Metabolism

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"Cell metabolism" redirects here. For the journal, see Cell Metabolism.
For the architectural movement, see Metabolism (architecture).

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Simplified view of the cellular metabolism

Structure of adenosine triphosphate (ATP), a central intermediate in energy metabolism

Metabolism (/məˈtæbəlɪzəm/, from Greek: μεταβολή metabolē, "change") is the set

of life-sustaining chemical reactions in organisms. The three main purposes of
metabolism are: the conversion of food to energy to run cellular processes; the
conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and
some carbohydrates; and the elimination of metabolic wastes. These enzyme-catalyzed
reactions allow organisms to grow and reproduce, maintain their structures, and
respond to their environments. (The word metabolism can also refer to the sum of all
chemical reactions that occur in living organisms, including digestion and the transport
of substances into and between different cells, in which case the above described set of
reactions within the cells is called intermediary metabolism or intermediate metabolism).
Metabolic reactions may be categorized as catabolic – the breaking down of
compounds (for example, the breaking down of glucose to pyruvate by cellular
respiration); or anabolic – the building up (synthesis) of compounds (such as proteins,
carbohydrates, lipids, and nucleic acids). Usually, catabolism releases energy, and
anabolism consumes energy.
The chemical reactions of metabolism are organized into metabolic pathways, in which
one chemical is transformed through a series of steps into another chemical, each step
being facilitated by a specific enzyme. Enzymes are crucial to metabolism because they
allow organisms to drive desirable reactions that require energy that will not occur by
themselves, by coupling them to spontaneous reactions that release energy. Enzymes
act as catalysts – they allow a reaction to proceed more rapidly – and they also allow
the regulation of the rate of a metabolic reaction, for example in response to changes in
the cell's environment or to signals from other cells.
The metabolic system of a particular organism determines which substances it will
find nutritious and which poisonous. For example, some prokaryotes use hydrogen
sulfide as a nutrient, yet this gas is poisonous to animals.[1] The basal metabolic rate of
an organism is the measure of the amount of energy consumed by all of these chemical
reactions.
A striking feature of metabolism is the similarity of the basic metabolic pathways among
vastly different species.[2] For example, the set of carboxylic acids that are best known
as the intermediates in the citric acid cycle are present in all known organisms, being
found in species as diverse as the unicellular bacterium Escherichia coli and
huge multicellular organisms like elephants.[3] These similarities in metabolic pathways
are likely due to their early appearance in evolutionary history, and their retention
because of their efficacy.[4][5] 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.[6]

Contents

 1Key biochemicals
o 1.1Amino acids and proteins
o 1.2Lipids
o 1.3Carbohydrates
o 1.4Nucleotides
o 1.5Coenzymes
o 1.6Mineral and cofactors
 2Catabolism
o 2.1Digestion
o 2.2Energy from organic compounds
 3Energy transformations
o 3.1Oxidative phosphorylation
o 3.2Energy from inorganic compounds
o 3.3Energy from light
  4Anabolism
o 4.1Carbon fixation
o 4.2Carbohydrates and glycans
o 4.3Fatty acids, isoprenoids and sterol
o 4.4Proteins
o 4.5Nucleotide synthesis and salvage
 5Xenobiotics and redox metabolism
 6Thermodynamics of living organisms
 7Regulation and control
 8Evolution
 9Investigation and manipulation
 10History
o 10.1Greek philosophy
o 10.2Islamic medicine
o 10.3Application of the scientific method
 11See also
 12References
 13Further reading
 14External links

Key biochemicals[edit]
Further information: Biomolecule, Cell (biology), and Biochemistry

Structure of a triacylglycerol lipid
This is a diagram depicting a large set of human metabolic pathways.

Most of the structures that make up animals, plants and microbes are made from four
basic classes of molecule: amino acids, carbohydrates , nucleic acid and lipids (often
called fats). As these molecules are vital for life, metabolic reactions either focus on
making these molecules during the construction of cells and tissues, or by breaking
them down and using them as a source of energy, by their digestion. These
biochemicals can be joined together to make polymers such as DNA and proteins,
essential macromolecules of life.[7]

Type of Name
Name of polymer forms Examples of polymer forms
molecule of monomer forms

Proteins (made of Fibrous proteins and globular

Amino acids Amino acids
polypeptides) proteins

Carbohydrates Monosaccharides Polysaccharides Starch, glycogen and cellulose

Nucleic acids Nucleotides Polynucleotides DNA and RNA

Amino acids and proteins[edit]

Proteins are made of amino acids arranged in a linear chain joined together by peptide
bonds. Many proteins are enzymes that catalyze the chemical reactions in metabolism.
Other proteins have structural or mechanical functions, such as those that form
the cytoskeleton, a system of scaffolding that maintains the cell shape.[8] Proteins are
also important in cell signaling, immune responses, cell adhesion, active
transport across membranes, and the cell cycle.[9] Amino acids also contribute to cellular
energy metabolism by providing a carbon source for entry into the citric acid cycle
(tricarboxylic acid cycle),[10] especially when a primary source of energy, such
as glucose, is scarce, or when cells undergo metabolic stress.[11]
Lipids[edit]
Lipids are the most diverse group of biochemicals. Their main structural uses are as
part of biological membranes both internal and external, such as the cell membrane, or
as a source of energy.[9] Lipids are usually defined
as hydrophobic or amphipathic biological molecules but will dissolve in organic
solvents such as alcohol, benzene or chloroform.[12] The fats are a large group of
compounds that contain fatty acids and glycerol; a glycerol molecule attached to three
fatty acid esters is called a triacylglyceride.[13] Several variations on this basic structure
exist, including backbones such as sphingosine in the sphingomyelin,
and hydrophilic groups such as phosphate as in phospholipids. Steroids such
as sterol are another major class of lipids.[14]
Carbohydrates[edit]

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

Carbohydrates are aldehydes or ketones, with many hydroxyl groups attached, that can

exist as straight chains or rings. Carbohydrates are the most abundant biological
molecules, and fill numerous roles, such as the storage and transport
of energy (starch, glycogen) and structural components (cellulose in plants, chitin in
animals).[9] The basic carbohydrate units are called monosaccharides and
include galactose, fructose, and most importantly glucose. Monosaccharides can be
linked together to form polysaccharides in almost limitless ways.[15]
Nucleotides[edit]
The two nucleic acids, DNA and RNA, are polymers of nucleotides. Each nucleotide is
composed of a phosphate attached to a ribose or deoxyribose sugar group which is
attached to a nitrogenous base. Nucleic acids are critical for the storage and use of
genetic information, and its interpretation through the processes
of transcription and protein biosynthesis.[9] This information is protected by DNA
repair mechanisms and propagated through DNA replication. Many viruses have
an RNA genome, such as HIV, which uses reverse transcription to create a DNA
template from its viral RNA genome.[16] RNA in ribozymes such
as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical
reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar.
These bases are heterocyclic rings containing nitrogen, classified
as purines or pyrimidines. Nucleotides also act as coenzymes in metabolic-group-
transfer reactions.[17]
Coenzymes[edit]

Structure of the coenzyme acetyl-CoA.The transferable acetyl group is bonded to the sulfur atom at the

extreme left.

Main article: 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 groups of atoms and their bonds
within molecules.[18] This common chemistry allows cells to use a small set of metabolic
intermediates to carry chemical groups between different reactions. [17] These group-
transfer intermediates are called coenzymes. Each class of group-transfer reactions is
carried out by a particular coenzyme, which is the substrate for a set of enzymes that
produce it, and a set of enzymes that consume it. These coenzymes are therefore
continuously made, consumed and then recycled. [19]
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. [19] 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.[20]
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.[21] Nicotinamide adenine dinucleotide (NAD+), a derivative of
vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor.
Hundreds of separate types of dehydrogenases remove electrons from their substrates
and reduce NAD+ into NADH. This reduced form of the coenzyme is then a substrate for
any of the reductases in the cell that need to reduce their substrates.[22] 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.[23]
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.

Mineral and cofactors[edit]

Further information: 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 compounds (proteins, lipids and carbohydrates) contain
the majority of the carbon and nitrogen; most of the oxygen and hydrogen is present as
water.[24]
The abundant inorganic elements act as electrolytes. The most important ions
are sodium, potassium, calcium, magnesium, chloride, phosphate and the organic
ion bicarbonate. The maintenance of precise ion gradients across cell
membranes maintains osmotic pressure and pH.[25] Ions are also critical
for nerve and muscle function, as action potentials in these tissues are produced by the
exchange of electrolytes between the extracellular fluid and the cell's fluid, the cytosol.
[26]
 Electrolytes enter and leave cells through proteins in the cell membrane called ion
channels. For example, muscle contraction depends upon the movement of calcium,
sodium and potassium through ion channels in the cell membrane and T-tubules.[27]
Transition metals are usually present as trace elements in organisms,
with zinc and iron being most abundant of those.[28] 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[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 as ferritin or metallothionein when not in use.[30][31]

Catabolism[edit]
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 and
carbon (their primary nutritional groups), as shown in the table below. Organic
molecules are used as a source of energy by organotrophs, while lithotrophs use
inorganic substrates, and phototrophs capture sunlight as chemical energy.[33] However,
all these different forms of metabolism depend on redox reactions that involve the
transfer of electrons from reduced donor molecules such as organic molecules,
water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such
as oxygen, nitrate or sulfate. In animals, these reactions involve complex organic
molecules that are broken down to simpler molecules, such as carbon dioxide and
water. In photosynthetic organisms, such as plants and cyanobacteria, these electron-
transfer reactions do not release energy but are used as a way of storing energy
absorbed from sunlight.[34]

Classification of organisms based on their metabolism [35]

sunlight photo-
Energy source  
Preformed molecules chemo-

organic compound organo-

Electron donor     -troph
inorganic compound litho-

organic compound hetero-

Carbon source  
inorganic compound auto-

The most common set of catabolic reactions in animals can be separated into three
main stages. In the first stage, large organic molecules, such
as proteins, polysaccharides or lipids, are digested into their smaller components
outside cells. Next, these smaller molecules are taken up by cells and converted to
smaller molecules, usually acetyl coenzyme A (acetyl-CoA), which releases some
energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in
the citric acid cycle and electron transport chain, releasing the energy that is stored by
reducing the coenzyme nicotinamide adenine dinucleotide (NAD+) into NADH.[32]
Digestion[edit]
Further information: Digestion and 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 were being used to digest these polymers. These digestive
enzymes include proteases that digest proteins into amino acids, as well as glycoside
hydrolases that digest polysaccharides into simple sugars known as monosaccharides[36]
Microbes simply secrete digestive enzymes into their surroundings, [37][38] while animals
only secrete these enzymes from specialized cells in their guts, including
the stomach and pancreas, and salivary glands.[39] The amino acids or sugars released
by these extracellular enzymes are then pumped into cells by active transport proteins.[40]
[41]
A simplified outline of the catabolism of proteins, carbohydrates and fats

Energy from organic compounds[edit]

Further information: Cellular respiration, Fermentation (biochemistry), Carbohydrate
catabolism, Fat catabolism, and Protein catabolism
Carbohydrate catabolism is the breakdown of carbohydrates into smaller units.
Carbohydrates are usually taken into cells once they have been digested
into monosaccharides.[42] 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.[43] Pyruvate is an intermediate in several metabolic pathways, but the majority
is converted to acetyl-CoA through aerobic (with oxygen) glycolysis and fed into
the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the
most important product is NADH, which is made from NAD + as the acetyl-CoA is
oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic
conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-
oxidizing NADH to NAD+ for re-use in glycolysis. [44] An alternative route for glucose
breakdown is the pentose phosphate pathway, which reduces the
coenzyme NADPH and produces pentose sugars such as ribose, the sugar component
of nucleic acids.
Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters
glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA,
which then is fed into the citric acid cycle. Fatty acids release more energy upon
oxidation than carbohydrates because carbohydrates contain more oxygen in their
structures. Steroids are also broken down by some bacteria in a process similar to beta
oxidation, and this breakdown process involves the release of significant amounts of
acetyl-CoA, propionyl-CoA, and pyruvate, which can all be used by the cell for
energy. M. tuberculosis can also grow on the lipid cholesterol as a sole source of
carbon, and genes involved in the cholesterol use pathway(s) have been validated as
important during various stages of the infection lifecycle of M. tuberculosis.[45]
Amino acids are either used to synthesize proteins and other biomolecules, or oxidized
to urea and carbon dioxide as a source of energy.[46] The oxidation pathway starts with
the removal of the amino group by a transaminase. The amino group is fed into the urea
cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these
keto acids are intermediates in the citric acid cycle, for example the deamination
of glutamate forms α-ketoglutarate.[47] The glucogenic amino acids can also be converted
into glucose, through gluconeogenesis (discussed below).[48]

Energy transformations[edit]
Oxidative phosphorylation[edit]
Further information: Oxidative phosphorylation, Chemiosmosis, and Mitochondrion
In oxidative phosphorylation, the electrons removed from organic molecules in areas
such as the protagon acid cycle are transferred to oxygen and the energy released is
used to make ATP. This is done in eukaryotes by a series of proteins in the membranes
of mitochondria called the electron transport chain. In prokaryotes, these proteins are
found in the cell's inner membrane.[49] These proteins use the energy released from
passing electrons from reduced molecules like NADH onto oxygen to
pump protons across a membrane.[50]

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

Pumping protons out of the mitochondria creates a proton concentration

difference across the membrane and generates an electrochemical gradient.[51] 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.[19]
Energy from inorganic compounds[edit]
Further information: Microbial metabolism and Nitrogen cycle
Chemolithotrophy is a type of metabolism found in prokaryotes where energy is
obtained from the oxidation of inorganic compounds. These organisms can
use hydrogen,[52] reduced sulfur compounds (such as sulfide, hydrogen
sulfide and thiosulfate),[1] ferrous iron (FeII)[53] or ammonia[54] as sources of reducing
power and they gain energy from the oxidation of these compounds with electron
acceptors such as oxygen or nitrite.[55] These microbial processes are important in
global biogeochemical cycles such as acetogenesis, nitrification and denitrification and
are critical for soil fertility.[56][57]
Energy from light[edit]
Further information: Phototroph, Photophosphorylation, and Chloroplast
The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green
sulfur bacteria and some protists. This process is often coupled to the conversion of
carbon dioxide into organic compounds, as part of photosynthesis, which is discussed
below. The energy capture and carbon fixation systems can however operate
separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight
as a source of energy, while switching between carbon fixation and the fermentation of
organic compounds.[58][59]
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[60] The electrons needed to drive this
electron transport chain come from light-gathering proteins called photosynthetic
reaction centres. Reaction centers are classed 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.[61]
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.[34] These protons move back through the
membrane as they drive the ATP synthase, as before. The electrons then flow
through photosystem I and can then either be used to reduce the coenzyme NADP +.
fThese cooenzyme can be used in the Calvin cycle, which is discussed below, or
[62]

recycled for further ATP generation.

Anabolism[edit]
Further information: Anabolism
Anabolism is the set of constructive metabolic processes where the energy released by
catabolism is used to synthesize complex molecules. In general, the complex molecules
that make up cellular structures are constructed step-by-step from small and simple
precursors. Anabolism involves three basic stages. First, the production of precursors
such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their
activation into reactive forms using energy from ATP, and thirdly, the assembly of these
precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic
acids.[63]
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 cells such as polysaccharides and proteins from simple molecules
like carbon dioxide and water. Heterotrophs, on the other hand, require a source of
more complex substances, such as monosaccharides and amino acids, to produce
these complex molecules. Organisms can be further classified by ultimate source of
their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas
chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation
reactions.[63]
Carbon fixation[edit]
Further information: Photosynthesis, Carbon fixation, and Chemosynthesis

Plant cells (bounded by purple walls) filled with chloroplasts (green), which are the site of photosynthesis

Photosynthesis is the synthesis of carbohydrates from sunlight and carbon

dioxide (CO2). In plants, cyanobacteria and algae, oxygenic photosynthesis splits water,
with oxygen produced as a waste product. This process uses the ATP and NADPH
produced by the photosynthetic reaction centres, as described above, to convert
CO2 into glycerate 3-phosphate, which can then be converted into glucose. This carbon-
fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin – Benson
cycle.[64] Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon
fixation and CAM photosynthesis. These differ by the route that carbon dioxide takes to
the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and CAM photosynthesis
incorporate the CO2 into other compounds first, as adaptations to deal with intense
sunlight and dry conditions.[65]
In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse.
Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a reversed citric
acid cycle,[66] or the carboxylation of acetyl-CoA.[67][68] Prokaryotic chemoautotrophs also fix
CO2 through the Calvin–Benson cycle, but use energy from inorganic compounds to
drive the reaction.[69]
Carbohydrates and glycans[edit]
Further information: Gluconeogenesis, Glyoxylate cycle, Glycogenesis,
and Glycosylation
In carbohydrate anabolism, simple organic acids can be converted
into monosaccharides such as glucose and then used to
assemble polysaccharides such as starch. The generation of glucose from compounds
like pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids is
called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-
phosphate through a series of intermediates, many of which are shared with glycolysis.
[43]
 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.[70][71]
Although fat is a common way of storing energy, in vertebrates such as humans
the fatty acids in these stores cannot be converted to glucose
through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate;
plants do, but animals do not, have the necessary enzymatic machinery. [72] 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. [73] 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.[72][74] 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. [75]
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-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.
[76]
 The polysaccharides produced can have structural or metabolic functions themselves,
or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases.[77]
[78]

Fatty acids, isoprenoids and sterol[edit]

Further information: Fatty acid synthesis and Steroid metabolism
Simplified version of the steroid synthesis pathway with the intermediates isopentenyl
pyrophosphate (IPP), dimethylallyl pyrophosphate (DMAPP), geranyl pyrophosphate (GPP)
and squalene shown. Some intermediates are omitted for clarity.

Fatty acids are made by fatty acid synthases that polymerize and then reduce acetyl-
CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that
add the acyl group, reduce it to an alcohol, dehydrate it to an alkene group and then
reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided
into two groups: in animals and fungi, all these fatty acid synthase reactions are carried
out by a single multifunctional type I protein, [79] while in plant plastids and bacteria
separate type II enzymes perform each step in the pathway. [80][81]
Terpenes and isoprenoids are a large class of lipids that include the carotenoids and
form the largest class of plant natural products.[82] These compounds are made by the
assembly and modification of isoprene units donated from the reactive
precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate.[83] These
precursors can be made in different ways. In animals and archaea, the mevalonate
pathway produces these compounds from acetyl-CoA,[84] while in plants and bacteria
the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as
substrates.[83][85] One important reaction that uses these activated isoprene donors
is sterol 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.
[86]
 Lanosterol can then be converted into other sterol such as cholesterol and ergosterol.
[86][87]

Proteins[edit]
Further information: Protein biosynthesis and 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 acids must be obtained from food.
[9]
 Some simple parasites, such as the bacteria Mycoplasma pneumoniae, lack all amino
acid synthesis and take their amino acids directly from their hosts. [88] 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 transaminated to form an amino acid.[89]
Amino acids are made into proteins by being joined together in a chain of peptide
bonds. Each different protein has a unique sequence of amino acid residues: this is
its primary structure. Just as the letters of the alphabet can be combined to form an
almost endless variety of words, amino acids can be linked in varying sequences to
form a huge variety of proteins. Proteins are made from amino acids that have been
activated by attachment to a transfer RNA molecule through an ester bond.
This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried out
by an aminoacyl tRNA synthetase.[90] 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.[91]
Nucleotide synthesis and salvage[edit]
Further information: Nucleotide salvage, Pyrimidine biosynthesis, and Purine
§  Metabolism
Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways
that require large amounts of metabolic energy. [92] Consequently, most organisms have
efficient systems to salvage preformed nucleotides.[92][93] Purines are synthesized
as nucleosides (bases attached to ribose).[94] Both adenine and guanine are made from
the precursor nucleoside inosine monophosphate, which is synthesized using atoms
from the amino acids glycine, glutamine, and aspartic acid, as well
as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the other
hand, are synthesized from the base orotate, which is formed from glutamine and
aspartate.[95]

Xenobiotics and redox metabolism[edit]

Further information: Xenobiotic metabolism, Drug metabolism, Alcohol metabolism,
and Antioxidant
All organisms are constantly exposed to compounds that they cannot use as foods and
would be harmful if they accumulated in cells, as they have no metabolic function.
These potentially damaging compounds are called xenobiotics.[96] 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,[97] UDP-
glucuronosyltransferases,[98] and glutathione S-transferases.[99] 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.[100] Many of these microbial reactions are shared with multicellular
organisms, but due to the incredible diversity of types of microbes these organisms are
able to deal with a far wider range of xenobiotics than multicellular organisms, and can
degrade even persistent organic pollutants such as organochloride compounds.[101]
A related problem for aerobic organisms is oxidative stress.[102] Here, processes
including oxidative phosphorylation and the formation of disulfide bonds during protein
folding produce reactive oxygen species such as hydrogen peroxide.[103] These
damaging oxidants are removed by antioxidant metabolites such as glutathione and
enzymes such as catalases and peroxidases.[104][105]

Thermodynamics of living organisms[edit]

Further information: Biological thermodynamics
Living organisms must obey the laws of thermodynamics, which describe the transfer of
heat and work. The second law of thermodynamics states that in any closed system, the
amount of entropy (disorder) cannot decrease. Although living organisms' amazing
complexity appears to contradict this law, life is possible as all organisms are open
systems that exchange matter and energy with their surroundings. Thus living systems
are not in equilibrium, but instead are dissipative systems that maintain their state of
high complexity by causing a larger increase in the entropy of their environments. [106] 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.[107]

Regulation and control[edit]

Further information: Metabolic pathway, Metabolic control
analysis, Hormone, Regulatory enzymes, and Cell signaling
As the environments of most organisms are constantly changing, the reactions of
metabolism must be finely regulated to maintain a constant set of conditions within cells,
a condition called homeostasis.[108][109] Metabolic regulation also allows organisms to
respond to signals and interact actively with their environments. [110] 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).[111] 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. [112]
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.[111] This type of regulation often involves allosteric regulation of
the activities of multiple enzymes in the pathway.[113] 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 hormones and growth factors and are detected by specific receptors on the cell
surface.[114] These signals are then transmitted inside the cell by second messenger
systems that often involved the phosphorylation of proteins.[115]
A very well understood example of extrinsic control is the regulation of glucose
metabolism by the hormone insulin.[116] 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.[117] The metabolism of glycogen is
controlled by activity of phosphorylase, the enzyme that breaks down glycogen,
and glycogen synthase, the enzyme that makes it. These enzymes are regulated in a
reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating
phosphorylase. Insulin causes glycogen synthesis by activating protein
phosphatases and producing a decrease in the phosphorylation of these enzymes. [118]

Evolution[edit]
Further information: Molecular evolution and Phylogenetics
Evolutionary tree showing the common ancestry of organisms from all three domains of life. Bacteria are
colored blue, eukaryotes red, and archaea green. Relative positions of some of the phyla included are shown
around the tree.

The central pathways of metabolism described above, such as glycolysis and the citric
acid cycle, are present in all three domains of living things and were present in the last
universal common ancestor.[3][119] This universal ancestral cell was prokaryotic and
probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and
lipid metabolism.[120][121] The retention of these ancient pathways during
later evolution may be the result of these reactions having been an optimal solution to
their particular metabolic problems, with pathways such as glycolysis and the citric acid
cycle producing their end products highly efficiently and in a minimal number of steps. [4]
[5]
 The first pathways of enzyme-based metabolism may have been parts
of purine nucleotide metabolism, while previous metabolic pathways were a part of the
ancient RNA world.[122]
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.[123] 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. [124] 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)
[125]
 These recruitment processes result in an evolutionary enzymatic mosaic. [126] 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. [127]
As well as the evolution of new metabolic pathways, evolution can also cause the loss
of metabolic functions. For example, in some parasites metabolic processes that are not
essential for survival are lost and preformed amino acids, nucleotides and
carbohydrates may instead be scavenged from the host.[128] Similar reduced metabolic
capabilities are seen in endosymbiotic organisms.[129]

Investigation and manipulation[edit]

Further information: Protein methods, Proteomics, Metabolomics, and Metabolic
network modelling

Metabolic network of the Arabidopsis thaliana citric acid cycle. Enzymes and metabolites are shown as red

squares and the interactions between them as black lines.

Classically, metabolism is studied by a reductionist approach that focuses on a single

metabolic pathway. Particularly valuable is the use of radioactive tracers at the whole-
organism, tissue and cellular levels, which define the paths from precursors to final
products by identifying radioactively labelled intermediates and products. [130] The
enzymes that catalyze these chemical reactions can then be purified and
their kinetics and responses to inhibitors investigated. A parallel approach is to identify
the small molecules in a cell or tissue; the complete set of these molecules is called
the metabolome. Overall, these studies give a good view of the structure and function of
simple metabolic pathways, but are inadequate when applied to more complex systems
such as the metabolism of a complete cell. [131]
An idea of the complexity of the metabolic networks in cells that contain thousands of
different enzymes is given by the figure showing the interactions between just 43
proteins and 40 metabolites to the right: the sequences of genomes provide lists
containing anything up to 26.500 genes.[132] 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. [133] 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.[134] Using these techniques, a
model of human metabolism has now been produced, which will guide future drug
discovery and biochemical research.[135] These models are now used in network analysis,
to classify human diseases into groups that share common proteins or metabolites. [136][137]
Bacterial metabolic networks are a striking example of bow-tie[138][139][140] organization, an
architecture able to input a wide range of nutrients and produce a large variety of
products and complex macromolecules using a relatively few intermediate common
currencies.
A major technological application of this information is metabolic engineering. Here,
organisms such as yeast, plants or bacteria are genetically modified to make them more
useful in biotechnology and aid the production of drugs such as antibiotics or industrial
chemicals such as 1,3-propanediol and shikimic acid.[141] These genetic modifications
usually aim to reduce the amount of energy used to produce the product, increase
yields and reduce the production of wastes. [142]

History[edit]
Further information: History of biochemistry and History of molecular biology
The term metabolism is derived from French "métabolisme" or Ancient Greek μεταβολή
– "Metabole" for "a change" which derived from μεταβάλλ –"Metaballein" means "To
change"[143]

Aristotle's metabolism as an open flow model

Greek philosophy[edit]
Aristotle's The Parts of Animals sets out enough details of his views on metabolism for
an open flow model to be made. He believed that at each stage of the process,
materials from food were transformed, with heat being released as the classical
element of fire, and residual materials being excreted as urine, bile, or faeces. [144]
Islamic medicine[edit]
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." [145]
Application of the scientific method[edit]
The history of the scientific study of metabolism spans several centuries and has moved
from examining whole animals in early studies, to examining individual metabolic
reactions in modern biochemistry. The first controlled experiments in human metabolism
were published by Santorio Santorio in 1614 in his book Ars de statica medicina.[146] 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, from Ars de statica medicina, first published 1614

In these early studies, the mechanisms of these metabolic processes had not been
identified and a vital force was thought to animate living tissue.[147] In the 19th century,
when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded
that fermentation was catalyzed by substances within the yeast cells he called
"ferments". He wrote that "alcoholic fermentation is an act correlated with the life and
organization of the yeast cells, not with the death or putrefaction of the cells." [148] This
discovery, along with the publication by Friedrich Wöhler in 1828 of a paper on the
chemical synthesis of urea,[149] and is notable for being the first organic compound
prepared from wholly inorganic precursors. This proved that the organic compounds
and chemical reactions found in cells were no different in principle than any other part of
chemistry.
It was the discovery of enzymes at the beginning of the 20th century by Eduard
Buchner that separated the study of the chemical reactions of metabolism from the
biological study of cells, and marked the beginnings of biochemistry.[150] The mass of
biochemical knowledge grew rapidly throughout the early 20th century. One of the most
prolific of these modern biochemists was Hans Krebs who made huge contributions to
the study of metabolism.[151] He discovered the urea cycle and later, working with Hans
Kornberg, the citric acid cycle and the glyoxylate cycle.[152][74] Modern biochemical
research has been greatly aided by the development of new techniques such
as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic
labelling, electron microscopy and molecular dynamics simulations. These techniques
have allowed the discovery and detailed analysis of the many molecules and metabolic
pathways in cells.

See also[edit]
 Metabolism portal

 Anthropogenic metabolism
 Antimetabolite
 Basal metabolic rate
 Calorimetry – Thermodynamic state measurement
 Isothermal microcalorimetry
 Inborn errors of metabolism
 Iron–sulfur world hypothesis – Hypothetical scenario for the origin of life, a
"metabolism first" theory of the origin of life
 Metabolic disorder
 Microphysiometry
 Primary nutritional groups
 Respirometry – Estimation of metabolic rates by measuring heat production
 Stream metabolism
 Sulfur metabolism
 Thermic effect of food
 Urban metabolism
 Water metabolism
 Overflow metabolism
 Reactome
 KEGG

Referenc