Metabolism

Metabolism (from Greek μεταβολισμός (metabolismós), "outthrow") is the set of chemical reactions that happen in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments(Akku Sony VAIO VGN-FZ31M). Metabolism is usually divided into two categories. Catabolism breaks down organic matter, for example to harvest energy in cellular respiration. Anabolism uses energy to construct components of cells such as proteins and nucleic acids(Akku Sony VAIO VGN-FZ31J).

The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, by a sequence of enzymes. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy and will not occur by themselves(Akku Sony VAIO VGN-FZ31E), by coupling them to spontaneous reactions that release energy. As enzymes act as catalyststhey allow these reactions to proceed quickly and efficiently. Enzymes also allow the regulation of metabolic pathways in response to changes in the cell's environment or signals from other cells(Akku Sony VAIO VGN-FZ38M).

The metabolism of an organism determines which substances it will find nutritious and which it will find poisonous. For example, some prokaryotes usehydrogen sulfide as a nutrient, yet this gas is poisonous to animals. The speed of metabolism, the metabolic rate, also influences how much food an organism will require(Akku Sony VAIO VGN-FZ21Z).

A striking feature of metabolism is the similarity of the basic metabolic pathways and components between even vastly different species. For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all organisms(Akku Sony VAIO VGN-FZ21S), being found in species as diverse as theunicellular bacteria Escherichia coli and huge multicellular organisms like elephants. These striking similarities in metabolic pathways are likely due to their early appearance in evolutionary history, and being retained because of their efficacy(Akku Sony VAIO VGN-FZ21M).

Key biochemicals

Most of the structures that make up animals, plants and microbes are made from three basic classes of molecule: amino acids, carbohydratesand 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(Akku Sony VAIO VGN-FZ21J), or breaking them down and using them as a source of energy, in the digestion and use of food. Many important biochemicals can be joined together to make polymers such asDNA and proteins. These macromolecules are essential(Akku Sony VAIO VGN-FZ21E).

Amino acids and proteins

Proteins are made of amino acids arranged in a linear chain and joined together by peptide bonds. Many proteins are the enzymes that catalyzethe chemical reactions in metabolism. Other proteins have structural or mechanical functions(Akku Sony VAIO VGN-FZ140E), such as the proteins that form the cytoskeleton, a system of scaffolding that maintains the cell shape. Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle(Akku Sony VAIO VGN-FZ130E/B).

Lipids

Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes such as the cell membrane, or as a source of energy. Lipids are usually defined as hydrophobicor amphipathic biological molecules that will dissolve in organic solventssuch as benzene or chloroform(Akku Sony VAIO VGN-FZ11Z). The fats are a large group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is a triacylglyceride. Several variations on this basic structure exist, including alternate backbones such as sphingosinein the sphingolipids(Akku Sony VAIO VGN-FZ11S), and hydrophilic groups such asphosphate in phospholipids. Steroids such as cholesterol are another major class of lipids that are made in cells.

Carbohydrates

Carbohydrates are straight-chain aldehydes or ketones with many hydroxyl groups that can exist as straight chains or rings(Akku Sony VAIO VGN-FZ11M). 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 monosaccharides and include galactose, fructose, and most importantly glucose(Akku Sony VAIO VGN-FZ11L). Monosaccharides can be linked together to form polysaccharides in almost limitless ways.

Nucleotides

The two nucleic acids, DNA and RNA are polymers of nucleotides, each nucleotide comprising a phosphate group, a ribose sugar group, and a nitrogenous base. Nucleic acids are critical for the storage and use of genetic information, through the processes of transcription and protein biosynthesis(Sony VAIO VGN-FZ11E Battery). This information is protected by DNA repair mechanisms and propagated through DNA replication. Many viruses have an RNA genome, for example HIV, which uses reverse transcription to create a DNA template from its viral RNA genome(Akku Sony VGN-NR11Z/T). 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 orpyrimidines(Akku Sony VGN-NR11Z/S). Nucleotides also act as coenzymes in metabolic group transfer reactions.

Coenzymes

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. This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions(Akku Sony VGN-NR11S/S). These group-transfer intermediates are called coenzymes. Each class of group-transfer reaction 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 being made, consumed and then recycled(Akku Sony VGN-NR11M/S).

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(Sony VAIO PCG-8Z2L Akku). ATP acts as a bridge between catabolism and anabolism, with catabolic reactions generating ATP and anabolic reactions consuming 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 the cells. In human nutrition, most vitamins function as coenzymes after modification(Sony VAIO PCG-8Z1L Akku); for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells. Nicotinamide adenine dinucleotide (NADH), 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(Sony VAIO PCG-8Y2L Akku). This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to reduce 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(Sony VAIO PCG-8Y1L Akku).

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 mammals' mass are the elements carbon, nitrogen, calcium, sodium, chlorine, potassium(Sony VAIO PCG-7z1L Akku), hydrogen, phosphorus, oxygen and sulfur. The organic compounds(proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen and most of the oxygen and hydrogen is present as water.

The abundant inorganic elements act as ionic electrolytes(Sony VAIO PCG-7z1L Akku). The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate, and the organic ion bicarbonate. The maintenance of precise gradientsacross cell membranes maintains osmotic pressure and pH(Sony VAIO PCG-7133L Akku). Ions are also critical fornerves and muscles, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cytosol. Electrolytes enter and leave cells through proteins in the cell membrane called ion channels(Sony VAIO PCG-7132L Akku). For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules.

The transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant. 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(Sony VAIO PCG-7131L Akku). These cofactors are bound tightly to a specific protein; although enzyme cofactors can be modified during catalysis, cofactors always return to their original state after catalysis has taken place(Sony VAIO PCG-7113L Akku). The metal micronutrients are taken up into organisms by specific transporters and bound to storage proteins such as ferritin ormetallothionein when not being used.

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(Sony VAIO PCG-7112L Akku). 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 (theirprimary nutritional groups), as shown in the table below. Organic molecules being used as a source of energy in organotrophs, while lithotrophs use inorganic substrates and phototrophs capture sunlight aschemical energy(Sony VAIO PCG-7111L Akku). However, all these different forms of metabolism depend on redoxreactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, water, ammonia,hydrogen sulfideor ferrous ions to acceptor molecules such as oxygen, nitrate or sulfate(Sony VAIO PCG-6W3L Akku). In animals these reactions involve complex organic molecules being 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(Sony VAIO PCG-6W2L Akku).

The most common set of catabolic reactions in animals can be separated into three main stages. In the first, 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 yet smaller molecules(Sony VAIO PCG-6W1L Akku), 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(Sony VAIO PCG-6S2L Akku).

Digestion

Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and need to 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(Sony VAIO PCG-6S1L Akku), as well as glycoside hydrolases that digest polysaccharides into monosaccharides.

Microbes simply secrete digestive enzymes into their surroundings, while animals only secrete these enzymes from specialized cells in their guts. The amino acids or sugars released by these extracellular enzymes are then pumped into cells by specific active transportproteins(Sony VAIO PCG-5K1L Akku).

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 intomonosaccharides. 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(Sony VAIO PCG-5K2L Akku). Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA 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(Sony VAIO PCG-5J2L Akku). 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(Sony VAIO PCG-5J1L Akku).

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(AKKU Sony VAIO PCG-5G3L ).

Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of 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(AKKU Sony VAIO PCG-5G2L). Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms α-ketoglutarate. The glucogenic amino acids can also be converted into glucose, through gluconeogenesis(discussed below) (AKKU Sony VAIO VGN-FW32Z).

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. Inprokaryotes(AKKU Sony VAIO VGN-FW31ZJ), these proteins are found in the cell's inner membrane. These proteins use the energy released from passing electrons from reduced molecules like NADH onto oxygen to pump protons across a membrane.

Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates an electrochemical gradient(AKKU Sony VAIO VGN-FW31Z). 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(AKKU Sony VAIO VGN-FW31E).

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 usehydrogen, reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate) (AKKU Sony VAIO VGN-FW31J), ferrous iron (FeII) or ammonia as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as oxygen or nitrite. These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrificationand denitrification and are critical for soil fertility(AKKU Sony VAIO VGN-FW31M).

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(AKKU Sony VAIO VGN-FW21M). 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(AKKU Sony VAIO VGN-FW21Z).

In many organisms the capture of solar energy is similar in principle to oxidative phosphorylation, as it involves energy being stored as a proton concentration gradient and this proton motive force then driving ATP synthesis(AKKU Sony VAIO VGN-FW21L). 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(AKKU Sony VAIO VGN-FW21I).

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(AKKU sony VAIO VGN-FW21E). These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow throughphotosystem 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(Akku Sony VGP-BPS14/B ).

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(Akku Sony VGP-BPL14/B). Firstly, 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(Akku Sony VGP-BPS14/S ).

Organisms differ in how many of the molecules in their cells they can construct for themselves. 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( Akku Sony VGP-BPL14 ), 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(Akku Sony VGP-BPL14).

Carbon fixation

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(Sony VGP-BPS21/S Akku), 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 enzyme RuBisCO as part of the Calvin – Benson cycle. Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon fixation and CAM photosynthesis(Sony VGP-BPS21A/B Akku). 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(Sony VGP-BPS21B Akku).

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 acidcycle, or the carboxylation of acetyl-CoA. Prokaryotic chemoautotrophs also fix CO2 through the Calvin – Benson cycle, but use energy from inorganic compounds to drive the reaction(Sony VGP-BPS21A Akku).

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-phosphateand amino acids is called gluconeogenesis(Sony VGP-BPS21 Akku). 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(Sony VGP-BPL9 Akku). 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 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(Sony VGP-BPL9A Akku); plants do, but animals do not, have the necessary enzymatic machinery. 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. In other organisms such as plants and bacteria(Sony VGP-BPL9A/B Akku), this metabolic problem is solved using the glyoxylate cycle, which bypasses the decarboxylationstep in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate, where it can be used for the production of glucose(Sony VGP-BPL9/S Akku).

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(Sony VGP-BPL9/B Akku). As any of the hydroxylgroups 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 oligosaccharyltransferases(Sony VGP-BPL9 Akku).

Fatty acids, isoprenoids and steroids

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 actyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group(Sony VGN-FZ130E/BB Battery). 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 plastids and bacteria separate type II enzymes perform each step in the pathway(Sony VGN-FZ130E/BA Battery).

Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products. These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphateanddimethylallyl pyrophosphate(Sony VGN-FZ130E/B Battery). These precursors can be made in different ways. In animals and archaea, the mevalonate pathwayproduces these compounds from acetyl-CoA, while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates(Sony VGP-BPL8A Battery). 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. Lanosterol can then be converted into other steroids such as cholesterol and ergosterol(Sony VGP-BPL8 Battery).

Proteins

Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can synthesize only eleven nonessential amino acids. Thus, nine essential amino acids must be obtained from food. All amino acids are synthesized from intermediates in glycolysis(AKKU Sony VGP-BPS13Q), the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamateand glutamine. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid(AKKU Sony VGP-BPS13B/Q).

Amino acids are made into proteins by being joined together in a chain by 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(AKKU Sony VGP-BPS13A/Q), 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(AKKU Sony VGP-BPS13A/S). 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.

Nucleotide synthesis and salvage

Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy(AKKU Sony VGP-BPS13B/S). Consequently, most organisms have efficient systems to salvage preformed nucleotides. Purines are synthesized as nucleosides (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(AKKU Sony VGP-BPS13/S), and aspartic acid, as well as formate transferred from the coenzymetetrahydrofolate. Pyrimidines, on the other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.

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(AKKU Sony VGP-BPS13B/B), as they have no metabolic function. These potentially damaging compounds are called xenobiotics. 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(AKKU Sony VGP-BPS13A/B), UDP-glucuronosyltransferases, and 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) (AKKU Sony VGP-BPS13). 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 pollutants such asorganochloride compounds(SONY VGP-BPS8 battery).

A related problem for aerobic organisms is oxidative stress. Here, processes including oxidative phosphorylation and the formation of disulfide bonds 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 catalases and peroxidases(SONY VAIO VGN-FZ Battery).

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) will tend to increase. Although living organisms' amazing complexity appears to contradict this law(SONY VAIO VGN-FZ11S Battery), 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(SONY vgp-bps9 battery). 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.

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(sony vgp-bpl9 battery), 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(SONY VAIO VGN-FZ32 Battery). Secondly, the controlexerted 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(SONY VAIO VGN-FZ440N Battery).

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(SONY VAIO VGN-FZ280E Battery). 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 soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface(SONY VAIO VGN-FZ460E Battery). These signals are then transmitted inside the cell by second messenger systems 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 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(SONY VAIO VGN-FZ190 Battery). 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(SONY VAIO VGN-FZ150E Battery). Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes.

Evolution

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 ancestor(SONY VAIO VGN-FZ260E Battery). This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism. The retention of these ancient pathways during laterevolutionmay be the result of these reactions being an optimal solution to their particular metabolic problems(SONY VAIO VGN-FZ140E Battery), with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps. Mutation changes that affect non-coding DNA segments may merely affect the metabolic efficiency of the individual for whom the mutation occurs(SONY VAIO VGN-FZ11l Battery). The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, with previous metabolic pathways being part of the ancient 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(SONY VAIO VGN-FZ11z Battery). 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 being created from pre-existing steps in the pathway. An alternative model comes from studies that trace the evolution of proteins' structures in metabolic networks(SONY VAIO VGN-FZ11m Battery), this has suggested that enzymes are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident in the MANET database) These recruitment processes result in an evolutionary enzymatic mosaic. 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(SONY VAIO VGN-FZ18m Battery).

As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For example, in someparasitesmetabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the host. Similar reduced metabolic capabilities are seen in endosymbiotic organisms(SONY VAIO VGN-FZ21m Battery).

Investigation and manipulation

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(SONY VAIO VGN-FZ410 Battery). The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitorsinvestigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called the metabolome(SONY VAIO VGN-FZ21 Battery). 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 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(SONY VAIO VGN-FZ160 Battery): the sequences of genomes provide lists containing anything up to 45,000 genes. 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(SONY VAIO VGN-FZ210CE Battery). 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. Using these techniques, a model of human metabolism has now been produced(SONY VAIO VGN-FZ38M Battery), which will guide future drug discovery and biochemical research. These models are now being used in network analysis, to classify human diseases into groups that share common proteins or metabolites.

Bacterial metabolic networks seem to be a striking example of 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(SONY VAIO VGN-FZ31z Battery).

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(Sony Vaio VGN-FZ31S battery). These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.

History

The term metabolism is derived from the Greek Μεταβολισμός – "Metabolismos" for "change", or "overthrow"(SONY VAIO VGN-FZ31E Battery). 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(SONY VAIO VGN-FZ31J Battery). The first controlled experiments 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, 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"(SONY VAIO VGN-FZ31M Battery).

In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue. 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"(SONY VAIO VGN-FZ31B Battery). 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 Wohler in 1828 of the chemical synthesis of urea, proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry(HP PAVILION DV6000 battery).

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. The mass of biochemical knowledge grew rapidly throughout the early 20th century(SONY VGP-BPS13 Battery). One of the most prolific of these modern biochemists was 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(SONY VGP-BPS13B/B Battery). 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(ASUS EEE PC battery).