Metabolism (/məˈtæbəlɪzəm/, fromGreek:μεταβολήmetabolē, "change") is the set oflife-sustainingchemical reactions inorganisms. The three main functions of metabolism are: the conversion of the energy in food toenergy available to run cellular processes; the conversion of food to building blocks ofproteins,lipids,nucleic acids, and somecarbohydrates; and the elimination ofmetabolic wastes. Theseenzyme-catalyzed reactions allow organisms to grow and reproduce, maintain theirstructures, and respond to their environments. The wordmetabolism can also refer to the sum of all chemical reactions that occur in living organisms, includingdigestion and the transportation of substances into and between different cells, in which case the above described set of reactions within the cells is called intermediary (or intermediate) metabolism.
Metabolic reactions may be categorized ascatabolic—thebreaking down of compounds (for example, of glucose to pyruvate bycellular respiration); oranabolic—thebuilding 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 intometabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step being facilitated by a specificenzyme. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that requireenergy and will not occur by themselves, bycoupling them tospontaneous reactions that release energy. Enzymes act ascatalysts—they allow a reaction to proceed more rapidly—and they also allow theregulation of the rate of a metabolic reaction, for example in response to changes in thecell's environment or tosignals from other cells.
The metabolic system of a particular organism determines which substances it will findnutritious and whichpoisonous. For example, someprokaryotes usehydrogen sulfide as a nutrient, yet this gas is poisonous to animals.[1] Thebasal 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 ofcarboxylic acids that are best known as the intermediates in thecitric acid cycle are present in all known organisms, being found in species as diverse as theunicellular bacteriumEscherichia coli and hugemulticellular organisms likeelephants.[3] These similarities in metabolic pathways are likely due to their early appearance inevolutionary history, and their retention is likely due to theirefficacy.[4][5] In various diseases, such astype II diabetes,metabolic syndrome, andcancer, normal metabolism is disrupted.[6] The metabolism of cancer cells is also different from the metabolism of normal cells, and these differences can be used to find targets for therapeutic intervention in cancer.[7]
Most of the structures that make up animals, plants and microbes are made from four basic classes ofmolecules:amino acids,carbohydrates,nucleic acid andlipids (often calledfats). As these molecules are vital for life, metabolic reactions either focus on making these molecules during the construction of cells and tissues, or on breaking them down and using them to obtain energy, by their digestion. These biochemicals can be joined to makepolymers such asDNA andproteins, essentialmacromolecules of life.[8]
Proteins are made ofamino acids arranged in a linear chain joined bypeptide bonds. Many proteins areenzymes thatcatalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as those that form thecytoskeleton, a system ofscaffolding that maintains the cell shape.[9] Proteins are also important incell signaling,immune responses,cell adhesion,active transport across membranes, and thecell cycle.[10] Amino acids also contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle (tricarboxylic acid cycle),[11] especially when a primary source of energy, such asglucose, is scarce, or when cells undergo metabolic stress.[12]
Carbohydrates arealdehydes orketones, with manyhydroxyl 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 ofenergy (starch,glycogen) and structural components (cellulose in plants,chitin in animals).[10] The basic carbohydrate units are calledmonosaccharides and includegalactose,fructose, and most importantlyglucose. Monosaccharides can be linked together to formpolysaccharides in almost limitless ways.[16]
Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer offunctional groups of atoms and their bonds within molecules.[19] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.[18] These group-transfer intermediates are calledcoenzymes. Each class of group-transfer reactions is carried out by a particular coenzyme, which is thesubstrate 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.[20]
One central coenzyme isadenosine triphosphate (ATP), the energy currency of cells. Thisnucleotide 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.[20] ATP acts as a bridge betweencatabolism andanabolism. 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 inphosphorylation reactions.[21]
Avitamin is an organic compound needed in small quantities that cannot be made in cells. Inhuman 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.[22]Nicotinamide adenine dinucleotide (NAD+), a derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types ofdehydrogenases remove electrons from their substrates andreduce NAD+ into NADH. This reduced form of the coenzyme is then a substrate for any of thereductases in the cell that need to transfer hydrogen atoms to their substrates.[23] 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.[24]
The structure of iron-containinghemoglobin. The protein subunits are in red and blue, and the iron-containingheme groups in green. FromPDB:1GZX.
Inorganic elements play critical roles in metabolism; some are abundant (e.g.sodium andpotassium) while others function at minute concentrations. About 99% of a human's body weight is made up of the elementscarbon,nitrogen,calcium,sodium,chlorine,potassium,hydrogen,phosphorus,oxygen andsulfur.Organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen; most of the oxygen and hydrogen is present as water.[25]
Transition metals are usually present astrace elements in organisms, withzinc andiron being most abundant of those.[29] 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 asferritin ormetallothionein when not in use.[30][31]
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.[32] The exact nature of these catabolic reactions differ from organism to organism, and organisms can be classified based on their sources of energy, hydrogen, and carbon (theirprimary nutritional groups), as shown in the table below. Organic molecules are used as a source of hydrogen atoms or electrons byorganotrophs, whilelithotrophs use inorganic substrates. Whereasphototrophs convert sunlight tochemical energy,[33]chemotrophs depend onredox reactions that involve the transfer of electrons from reduced donor molecules such asorganic molecules,hydrogen,hydrogen sulfide orferrous ions tooxygen,nitrate orsulfate. In animals, these reactions involve complexorganic molecules that are broken down to simpler molecules, such ascarbon dioxide and water.Photosynthetic organisms, such as plants andcyanobacteria, use similar electron-transfer reactions to store energy absorbed from sunlight.[34]
Classification of organisms based on their metabolism[35]
The most common set of catabolic reactions in animals can be separated into three main stages. In the first stage, large organic molecules, such asproteins,polysaccharides orlipids, are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to smaller molecules, usuallyacetyl coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on acetyl-CoA is oxidized to water and carbon dioxide in thecitric acid cycle andelectron transport chain, releasing more energy while reducing the coenzymenicotinamide adenine dinucleotide (NAD+) into NADH.[32]
Macromolecules cannot be directly processed by cells. Macromolecules must be broken into smaller units before they can be used in cell metabolism. Different classes of enzymes are used to digest these polymers. Thesedigestive enzymes includeproteases that digest proteins into amino acids, as well asglycoside hydrolases that digest polysaccharides into simple sugars known asmonosaccharides.[36]
Microbes simply secrete digestive enzymes into their surroundings,[37][38] while animals only secrete these enzymes from specialized cells in theirguts, including thestomach andpancreas, and insalivary glands.[39] The amino acids or sugars released by these extracellular enzymes are then pumped into cells byactive transport proteins.[40][41]
Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells after they have been digested intomonosaccharides such asglucose andfructose.[42] Once inside, the major route of breakdown isglycolysis, in which glucose is converted intopyruvate. This process generates the energy-conveying moleculeNADH from NAD+, and generatesATP fromADP for use in powering many processes within the cell.[43] Pyruvate is an intermediate in several metabolic pathways, but the majority is converted toacetyl-CoA and fed into thecitric acid cycle, which enables more ATP production by means ofoxidative phosphorylation. This oxidation consumes molecular oxygen and releases water and the waste product carbon dioxide. When oxygen is lacking, or when pyruvate is temporarily produced faster than it can be consumed by the citric acid cycle (as in intense muscular exertion), pyruvate is converted tolactate by the enzymelactate dehydrogenase, a process that also oxidizes NADH back to NAD+ for re-use in further glycolysis, allowing energy production to continue.[44] The lactate is later converted back to pyruvate for ATP production where energy is needed, or back to glucose in theCori cycle. An alternative route for glucose breakdown is thepentose phosphate pathway, which produces less energy but supportsanabolism (biomolecule synthesis). This pathway reduces the coenzymeNADP+ to NADPH and producespentose compounds such asribose 5-phosphate for synthesis of many biomolecules such asnucleotides andaromatic amino acids.[45]
Carbon Catabolism pathway map for free energy including carbohydrate and lipid sources of energy
Fats are catabolized byhydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down bybeta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates. 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 lipidcholesterol 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 ofM. tuberculosis.[46]
Amino acids are either used to synthesize proteins and other biomolecules, or oxidized tourea and carbon dioxide to produce energy.[47] The oxidation pathway starts with the removal of the amino group by atransaminase. The amino group is fed into theurea cycle, leaving a deaminated carbon skeleton in the form of aketo acid. Several of these keto acids are intermediates in the citric acid cycle, for example α-ketoglutarate formed by deamination ofglutamate.[48] Theglucogenic amino acids can also be converted into glucose, throughgluconeogenesis.[49]
In oxidative phosphorylation, the electrons removed from organic molecules in areas such as the citric acid cycle are transferred to oxygen and the energy released is used to make ATP. This is done ineukaryotes by a series of proteins in the membranes of mitochondria called theelectron transport chain. Inprokaryotes, these proteins are found in the cell'sinner membrane.[50] These proteins use the energy fromreduced molecules like NADH to pumpprotons across a membrane.[51]
Mechanism ofATP 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 protonconcentration difference across the membrane and generates anelectrochemical gradient.[52] This force drives protons back into the mitochondrion through the base of an enzyme calledATP synthase. The flow of protons makes the stalk subunit rotate, causing theactive site of the synthase domain to change shape and phosphorylateadenosine diphosphate—turning it into ATP.[20]
The energy in sunlight is captured byplants,cyanobacteria,purple bacteria,green sulfur bacteria and someprotists. 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.[59][60]
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.[61] The electrons needed to drive this electron transport chain come from light-gathering proteins calledphotosynthetic reaction centres. Reaction centers are classified into two types depending on the nature ofphotosynthetic pigment present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have two.[62]
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 thecytochrome b6f complex, which uses their energy to pump protons across thethylakoid membrane in thechloroplast.[34] These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow throughphotosystem I and can then be used to reduce the coenzyme NADP+.[63] This coenzyme can enter theCalvin cycle or be recycled for further ATP generation.[64]
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 smaller and simpler precursors. Anabolism involves three basic stages. First, the production of precursors such asamino acids,monosaccharides,isoprenoids andnucleotides, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such asproteins,polysaccharides,lipids andnucleic acids.[65]
Anabolism in organisms can be different according to the source of constructed molecules in their cells.Autotrophs such as plants can construct the complex organic molecules in their cells such as polysaccharides and proteins from simple molecules likecarbon 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 oxidation reactions.[65]
Plant cells (bounded by purple walls) filled with chloroplasts (green), which are the site of photosynthesis
Photosynthesis is the synthesis of carbohydrates from sunlight andcarbon 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 thephotosynthetic reaction centres, as described above, to convert CO2 intoglycerate 3-phosphate, which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzymeRuBisCO as part of theCalvin–Benson cycle.[66] Three types of photosynthesis occur in plants,C3 carbon fixation,C4 carbon fixation andCAM 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.[67]
In photosyntheticprokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin–Benson cycle, areversed citric acid cycle,[68] or thecarboxylation of acetyl-CoA.[69][70] Prokaryoticchemoautotrophs also fix CO2 through the Calvin–Benson cycle, but use energy from inorganic compounds to drive the reaction.[71]
Although fat is a common way of storing energy, invertebrates such as humans thefatty acids in these stores cannot be converted to glucose throughgluconeogenesis as these organisms cannot convert acetyl-CoA intopyruvate; plants do, but animals do not, have the necessary enzymatic machinery.[74] As a result, after long-term starvation, vertebrates need to produceketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids.[75] In other organisms such as plants and bacteria, this metabolic problem is solved using theglyoxylate cycle, which bypasses thedecarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA tooxaloacetate, where it can be used for the production of glucose.[74][76] Other than fat, glucose is stored in most tissues, as an energy resource available within the tissue through glycogenesis which was usually being used to maintained glucose level in blood.[77]
Polysaccharides andglycans are made by the sequential addition of monosaccharides byglycosyltransferase from a reactive sugar-phosphate donor such asuridine diphosphate glucose (UDP-Glc) to an acceptorhydroxyl group on the growing polysaccharide. As any of thehydroxyl groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures.[78] The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by the enzymesoligosaccharyltransferases.[79][80]
Fatty acids are made byfatty 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 analkene group and then reduce it again to analkane 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,[81] while in plantplastids and bacteria separate type II enzymes perform each step in the pathway.[82][83]
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 nineessential amino acids must be obtained from food.[10] Some simpleparasites, such as the bacteriaMycoplasma pneumoniae, lack all amino acid synthesis and take their amino acids directly from their hosts.[90] All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided byglutamate andglutamine. Nonessensial amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is thentransaminated to form an amino acid.[91]
Amino acids are made into proteins by being joined in a chain ofpeptide bonds. Each different protein has a unique sequence of amino acid residues: this is itsprimary 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 atransfer RNA molecule through anester bond. Thisaminoacyl-tRNA precursor is produced in anATP-dependent reaction carried out by anaminoacyl tRNA synthetase.[92] This aminoacyl-tRNA is then a substrate for theribosome, which joins the amino acid onto the elongating protein chain, using the sequence information in amessenger RNA.[93]
Nucleotides are made from amino acids, carbon dioxide andformic acid in pathways that require large amounts of metabolic energy.[94] Consequently, most organisms have efficient systems to salvage preformed nucleotides.[94][95]Purines are synthesized asnucleosides (bases attached toribose).[96] Bothadenine andguanine are made from the precursor nucleosideinosine monophosphate, which is synthesized using atoms from the amino acidsglycine,glutamine, andaspartic acid, as well asformate transferred from thecoenzymetetrahydrofolate.Pyrimidines, on the other hand, are synthesized from the baseorotate, which is formed from glutamine and aspartate.[97]
All organisms are constantly exposed to compounds that they cannot use as foods and that would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are calledxenobiotics.[98] Xenobiotics such assynthetic drugs,natural poisons andantibiotics are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these includecytochrome P450 oxidases,[99]UDP-glucuronosyltransferases,[100] andglutathioneS-transferases.[101] 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). Inecology, these reactions are particularly important in microbialbiodegradation of pollutants and thebioremediation ofcontaminated land and oil spills.[102] 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 evenpersistent organic pollutants such asorganochloride compounds.[103]
Living organisms must obey thelaws of thermodynamics, which describe the transfer of heat andwork. Thesecond law of thermodynamics states that in anyisolated system, the amount ofentropy (disorder) cannot decrease. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms areopen systems that exchange matter and energy with their surroundings. Living systems are not inequilibrium, but instead aredissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments.[108] The metabolism of a cell achieves this by coupling thespontaneous processes of catabolism to the non-spontaneous processes of anabolism. Inthermodynamic terms, metabolism maintains order by creating disorder.[109]
As the environments of most organisms are constantly changing, the reactions of metabolism must be finelyregulated to maintain a constant set of conditions within cells, a condition calledhomeostasis.[110][111] Metabolic regulation also allows organisms to respond to signals and interact actively with their environments.[112] Two closely linked concepts are important for understanding how metabolic pathways are controlled. Firstly, theregulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, thecontrol exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (theflux through the pathway).[113] 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.[114]
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 theplasma membrane and influx of glucose (3),glycogen synthesis (4),glycolysis (5) andfatty acid synthesis (6).[image reference needed]
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 theflux through the pathway to compensate.[113] This type of regulation often involvesallosteric regulation of the activities of multiple enzymes in the pathway.[115] 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 water-soluble messengers such ashormones andgrowth factors and are detected by specificreceptors on the cell surface.[116] These signals are then transmitted inside the cell bysecond messenger systems that often involved thephosphorylation of proteins.[117]
A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormoneinsulin.[118] Insulin is produced in response to rises inblood glucose levels. Binding of the hormone toinsulin receptors on cells then activates a cascade ofprotein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids andglycogen.[119] The metabolism of glycogen is controlled by activity ofphosphorylase, the enzyme that breaks down glycogen, andglycogen 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 activatingprotein phosphatases and producing a decrease in the phosphorylation of these enzymes.[120]
Evolutionary tree showing the common ancestry of organisms from all threedomains of life.Bacteria are colored blue,eukaryotes red, andarchaea green. Relative positions of some of thephyla included are shown around the tree.
The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in allthree domains of living things and were present in thelast universal common ancestor.[3][121] This universal ancestral cell wasprokaryotic and probably amethanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism.[122][123] The retention of these ancient pathways during laterevolution 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 ofpurine nucleotide metabolism, while previous metabolic pathways were a part of the ancientRNA world.[124]
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.[125] 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.[126] 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 theMANET database)[127] These recruitment processes result in an evolutionary enzymatic mosaic.[128] 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.[129]
As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For example, in someparasites metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from thehost.[130] Similar reduced metabolic capabilities are seen inendosymbiotic organisms.[131]
Classically, metabolism is studied by areductionist approach that focuses on a single metabolic pathway. Particularly valuable is the use ofradioactive 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.[132] The enzymes that catalyze these chemical reactions can then bepurified and theirkinetics and responses toinhibitors investigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called themetabolome. 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.[133]
An idea of the complexity of themetabolic 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 26.500 genes.[134] However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce moreholistic mathematical models that may explain and predict their behavior.[135] These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data ongene expression fromproteomic andDNA microarray studies.[136] Using these techniques, a model of human metabolism has now been produced, which will guide future drug discovery and biochemical research.[137] These models are now used innetwork analysis, to classify human diseases into groups that share common proteins or metabolites.[138][139]
Bacterial metabolic networks are a striking example ofbow-tie[140][141][142] 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.[143]
A major technological application of this information ismetabolic engineering. Here, organisms such asyeast, plants orbacteria are genetically modified to make them more useful inbiotechnology and aid the production ofdrugs such asantibiotics or industrial chemicals such as1,3-propanediol andshikimic acid.[144][145][146] These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.[147]
The termmetabolism is derived from theAncient Greek word μεταβολή—"metabole" for "a change" which is derived from μεταβάλλειν—"metaballein", meaning "to change"[148]
Aristotle'sThe Parts of Animals sets out enough details ofhis 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 theclassical element of fire, and residual materials being excreted as urine, bile, or faeces.[149]
Ibn al-Nafis described metabolism in his 1260 AD work titledAl-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."[150]
Application of the scientific method and Modern metabolic theories
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 controlledexperiments in human metabolism were published bySantorio Santorio in 1614 in his bookArs de statica medicina.[151] 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".
Santorio Santorio in his steelyard balance, fromArs de statica medicina, first published 1614
In these early studies, the mechanisms of these metabolic processes had not been identified and avital force was thought to animate living tissue.[152] In the 19th century, when studying thefermentation of sugar toalcohol byyeast,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."[153] This discovery, along with the publication byFriedrich Wöhler in 1828 of a paper on the chemical synthesis ofurea,[154] 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 ofenzymes at the beginning of the 20th century byEduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings ofbiochemistry.[155] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists wasHans Krebs who made huge contributions to the study of metabolism.[156] He discovered the urea cycle and later, working withHans Kornberg, the citric acid cycle and the glyoxylate cycle.[157][158][76]Modern biochemical research has been greatly aided by the development of new techniques such aschromatography,X-ray diffraction,NMR spectroscopy,radioisotopic labelling,electron microscopy andmolecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.[citation needed]
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