Metabolism: Difference between revisions

{{Short description|Set of chemical reactions in organisms}}

[[File:Metabolism.png|thumb|Simplified view of the cellular metabolism]]

[[File:ATP-3D-vdW.png|thumb|right|Structure of [[adenosine triphosphate]] (ATP), a central intermediate in energy metabolism]]

{{Biochemistry sidebar}}

'''Metabolism''' ({{IPAc-en|m|ə|ˈ|t|æ|b|ə|l|ɪ|z|ə|m}}, from {{lang-el|μεταβολή}} ''metabolē'', "change") is the set of [[life]]-sustaining [[chemical reactions]] in [[organisms]]. The three main functions of metabolism are: the conversion of the energy in food to [[energy]] available to run cellular processes; the conversion of food to building blocks of [[protein]]s, [[lipid]]s, [[nucleic acid]]s, and some [[carbohydrate]]s; and the elimination of [[metabolic waste]]s. These [[enzyme]]-catalyzed reactions allow organisms to grow and reproduce, maintain their [[Structures#Biological|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 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 as ''[[catabolic]]'' – the ''breaking down'' of compounds (for example, of glucose to pyruvate by [[cellular respiration]]); or ''[[anabolic]]'' – the ''building up'' ([[biosynthesis|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 pathway]]s, 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]] and will not occur by themselves, by [[Coupling (physics)|coupling]] them to [[spontaneous process|spontaneous reactions]] that release energy. Enzymes act as [[Catalysis|catalysts]] – they allow a reaction to proceed more rapidly – and they also allow the [[Metabolic pathway#Regulation|regulation]] of the rate of a metabolic reaction, for example in response to changes in the [[cell (biology)|cell's]] environment or to [[cell signaling|signals]] from other cells.

The metabolic system of a particular organism determines which substances it will find [[nutrition|nutritious]] and which [[poison]]ous. For example, some [[prokaryote]]s use [[hydrogen sulfide]] as a nutrient, yet this gas is poisonous to animals. 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. For example, the set of [[carboxylic acid]]s 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 organism|unicellular]] bacterium ''[[Escherichia coli]]'' and huge [[multicellular organism]]s like [[elephant]]s. These similarities in metabolic pathways are likely due to their early appearance in [[evolutionary history of life|evolutionary history]], and their retention is likely due to their [[efficacy]]. In various diseases, such as [[type II diabetes]], [[metabolic syndrome]], and [[cancer]], normal metabolism is disrupted. 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.

{{further|Biomolecule|Cell (biology)|Biochemistry}}

[[File:Trimyristin-3D-vdW.png|right|thumb|upright=1.15|Structure of a [[triacylglycerol]] lipid]]

|}

{{Main|Protein}}

Proteins are made of [[amino acid]]s arranged in a linear chain joined by [[peptide bond]]s. Many proteins are [[enzyme]]s that [[catalysis|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. Proteins are also important in [[cell signaling]], [[antibody|immune responses]], [[cell adhesion]], [[active transport]] across membranes, and the [[cell cycle]]. Amino acids also contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle ([[tricarboxylic acid cycle]]), especially when a primary source of energy, such as [[glucose]], is scarce, or when cells undergo metabolic stress.

{{Main|Biolipid}}

Lipids are the most diverse group of biochemicals. Their main structural uses are as part of [[biological membrane]]s both internal and external, such as the [[cell membrane]]. Their [[chemical energy]] can also be used. Lipids are the polymers of fatty acids that contain a long, non-polar hydrocarbon chain with a small polar region containing oxygen. Lipids are usually defined as [[hydrophobe|hydrophobic]] or [[amphiphiles|amphipathic]] biological molecules but will dissolve in [[organic solvent]]s such as [[ethanol]], [[benzene]] or [[chloroform]]. The [[fat]]s are a large group of compounds that contain [[fatty acid]]s and [[glycerol]]; a glycerol molecule attached to three fatty acids by [[ester]] linkages is called a [[triglyceride|triacylglyceride]]. Several variations on this basic structure exist, including backbones such as [[sphingosine]] in [[sphingomyelin]], and [[hydrophile|hydrophilic]] groups such as [[phosphate]] as in [[phospholipid]]s. [[Steroid]]s such as [[sterol]] are another major class of lipids.

[[File:Glucose Fisher to Haworth.gif|thumb|upright=1.15|right|alt=The straight chain form consists of four C H O H groups linked in a row, capped at the ends by an aldehyde group C O H and a methanol group C H 2 O H.  To form the ring, the aldehyde group combines with the O H group of the next-to-last carbon at the other end, just before the methanol group.|[[Glucose]] can exist in both a straight-chain and ring form.]]{{Main|Carbohydrate}}

Carbohydrates are [[aldehyde]]s or [[ketone]]s, 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). The basic carbohydrate units are called [[monosaccharide]]s and include [[galactose]], [[fructose]], and most importantly [[glucose]]. Monosaccharides can be linked together to form [[polysaccharide]]s in almost limitless ways.

{{Main|Nucleotide}}

The two nucleic acids, DNA and [[RNA]], are polymers of [[nucleotide]]s. 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 (genetics)|transcription]] and [[protein biosynthesis]]. This information is protected by [[DNA repair]] mechanisms and propagated through [[DNA replication]]. Many [[virus]]es have an [[RNA virus|RNA genome]], such as [[HIV]], which uses [[reverse transcription]] to create a DNA template from its viral RNA genome. RNA in [[ribozyme]]s such as [[spliceosome]]s and [[ribosome]]s is similar to enzymes as it can catalyze chemical reactions. Individual [[nucleoside]]s are made by attaching a [[nucleobase]] to a [[ribose]] sugar. These bases are [[heterocyclic]] rings containing nitrogen, classified as [[purine]]s or [[pyrimidine]]s. Nucleotides also act as coenzymes in metabolic-group-transfer reactions.

[[File:Acetyl-CoA-2D.svg|thumb|right|upright=1.35|Structure of the [[coenzyme]] [[acetyl-CoA]]. The transferable [[acetyl|acetyl group]] is bonded to the sulfur atom at the extreme left.]]

{{main|Coenzyme}}

Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of [[functional group]]s of atoms and their bonds within molecules. This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions. These group-transfer intermediates are called [[coenzyme]]s. Each class of group-transfer reactions is carried out by a particular coenzyme, which is the [[substrate (biochemistry)|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.

One central coenzyme is [[adenosine triphosphate]] (ATP), the 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. 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. [[Nicotinamide adenine dinucleotide]] (NAD⁺), a derivative of vitamin B₃ ([[Niacin (nutrient)|niacin]]), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of [[dehydrogenase]]s remove electrons from their substrates and [[redox|reduce]] NAD⁺ into NADH. This reduced form of the coenzyme is then a substrate for any of the [[reductase]]s in the cell that need to transfer hydrogen atoms to their substrates. 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.

[[File:1GZX Haemoglobin.png|thumb|upright=1.35|right|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}}.]]

{{further||Bioinorganic chemistry}}

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 human's body weight is made up of the elements [[carbon]], [[nitrogen]], [[calcium]], [[sodium]], [[chlorine]], [[potassium]], [[hydrogen]], [[phosphorus]], [[oxygen]] and [[sulfur]]. [[Organic compound]]s (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen; most of the oxygen and hydrogen is present as water.

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

[[Transition metal]]s are usually present as [[trace element]]s in organisms, with [[zinc]] and [[iron]] being most abundant of those. 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.

{{Main|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, hydrogen, and carbon (their [[primary nutritional groups]]), as shown in the table below. Organic molecules are used as a source of hydrogen atoms or electrons by [[organotroph]]s, while [[lithotroph]]s use inorganic substrates. Whereas [[phototroph]]s convert sunlight to [[Potential energy#Chemical potential energy|chemical energy]], [[chemotroph]]s depend on [[redox]] reactions that involve the transfer of electrons from reduced donor molecules such as [[organic molecule]]s, [[hydrogen]], [[hydrogen sulfide]] or [[Ferrous|ferrous ions]] to [[oxygen]], [[nitrate]] or [[sulfate]]. In animals, these reactions involve complex [[organic molecule]]s that are broken down to simpler molecules, such as [[carbon dioxide]] and water. [[photosynthesis|Photosynthetic]] organisms, such as plants and [[cyanobacteria]], use similar electron-transfer reactions to store energy absorbed from sunlight.

{| class="wikitable float-right"  style="text-align:center; width:50%;"

|+Classification of organisms based on their metabolism  

|}

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 [[protein]]s, [[polysaccharide]]s or [[lipid]]s, are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to smaller molecules, usually [[acetyl-CoA|acetyl coenzyme A]] (acetyl-CoA), which releases some energy. Finally, the acetyl group on acetyl-CoA is oxidized to water and carbon dioxide in the [[citric acid cycle]] and [[electron transport chain]], releasing more energy while reducing the coenzyme [[nicotinamide adenine dinucleotide]] (NAD⁺) into NADH.

{{further|Digestion|Gastrointestinal tract}}

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. These [[digestive enzyme]]s include [[protease]]s that digest proteins into amino acids, as well as [[glycoside hydrolase]]s that digest polysaccharides into simple sugars known as [[monosaccharides]].

Microbes simply secrete digestive enzymes into their surroundings, while animals only secrete these enzymes from specialized cells in their [[Gastrointestinal tract|guts]], including the [[stomach]] and [[pancreas]], and in [[salivary gland]]s. The amino acids or sugars released by these extracellular enzymes are then pumped into cells by [[active transport]] proteins.

[[File:Catabolism schematic.svg|thumb|left|upright=1.35|A simplified outline of the catabolism of [[protein]]s, [[carbohydrate]]s and [[fat]]s]]

{{further|Cellular respiration|Fermentation (biochemistry)|Carbohydrate catabolism|Fat catabolism|Protein catabolism}}

Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells after they have been digested into [[monosaccharide]]s. Once inside, the major route of breakdown is [[glycolysis]], where sugars such as [[glucose]] and [[fructose]] are converted into [[pyruvic acid|pyruvate]] and some ATP is generated. 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 [[lactic acid|lactate]], through the enzyme [[lactate dehydrogenase]] re-oxidizing NADH to NAD+ for re-use in glycolysis.  

[[File:Carbon Catabolism.png|thumb|500px|Carbon Catabolism pathway map for free energy including carbohydrate and lipid sources of energy]]

Fats are catabolized 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. 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''.

[[Amino acid]]s are either used to synthesize proteins and other biomolecules, or oxidized to [[urea]] and carbon dioxide to produce energy. 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 α-[[alpha-Ketoglutaric acid|ketoglutarate]] formed by deamination of [[glutamate]]. The [[glucogenic amino acid]]s can also be converted into glucose, through [[gluconeogenesis]] (discussed below).

{{further|Oxidative phosphorylation|Chemiosmosis|Mitochondrion}}

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 in [[eukaryote]]s by a series of proteins in the membranes of mitochondria called the [[electron transport chain]]. In [[prokaryote]]s, these proteins are found in the cell's [[bacterial cell structure|inner membrane]]. These proteins use the energy from [[reducing agent|reduced]] molecules like NADH to pump [[proton]]s across a membrane.

[[File:ATPsyn.gif|thumb|right|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 [[diffusion|concentration difference]] across the membrane and generates an [[electrochemical gradient]]. 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.

{{further|Microbial metabolism|Nitrogen cycle}}

[[Chemolithotroph]]y is a type of metabolism found in [[prokaryote]]s where energy is obtained from the oxidation of [[inorganic compound]]s. These organisms can use [[hydrogen]], reduced [[sulfur]] compounds (such as [[sulfide]], [[hydrogen sulfide]] and [[thiosulfate]]), [[Iron(II) oxide|ferrous iron (Fe(II))]] or [[ammonia]] as sources of reducing power and they gain energy from the oxidation of these compounds. These microbial processes are important in global [[biogeochemical cycle]]s such as [[acetogenesis]], [[nitrification]] and [[denitrification]] and are critical for [[fertility (soil)|soil fertility]].

{{further|Phototroph|Photophosphorylation|Chloroplast}}

The energy in sunlight is captured by [[plant]]s, [[cyanobacteria]], [[purple bacteria]], [[green sulfur bacteria]] and some [[protist]]s. 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.

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. The electrons needed to drive this electron transport chain come from light-gathering proteins called [[photosynthetic reaction centre]]s. Reaction centers are classified into two types depending on the nature of [[photosynthetic pigment]] present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have two.

In plants, algae, and cyanobacteria, [[photosystem|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]]. These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through [[photosystem|photosystem I]] and can then be used to reduce the coenzyme NADP⁺.

{{further|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 smaller and simpler precursors. Anabolism involves three basic stages. First, the production of precursors such as [[amino acid]]s, [[monosaccharide]]s, [[Terpenoid|isoprenoids]] and [[nucleotide]]s, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as [[protein]]s, [[polysaccharide]]s, [[lipid]]s and [[nucleic acid]]s.

Anabolism in organisms can be different according to the source of constructed molecules in their cells. [[Autotroph]]s such as plants can construct the complex organic molecules in their cells such as polysaccharides and proteins from simple molecules like [[carbon dioxide]] and water. [[Heterotroph]]s, 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.

{{further|Photosynthesis|Carbon fixation|Chemosynthesis}}

[[File:Plagiomnium affine laminazellen.jpeg|thumb|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 centre]]s, 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 cycle|Calvin – Benson cycle]]. Three types of photosynthesis occur in plants, [[C3 carbon fixation]], [[C4 carbon fixation]] and [[Crassulacean acid metabolism|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.

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

{{further|Gluconeogenesis|Glyoxylate cycle|Glycogenesis|Glycosylation}}

In carbohydrate anabolism, simple organic acids can be converted into [[monosaccharide]]s such as [[glucose]] and then used to assemble [[polysaccharide]]s such as [[starch]]. The generation of [[glucose]] from compounds like [[pyruvate]], [[lactic acid|lactate]], [[glycerol]], [[glycerate 3-phosphate]] and [[amino acid]]s is called [[gluconeogenesis]]. Gluconeogenesis converts pyruvate to [[glucose-6-phosphate]] through a series of intermediates, many of which are shared with [[glycolysis]]. 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]].

Although fat is a common way of storing energy, in [[vertebrate]]s such as humans the [[fatty acid]]s 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. As a result, after long-term starvation, vertebrates need to produce [[Ketone body|ketone bodies]] from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids. 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. 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.

Polysaccharides and [[glycan]]s are made by the sequential addition of monosaccharides by [[glycosyltransferase]] from a reactive sugar-phosphate donor such as [[uridine diphosphate glucose]] (UDP-Glc) 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. The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called [[oligosaccharyltransferase]]s.

{{further|Fatty acid synthesis|Steroid metabolism}}

[[File:Sterol synthesis.svg|thumb|right|upright=1.6|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 synthase]]s 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, [[dehydration reaction|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, while in plant [[plastid]]s and bacteria separate type II enzymes perform each step in the pathway.

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

{{further|Protein biosynthesis|Amino acid synthesis}}

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 acid]]s must be obtained from food. Some simple [[parasite]]s, such as the bacteria ''[[Mycoplasma pneumoniae]]'', lack all amino acid synthesis and take their amino acids directly from their hosts. 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]]. Nonessensial amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then [[Transaminase|transaminated]] to form an amino acid.

Amino acids are made into proteins by being joined in a chain of [[peptide bond]]s. 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 [[Adenosine triphosphate|ATP]]-dependent reaction carried out by an [[aminoacyl tRNA synthetase]]. 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]].

{{further|Nucleotide salvage|Pyrimidine biosynthesis|Purine#Metabolism}}

Nucleotides are made from amino acids, carbon dioxide and [[formic acid]] in pathways that require large amounts of metabolic energy. Consequently, most organisms have efficient systems to salvage preformed nucleotides. [[Purine]]s are synthesized as [[nucleoside]]s (bases attached to [[ribose]]). 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]] [[folic acid|tetrahydrofolate]]. [[Pyrimidine]]s, on the other hand, are synthesized from the base [[Pyrimidinecarboxylic acid|orotate]], which is formed from glutamine and aspartate.

{{further|Xenobiotic metabolism|Drug metabolism|Alcohol metabolism|Antioxidant}}

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 called [[xenobiotic]]s. Xenobiotics such as [[drug|synthetic drugs]], [[poison|natural poisons]] and [[antibiotic]]s are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include [[cytochrome P450|cytochrome P450 oxidases]], [[Glucuronosyltransferase|UDP-glucuronosyltransferases]], and [[glutathione S-transferase|glutathione ''S''-transferases]]. 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. 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 pollutant]]s such as [[organochloride]] compounds.

A related problem for [[aerobic organism]]s is [[oxidative stress]]. Here, processes including [[oxidative phosphorylation]] and the formation of [[disulfide bond]]s during [[protein folding]] produce [[reactive oxygen species]] such as [[hydrogen peroxide]]. These damaging oxidants are removed by [[antioxidant]] metabolites such as [[glutathione]] and enzymes such as [[catalase]]s and [[peroxidase]]s.

{{further|Biological thermodynamics}}

Living organisms must obey the [[laws of thermodynamics]], which describe the transfer of heat and [[work (thermodynamics)|work]]. The [[second law of thermodynamics]] states that in any [[isolated 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 system (systems theory)|open systems]] that exchange matter and energy with their surroundings. Living systems are not in [[Thermodynamic equilibrium|equilibrium]], but instead are [[dissipative system]]s that maintain their state of high complexity by causing a larger increase in the entropy of their environments. The metabolism of a cell achieves this by coupling the [[spontaneous process]]es of catabolism to the non-spontaneous processes of anabolism. In [[non-equilibrium thermodynamics|thermodynamic]] terms, metabolism maintains order by creating disorder.

{{further|Metabolic pathway|Metabolic control analysis|Hormone|Regulatory enzymes|Cell signaling}}

As the environments of most organisms are constantly changing, the reactions of metabolism must be finely [[Control theory|regulated]] to maintain a constant set of conditions within cells, a condition called [[homeostasis]]. Metabolic regulation also allows organisms to respond to signals and interact actively with their environments. 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). 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.

[[File:Insulin glucose metabolism ZP.svg|thumb|right|upright=1.35|'''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. This type of regulation often involves [[allosteric regulation]] of the activities of multiple enzymes in the pathway. 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 as [[hormone]]s and [[growth factor]]s and are detected by specific [[receptor (biochemistry)|receptors]] on the cell surface. These signals are then transmitted inside the cell by [[second messenger system]]s that often involved the [[phosphorylation]] of proteins.

A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone [[insulin]]. Insulin is produced in response to rises in [[blood sugar|blood glucose levels]]. Binding of the hormone to [[insulin receptor]]s on cells then activates a cascade of [[protein kinase]]s that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and [[glycogen]]. 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 [[phosphatase|protein phosphatases]] and producing a decrease in the phosphorylation of these enzymes.

{{further|Proto-metabolism|Molecular evolution|Phylogenetics}}

[[File:Tree of life int.svg|thumb|right|upright=1.8|[[Phylogenetic tree|Evolutionary tree]] showing the common ancestry of organisms from all three [[Domain (biology)|domains]] of life. [[Bacteria]] are colored blue, [[eukaryote]]s red, and [[archaea]] green. Relative positions of some of the [[phylum|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-domain system|three domains]] of living things and were present in the [[last universal common ancestor]]. This universal ancestral cell was [[prokaryote|prokaryotic]] and probably a [[methanogen]] that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism. 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. 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 hypothesis|RNA world]].

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. 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. 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]]) 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.

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

{{further|Protein methods|Proteomics|Metabolomics|Metabolic network modelling}}

[[File:A thaliana metabolic network.png|thumb|upright=1.35|right|[[Metabolic network]] of the ''[[Arabidopsis thaliana]]'' [[citric acid cycle]]. [[Enzyme]]s and [[metabolite]]s are shown as red squares and the interactions between them as black lines.]]

Classically, metabolism is studied by a [[reductionism|reductionist]] approach that focuses on a single metabolic pathway. Particularly valuable is the use of [[radioactive tracer]]s at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively labelled intermediates and products. The enzymes that catalyze these chemical reactions can then be [[protein purification|purified]] and their [[enzyme kinetics|kinetics]] and responses to [[enzyme inhibitor|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.

An idea of the complexity of the [[metabolic network]]s 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. However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more [[Holism|holistic]] mathematical models that may explain and predict their behavior. These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on [[gene expression]] from [[proteomics|proteomic]] and [[DNA microarray]] studies. Using these techniques, a model of human metabolism has now been produced, which will guide future drug discovery and biochemical research. These models are now used in [[Network theory|network analysis]], to classify human diseases into groups that share common proteins or metabolites.

Bacterial metabolic networks are a striking example of [[Bow tie (biology)|bow-tie]] 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 [[drug]]s such as [[antibiotic]]s or industrial chemicals such as [[1,3-Propanediol|1,3-propanediol]] and [[shikimic acid]]. These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.

{{further|History of biochemistry|History of molecular biology}}

The term ''metabolism'' is derived from the [[Ancient Greek]] word μεταβολή – "Metabole" for "a change" which derived from μεταβάλλ –"Metaballein" means "To change"

[[File:Aristotle's metabolism.png|thumb|right|upright=1.4|[[Aristotle's biology|Aristotle's metabolism]] as an open flow model]]

[[Aristotle]]'s ''[[The Parts of Animals]]'' sets out enough details of [[Aristotle's biology|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.

[[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."

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 [[experiment]]s in human metabolism were published by [[Santorio Santorio]] in 1614 in his book ''Ars de statica medicina''. He described how he weighed himself before and after eating, [[sleeping|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]]".

[[File:SantoriosMeal.jpg|thumb|right|upright=0.7|[[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 [[vitalism|vital force]] was thought to animate living tissue. In the 19th century, when studying the [[fermentation (food)|fermentation]] of sugar to [[ethanol|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." This discovery, along with the publication by [[Friedrich Woehler|Friedrich Wöhler]] in 1828 of a paper on the chemical synthesis of [[urea]], 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 [[enzyme]]s 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]]. The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was [[Hans Adolf Krebs|Hans Krebs]] who made huge contributions to the study of metabolism. He discovered the urea cycle and later, working with [[Hans Kornberg]], the citric acid cycle and the glyoxylate cycle.

* {{annotated link|Anthropogenic metabolism}}

* {{annotated link|Antimetabolite}}

* {{annotated link|KEGG}}

{{reflist}}

{{Library resources box

  |onlinebooks=yes

{{refend}}

'''Advanced'''

{{refbegin}}

{{refend}}

{{Wikiversity|Topic:Biochemistry}}

{{wikibooks}}

* [http://www.sciencegateway.org/resources/biologytext/index.html MIT Biology Hypertextbook] Undergraduate-level guide to molecular biology.

'''Human metabolism'''

* [http://library.med.utah.edu/NetBiochem/titles.htm Topics in Medical Biochemistry] Guide to human metabolic pathways. School level.

* [http://themedicalbiochemistrypage.org/ THE Medical Biochemistry Page] Comprehensive resource on human metabolism.

'''Databases'''

* [http://www.expasy.org/cgi-bin/show_thumbnails.pl Flow Chart of Metabolic Pathways] at [[ExPASy]]

* [http://bioinformatics.charite.de/supercyp/ SuperCYP: Database for Drug-Cytochrome-Metabolism] {{Webarchive|url=https://web.archive.org/web/20111103123642/http://bioinformatics.charite.de/supercyp/ |date=3 November 2011 }}

'''Metabolic pathways'''

* [http://www.genome.ad.jp/kegg/pathway/map/map01100.html Metabolism reference Pathway] {{Webarchive|url=https://web.archive.org/web/20090223112439/http://www.genome.ad.jp/kegg/pathway/map/map01100.html |date=23 February 2009 }}

* {{webarchive |url=https://web.archive.org/web/*/helios.bto.ed.ac.uk/bto/microbes/nitrogen.htm |date=* |title=The Nitrogen cycle and Nitrogen fixation }}

{{featured article}}

{{Navboxes

|title = Articles related to Metabolism

{{Food science}}

{{二次利用|date=20 January 2024}}

[[Category:Metabolism| ]]

[[Category:Underwater diving physiology]]