen P (2000). "The regulation of protein function by multisite phosphorylation—a 25 year update". Trends Biochem Sci. 25 (12): 596–601. doi:10.1016/S0968-0004(00)01712-6. PMID 11116185.
  106. ^ Lienhard G, Slot J, James D, Mueckler M (1992). "How cells absorb glucose". Sci Am. 266 (1): 86–91. Bibcode:1992SciAm.266a..86L. doi:10.1038/scientificamerican0192-86. PMID 1734513.
  107. ^ Roach P (2002). "Glycogen and its metabolism". Curr Mol Med. 2 (2): 101–20. doi:10.2174/1566524024605761. PMID 11949930.
  108. ^ Newgard C, Brady M, O'Doherty R, Saltiel A (2000). "Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1" (PDF). Diabetes. 49 (12): 1967–77. doi:10.2337/diabetes.49.12.1967. PMID 11117996.
  109. ^ Romano A, Conway T (1996). "Evolution of carbohydrate metabolic pathways". Res Microbiol. 147 (6–7): 448–55. doi:10.1016/0923-2508(96)83998-2. PMID 9084754.
  110. ^ Koch A (1998). How did bacteria come to be?. Adv Microb Physiol. Advances in Microbial Physiology. 40. pp. 353–99. doi:10.1016/S0065-2911(08)60135-6. ISBN 978-0-12-027740-7. PMID 9889982.
  111. ^ Ouzounis C, Kyrpides N (1996). "The emergence of major cellular processes in evolution". FEBS Lett. 390 (2): 119–23. doi:10.1016/0014-5793(96)00631-X. PMID 8706840.
  112. ^ Caetano-Anolles G, Kim HS, Mittenthal JE (2007). "The origin of modern metabolic networks inferred from phylogenomic analysis of protein architecture". Proc Natl Acad Sci USA. 104 (22): 9358–63. Bibcode:2007PNAS..104.9358C. doi:10.1073/pnas.0701214104. PMC 1890499. PMID 17517598.
  113. ^ Schmidt S, Sunyaev S, Bork P, Dandekar T (2003). "Metabolites: a helping hand for pathway evolution?". Trends Biochem Sci. 28 (6): 336–41. doi:10.1016/S0968-0004(03)00114-2. PMID 12826406.
  114. ^ Light S, Kraulis P (2004). "Network analysis of metabolic enzyme evolution in Escherichia coli". BMC Bioinformatics. 5: 15. doi:10.1186/1471-2105-5-15. PMC 394313. PMID 15113413. Alves R, Chaleil R, Sternberg M (2002). "Evolution of enzymes in metabolism: a network perspective". J Mol Biol. 320 (4): 751–70. doi:10.1016/S0022-2836(02)00546-6. PMID 12095253.
  115. ^ Kim HS, Mittenthal JE, Caetano-Anolles G (2006). "MANET: tracing evolution of protein architecture in metabolic networks". BMC Bioinformatics. 7: 351. doi:10.1186/1471-2105-7-351. PMC 1559654. PMID 16854231.
  116. ^ Teichmann SA, Rison SC, Thornton JM, Riley M, Gough J, Chothia C (2001). "Small-molecule metabolsim: an enzyme mosaic". Trends Biotechnol. 19 (12): 482–6. doi:10.1016/S0167-7799(01)01813-3. PMID 11711174.
  117. ^ Spirin V, Gelfand M, Mironov A, Mirny L (June 2006). "A metabolic network in the evolutionary context: Multiscale structure and modularity". Proc Natl Acad Sci USA. 103 (23): 8774–9. Bibcode:2006PNAS..103.8774S. doi:10.1073/pnas.0510258103. PMC 1482654. PMID 16731630.
  118. ^ Lawrence J (2005). "Common themes in the genome strategies of pathogens". Curr Opin Genet Dev. 15 (6): 584–8. doi:10.1016/j.gde.2005.09.007. PMID 16188434. Wernegreen J (2005). "For better or worse: genomic consequences of intracellular mutualism and parasitism". Curr Opin Genet Dev. 15 (6): 572–83. doi:10.1016/j.gde.2005.09.013. PMID 16230003.
  119. ^ Pál C, Papp B, Lercher M, Csermely P, Oliver S, Hurst L (2006). "Chance and necessity in the evolution of minimal metabolic networks". Nature. 440 (7084): 667–70. Bibcode:2006Natur.440..667P. doi:10.1038/nature04568. PMID 16572170.
  120. ^ Rennie M (1999). "An introduction to the use of tracers in nutrition and metabolism". Proc Nutr Soc. 58 (4): 935–44. doi:10.1017/S002966519900124X. PMID 10817161.
  121. ^ Phair R (1997). "Development of kinetic models in the nonlinear world of molecular cell biology". Metabolism. 46 (12): 1489–95. doi:10.1016/S0026-0495(97)90154-2. PMID 9439549.
  122. ^ Sterck L, Rombauts S, Vandepoele K, Rouzé P, Van de Peer Y (2007). "How many genes are there in plants (... and why are they there)?". Curr Opin Plant Biol. 10 (2): 199–203. doi:10.1016/j.pbi.2007.01.004. PMID 17289424.
  123. ^ Borodina I, Nielsen J (2005). "From genomes to in silico cells via metabolic networks". Curr Opin Biotechnol. 16 (3): 350–5. doi:10.1016/j.copbio.2005.04.008. PMID 15961036.
  124. ^ Gianchandani E, Brautigan D, Papin J (2006). "Systems analyses characterize integrated functions of biochemical networks". Trends Biochem Sci. 31 (5): 284–91. doi:10.1016/j.tibs.2006.03.007. PMID 16616498.
  125. ^ Duarte NC, Becker SA, Jamshidi N, et al. (February 2007). "Global reconstruction of the human metabolic network based on genomic and bibliomic data". Proc. Natl. Acad. Sci. U.S.A. 104 (6): 1777–82. Bibcode:2007PNAS..104.1777D. doi:10.1073/pnas.0610772104. PMC 1794290. PMID 17267599.
  126. ^ Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabási AL (May 2007). "The human disease network". Proc. Natl. Acad. Sci. U.S.A. 104 (21): 8685–90. Bibcode:2007PNAS..104.8685G. doi:10.1073/pnas.0701361104. PMC 1885563. PMID 17502601.
  127. ^ Lee DS, Park J, Kay KA, Christakis NA, Oltvai ZN, Barabási AL (July 2008). "The implications of human metabolic network topology for disease comorbidity". Proc. Natl. Acad. Sci. U.S.A. 105 (29): 9880–9885. Bibcode:2008PNAS..105.9880L. doi:10.1073/pnas.0802208105. PMC 2481357. PMID 18599447.
  128. ^ Csete M, Doyle J (2004). "Bow ties, metabolism and disease". Trends Biotechnol. 22 (9): 446–50. doi:10.1016/j.tibtech.2004.07.007. PMID 15331224.
  129. ^ Ma HW, Zeng AP (2003). "The connectivity structure, giant strong component and centrality of metabolic networks". Bioinformatics. 19 (11): 1423–30. CiteSeerX 10.1.1.605.8964. doi:10.1093/bioinformatics/btg177. PMID 12874056.
  130. ^ Zhao J, Yu H, Luo JH, Cao ZW, Li YX (2006). "Hierarchical modularity of nested bow-ties in metabolic networks". BMC Bioinformatics. 7: 386. doi:10.1186/1471-2105-7-386. PMC 1560398. PMID 16916470.
  131. ^ Thykaer J, Nielsen J (2003). "Metabolic engineering of beta-lactam production". Metab Eng. 5 (1): 56–69. doi:10.1016/S1096-7176(03)00003-X. PMID 12749845. González-Pajuelo M, Meynial-Salles I, Mendes F, Andrade J, Vasconcelos I, Soucaille P (2005). "Metabolic engineering of Clostridium acetobutylicum for the industrial production of 1,3-propanediol from glycerol". Metab Eng. 7 (5–6): 329–36. doi:10.1016/j.ymben.2005.06.001. PMID 16095939. Krämer M, Bongaerts J, Bovenberg R, Kremer S, Müller U, Orf S, Wubbolts M, Raeven L (2003). "Metabolic engineering for microbial production of shikimic acid". Metab Eng. 5 (4): 277–83. doi:10.1016/j.ymben.2003.09.001. PMID 14642355.
  132. ^ Koffas M, Roberge C, Lee K, Stephanopoulos G (1999). "Metabolic engineering". Annu Rev Biomed Eng. 1: 535–57. doi:10.1146/annurev.bioeng.1.1.535. PMID 11701499.
  133. ^ "Metabolism". The Online Etymology Dictionary. Retrieved 20 February 2007.
  134. ^ Leroi, Armand Marie (2014). The Lagoon: How Aristotle Invented Science. Bloomsbury. pp. 400–401. ISBN 978-1-4088-3622-4.
  135. ^ Dr. Abu Shadi Al-Roubi (1982), "Ibn Al-Nafis as a philosopher", Symposium on Ibn al-Nafis, Second International Conference on Islamic Medicine: Islamic Medical Organization, Kuwait (cf. Ibn al-Nafis As a Philosopher, Encyclopedia of Islamic World [1])
  136. ^ Eknoyan G (1999). "Santorio Sanctorius (1561–1636) – founding father of metabolic balance studies". Am J Nephrol. 19 (2): 226–33. doi:10.1159/000013455. PMID 10213823.
  137. ^ Williams, H. S. (1904) A History of Science: in Five Volumes. Volume IV: Modern Development of the Chemical and Biological Sciences Harper and Brothers (New York) Retrieved on 26 March 2007
  138. ^ Dubos J. (1951). "Louis Pasteur: Free Lance of Science, Gollancz. Quoted in Manchester K. L. (1995) Louis Pasteur (1822–1895)—chance and the prepared mind". Trends Biotechnol. 13 (12): 511–515. doi:10.1016/S0167-7799(00)89014-9. PMID 8595136.
  139. ^ Kinne-Saffran E, Kinne R (1999). "Vitalism and synthesis of urea. From Friedrich Wöhler to Hans A. Krebs". Am J Nephrol. 19 (2): 290–4. doi:10.1159/000013463. PMID 10213830.
  140. ^ Eduard Buchner's 1907 Nobel lecture at http://nobelprize.org Accessed 20 March 2007
  141. ^ Kornberg H (2000). "Krebs and his trinity of cycles". Nat Rev Mol Cell Biol. 1 (3): 225–8. doi:10.1038/35043073. PMID 11252898.
  142. ^ Krebs HA, Henseleit K (1932). "Untersuchungen über die Harnstoffbildung im tierkorper". Z. Physiol. Chem. 210 (1–2): 33–66. doi:10.1515/bchm2.1932.210.1-2.33.
    Krebs H, Johnson W (April 1937). "Metabolism of ketonic acids in animal tissues". Biochem J. 31 (4): 645–60. doi:10.1042/bj0310645. PMC 1266984. PMID 16746382.

Further reading

Introductory

  • Rose, S. and Mileusnic, R., The Chemistry of Life. (Penguin Press Science, 1999), ISBN 0-14-027273-9
  • Schneider, E. D. and Sagan, D., Into the Cool: Energy Flow, Thermodynamics, and Life. (University Of Chicago Press, 2005), ISBN 0-226-73936-8
  • Lane, N., Oxygen: The Molecule that Made the World. (Oxford University Press, USA, 2004), ISBN 0-19-860783-0

Advanced

  • Price, N. and Stevens, L., Fundamentals of Enzymology: Cell and Molecular Biology of Catalytic Proteins. (Oxford University Press, 1999), ISBN 0-19-850229-X
  • Berg, J. Tymoczko, J. and Stryer, L., Biochemistry. (W. H. Freeman and Company, 2002), ISBN 0-7167-4955-6
  • Cox, M. and Nelson, D. L., Lehninger Principles of Biochemistry. (Palgrave Macmillan, 2004), ISBN 0-7167-4339-6
  • Brock, T. D. Madigan, M. T. Martinko, J. and Parker J., Brock's Biology of Microorganisms. (Benjamin Cummings, 2002), ISBN 0-13-066271-2
  • Da Silva, J.J.R.F. and Williams, R. J. P., The Biological Chemistry of the Elements: The Inorganic Chemistry of Life. (Clarendon Press, 1991), ISBN 0-19-855598-9
  • Nicholls, D. G. and Ferguson, S. J., Bioenergetics. (Academic Press Inc., 2002), ISBN 0-12-518121-3

External links

General information

Human metabolism

Databases

Metabolic pathways

Acetyl-CoA

Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for energy production. Coenzyme A (CoASH or CoA) consists of a β-mercaptoethylamine group linked to the vitamin pantothenic acid through an amide linkage and 3'-phosphorylated ADP. The acetyl group (indicated in blue in the structural diagram on the right) of acetyl-CoA is linked to the sulfhydryl substituent of the β-mercaptoethylamine group. This thioester linkage is a "high energy" bond, which is particularly reactive. Hydrolysis of the thioester bond is exergonic (−31.5 kJ/mol).

CoA is acetylated to acetyl-CoA by the breakdown of carbohydrates through glycolysis and by the breakdown of fatty acids through β-oxidation. Acetyl-CoA then enters the citric acid cycle, where the acetyl group is oxidized to carbon dioxide and water, and the energy released captured in the form of 11 ATP and one GTP per acetyl group.

Konrad Bloch and Feodor Lynen were awarded the 1964 Nobel Prize in Physiology and Medicine for their discoveries linking acetyl-CoA and fatty acid metabolism. Fritz Lipmann won the Nobel Prize in 1953 for his discovery of the cofactor coenzyme A.

Alanine

Alanine (symbol Ala or A) is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side chain. Consequently, its IUPAC systematic name is 2-aminopropanic acid, and it is classified as a nonpolar, aliphatic α-amino acid. Under biological conditions, it exists in its zwitterionic form with its amine group protonated (as −NH3+) and its carboxyl group deprotonated (as −CO2−). It is non-essential to humans as it can be synthesised metabolically and does not need to be present in the diet. It is encoded by all codons starting with GC (GCU, GCC, GCA, and GCG).

The L-isomer of alanine (left-handed) is the one that is incorporated into proteins. L-Alanine is second only to leucine in rate of occurrence, accounting for 7.8% of the primary structure in a sample of 1,150 proteins. The right-handed form, D-Alanine occurs in polypeptides in some bacterial cell walls and in some peptide antibiotics, and occurs in the tissues of many crustaceans and molluscs as an osmolyte.

Basal metabolic rate

Basal metabolic rate (BMR) is the rate of energy expenditure per unit time by endothermic animals at rest. It is reported in energy units per unit time ranging from watt (joule/second) to ml O2/min or joule per hour per kg body mass J/(h·kg). Proper measurement requires a strict set of criteria be met. These criteria include being in a physically and psychologically undisturbed state, in a thermally neutral environment, while in the post-absorptive state (i.e., not actively digesting food). In bradymetabolic animals, such as fish and reptiles, the equivalent term standard metabolic rate (SMR) is used. It follows the same criteria as BMR, but requires the documentation of the temperature at which the metabolic rate was measured. This makes BMR a variant of standard metabolic rate measurement that excludes the temperature data, a practice that has led to problems in defining "standard" rates of metabolism for many mammals.Metabolism comprises the processes that the body needs to function. Basal metabolic rate is the amount of energy per unit time that a person needs to keep the body functioning at rest. Some of those processes are breathing, blood circulation, controlling body temperature, cell growth, brain and nerve function, and contraction of muscles. Basal metabolic rate (BMR) affects the rate that a person burns calories and ultimately whether that individual maintains, gains, or loses weight. The basal metabolic rate accounts for about 60 to 75% of the daily calorie expenditure by individuals. It is influenced by several factors. BMR typically declines by 1–2% per decade after age 20, mostly due to loss of fat-free mass, although the variability between individuals is high.

Bilirubin

Bilirubin is a yellow compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the destruction of aged red blood cells. First the hemoglobin gets stripped of the heme molecule which thereafter passes through various processes of porphyrin catabolism, depending on the part of the body in which the breakdown occurs. For example, the molecules excreted in the urine differ from those in the feces. The production of biliverdin from heme is the first major step in the catabolic pathway, after which the enzyme biliverdin reductase performs the second step, producing bilirubin from biliverdin.

Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. It is responsible for the yellow color of bruises and the yellow discoloration in jaundice. Its subsequent breakdown products, such as stercobilin, cause the brown color of faeces. A different breakdown product, urobilin, is the main component of the straw-yellow color in urine.

It has also been found in plants.

Carbohydrate metabolism

Various biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.

Carbohydrates are central to many essential metabolic pathways. Plants synthesize carbohydrates from carbon dioxide and water through photosynthesis, allowing them to store energy absorbed from sunlight internally. When animals and fungi consume plants, they use cellular respiration to break down these stored carbohydrates to make energy available to cells. Both animals and plants temporarily store the released energy in the form of high energy molecules, such as ATP, for use in various cellular processes.Although humans consume a variety of carbohydrates, digestion breaks down complex carbohydrates into a few simple monomers (monosaccharides) for metabolism: glucose, fructose, and galactose. Glucose constitutes about 80% of the products, and is the primary structure that is distributed to cells in the tissues, where it is broken down or stored as glycogen. In aerobic respiration, the main form of cellular respiration used by humans, glucose and oxygen are metabolized to release energy, with carbon dioxide and water as byproducts. Most of the fructose and galactose travel to the liver, where they can be converted to glucose.Some simple carbohydrates have their own enzymatic oxidation pathways, as do only a few of the more complex carbohydrates. The disaccharide lactose, for instance, requires the enzyme lactase to be broken into its monosaccharide components, glucose and galactose.

Cellular respiration

Cellular respiration is a set of metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate (ATP), and then release waste products. The reactions involved in respiration are catabolic reactions, which break large molecules into smaller ones, releasing energy in the process, as weak so-called "high-energy" bonds are replaced by stronger bonds in the products. Respiration is one of the key ways a cell releases chemical energy to fuel cellular activity. Cellular respiration is considered an exothermic redox reaction which releases heat. The overall reaction occurs in a series of biochemical steps, most of which are redox reactions themselves. Although cellular respiration is technically a combustion reaction, it clearly does not resemble one when it occurs in a living cell because of the slow release of energy from the series of reactions.

Nutrients that are commonly used by animal and plant cells in respiration include sugar, amino acids and fatty acids, and the most common oxidizing agent (electron acceptor) is molecular oxygen (O2). The chemical energy stored in ATP (its third phosphate group is weakly bonded to the rest of the molecule and is cheaply broken allowing stronger bonds to form, thereby transferring energy for use by the cell) can then be used to drive processes requiring energy, including biosynthesis, locomotion or transportation of molecules across cell membranes.

Cytochrome P450

Cytochromes P450 (CYPs) are proteins of the superfamily containing heme as a cofactor and, therefore, are hemeproteins. CYPs use a variety of small and large molecules as substrates in enzymatic reactions. They are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. The term "P450" is derived from the spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed with carbon monoxide.

CYP enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, archaea, and even in viruses. However, they are not omnipresent; for example, they have not been found in Escherichia coli. More than 50,000 distinct CYP proteins are known.Most CYPs require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen). Based on the nature of the electron transfer proteins, CYPs can be classified into several groups:

Microsomal P450 systems, in which electrons are transferred from NADPH via cytochrome P450 reductase (variously CPR, POR, or CYPOR). Cytochrome b5 (cyb5) can also contribute reducing power to this system after being reduced by cytochrome b5 reductase (CYB5R).

Mitochondrial P450 systems, which employ adrenodoxin reductase and adrenodoxin to transfer electrons from NADPH to P450.

Bacterial P450 systems, which employ a ferredoxin reductase and a ferredoxin to transfer electrons to P450.

CYB5R/cyb5/P450 systems, in which both electrons required by the CYP come from cytochrome b5.

FMN/Fd/P450 systems, originally found in Rhodococcus species, in which a FMN-domain-containing reductase is fused to the CYP.

P450 only systems, which do not require external reducing power. Notable ones include thromboxane synthase (CYP5), prostacyclin synthase (CYP8), and CYP74A (allene oxide synthase).The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH) while the other oxygen atom is reduced to water:

RH + O2 + NADPH + H+ → ROH + H2O + NADP+

Many hydroxylation reactions (insertion of hydroxyl groups) use CYP enzymes.

Drug metabolism

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms, and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is called pharmacokinetics.

The metabolism of pharmaceutical drugs is an important aspect of pharmacology and medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer, and the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down during bioremediation, or persist in the environment. The enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides.

Drug metabolism is divided into three phases. In phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters and pumped out of cells. Drug metabolism often converts lipophilic compounds into hydrophilic products that are more readily excreted.

Fermentation

Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In the context of food production, it may more broadly refer to any process in which the activity of microorganisms brings about a desirable change to a foodstuff or beverage. The science of fermentation is known as zymology.

In microorganisms, fermentation is the primary means of producing ATP by the degradation of organic nutrients anaerobically. Humans have used fermentation to produce foodstuffs and beverages since the Neolithic age. For example, fermentation is used for preservation in a process that produces lactic acid found in such sour foods as pickled cucumbers, kimchi, and yogurt, as well as for producing alcoholic beverages such as wine and beer. Fermentation occurs within the gastrointestinal tracts of all animals, including humans.

Glutamic acid

Glutamic acid (symbol Glu or E) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is non-essential in humans, meaning the body can synthesize it. It is also an excitatory neurotransmitter, in fact the most abundant one, in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABA-ergic neurons.

It has a formula C5H9O4N. Its molecular structure could be idealized as HOOC-CH(NH2)-(CH2)2-COOH, with two carboxyl groups -COOH and one amino group -NH2. However, in the solid state and mildly acid water solutions, the molecule assumes an electrically neutral zwitterion structure −OOC-CH(NH+3)-(CH2)2-COOH. It is encoded by the codons GAA or GAG.

The acid can lose one proton from its second carboxyl group to form the conjugate base, the singly-negative anion glutamate −OOC-CH(NH+3)-(CH2)2-COO−. This form of the compound is prevalent in neutral solutions. The glutamate neurotransmitter plays the principal role in neural activation. This anion is also responsible for the savory flavor (umami) of certain foods, and used in glutamate flavorings such as MSG. In Europe it is classified as food additive E620. In highly alkaline solutions the doubly negative anion −OOC-CH(NH2)-(CH2)2-COO− prevails. The radical corresponding to glutamate is called glutamyl.

Human iron metabolism

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron deficiency anemia.

Inborn errors of metabolism

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic disorders.

The term inborn errors of metabolism was coined by a British physician, Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.

Lipid metabolism

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food or are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered as the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates (including humans) use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

Liver

The liver, an organ only found in vertebrates, detoxifies various metabolites, synthesizes proteins, and produces biochemicals necessary for digestion. In humans, it is located in the right upper quadrant of the abdomen, below the diaphragm. Its other roles in metabolism include the regulation of glycogen storage, decomposition of red blood cells and the production of hormones.The liver is an accessory digestive gland that produces bile, an alkaline compound which helps the breakdown of fat. Bile aids in digestion via the emulsification of lipids. The gallbladder, a small pouch that sits just under the liver, stores bile produced by the liver which is afterwards moved to the small intestine to complete digestion. The liver's highly specialized tissue consisting of mostly hepatocytes regulates a wide variety of high-volume biochemical reactions, including the synthesis and breakdown of small and complex molecules, many of which are necessary for normal vital functions. Estimates regarding the organ's total number of functions vary, but textbooks generally cite it being around 500.Terminology related to the liver often starts in hepat- from ἡπατο-, from the Greek word for liver.No way is yet known to compensate for the absence of liver function in the long term, although liver dialysis techniques can be used in the short term. Artificial livers are yet to be developed to promote long-term replacement in the absence of the liver. As of 2018, liver transplantation is the only option for complete liver failure.

Metabolic disorder

A metabolic disorder can happen when abnormal chemical reactions in the body alter the normal metabolic process. It can also be defined as inherited single gene anomaly, most of which are autosomal recessive.

Metabolic pathway

In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reactions catalyzed by enzymes. In most cases of a metabolic pathway, the product of one enzyme acts as the substrate for the next. However, side products are considered waste and removed from the cell. These enzymes often require dietary minerals, vitamins, and other cofactors to function.

Different metabolic pathways function based on the position within a eukaryotic cell and the significance of the pathway in the given compartment of the cell. For instance, the, electron transport chain, and oxidative phosphorylation all take place in the mitochondrial membrane. In contrast, glycolysis, pentose phosphate pathway, and fatty acid biosynthesis all occur in the cytosol of a cell.There are two types of metabolic pathways that are characterized by their ability to either synthesize molecules with the utilization of energy (anabolic pathway) or break down of complex molecules by releasing energy in the process (catabolic pathway). The two pathways complement each other in that the energy released from one is used up by the other. The degradative process of a catabolic pathway provides the energy required to conduct a biosynthesis of an anabolic pathway. In addition to the two distinct metabolic pathways is the amphibolic pathway, which can be either catabolic or anabolic based on the need for or the availability of energy.Pathways are required for the maintenance of homeostasis within an organism and the flux of metabolites through a pathway is regulated depending on the needs of the cell and the availability of the substrate. The end product of a pathway may be used immediately, initiate another metabolic pathway or be stored for later use. The metabolism of a cell consists of an elaborate network of interconnected pathways that enable the synthesis and breakdown of molecules (anabolism and catabolism).

Metabolite

A metabolite is the intermediate end product of metabolism. The term metabolite is usually restricted to small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, catalytic activity of their own (usually as a cofactor to an enzyme), defense, and interactions with other organisms (e.g. pigments, odorants, and pheromones). A primary metabolite is directly involved in normal "growth", development, and reproduction. Ethylene is an example of a primary metabolite produced in large-scale by industrial microbiology. A secondary metabolite is not directly involved in those processes, but usually has an important ecological function. Examples include antibiotics and pigments such as resins and terpenes etc. Some antibiotics use primary metabolites as precursors, such as actinomycin which is created from the primary metabolite, tryptophan. Some sugars are metabolites, such as fructose or glucose, which are both present in the metabolic pathways.

Examples of primary metabolites produced by industrial microbiology:

The metabolome forms a large network of metabolic reactions, where outputs from one enzymatic chemical reaction are inputs to other chemical reactions.

Metabolites from chemical compounds, whether inherent or pharmaceutical, are formed as part of the natural biochemical process of degrading and eliminating the compounds. The rate of degradation of a compound is an important determinant of the duration and intensity of its action. Profiling metabolites of pharmaceutical compounds, drug metabolism, is an important part of drug discovery, leading to an understanding of any undesirable side effects.

Pyruvic acid

Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate (), the conjugate base, CH3COCOO−, is a key intermediate in several metabolic pathways throughout the cell.

Pyruvic acid can be made from glucose through glycolysis, converted back to carbohydrates (such as glucose) via gluconeogenesis, or to fatty acids through a reaction with acetyl-CoA. It can also be used to construct the amino acid alanine and can be converted into ethanol or lactic acid via fermentation.

Pyruvic acid supplies energy to cells through the citric acid cycle (also known as the Krebs cycle) when oxygen is present (aerobic respiration), and alternatively ferments to produce lactate when oxygen is lacking (lactic acid fermentation).

Vitamin B6

Vitamin B6 refers to a group of chemically similar compounds which can be interconverted in biological systems. Vitamin B6 is part of the vitamin B group of essential nutrients. Its active form, pyridoxal 5′-phosphate, serves as a coenzyme in some 100 enzyme reactions in amino acid, glucose, and lipid metabolism.

General
Food industry
Food politics
Institutions
Diving
physics
Diving
physiology
Diving
environment

This page is based on a Wikipedia article written by authors (here).
Text is available under the CC BY-SA 3.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.