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A cofactor is a non-
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...
or metallic ion that is required for an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
's role as a
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
(a catalyst is a substance that increases the rate of a
chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking ...
). Cofactors can be considered "helper molecules" that assist in
biochemical Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology an ...
transformations. The rates at which these happen are characterized in an area of study called
enzyme kinetics Enzyme kinetics is the study of the rates of enzyme-catalysed chemical reactions. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction are investigated. Studying an enzyme's kinetics in thi ...
. Cofactors typically differ from
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
in that they often derive their function by remaining bound. Cofactors can be divided into two types: inorganic ions and complex
organic molecule In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
s called coenzymes. Coenzymes are mostly derived from
vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
s and other organic
essential nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excre ...
s in small amounts. (Note that some scientists limit the use of the term "cofactor" for inorganic substances; both types are included here.) Coenzymes are further divided into two types. The first is called a "prosthetic group", which consists of a coenzyme that is tightly (or even covalently) and permanently bound to a protein. The second type of coenzymes are called "cosubstrates", and are transiently bound to the protein. Cosubstrates may be released from a protein at some point, and then rebind later. Both prosthetic groups and cosubstrates have the same function, which is to facilitate the reaction of enzymes and proteins. An inactive enzyme without the cofactor is called an
apoenzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
, while the complete enzyme with cofactor is called a
holoenzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
. (Note that the International Union of Pure and Applied Chemistry (IUPAC) defines "coenzyme" a little differently, namely as a low-molecular-weight, non-protein organic compound that is loosely attached, participating in enzymatic reactions as a dissociable carrier of chemical groups or electrons; a prosthetic group is defined as a tightly bound, nonpolypeptide unit in a protein that is regenerated in each enzymatic turnover.) Some enzymes or enzyme complexes require several cofactors. For example, the multienzyme complex
pyruvate dehydrogenase Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate. Pyruvate dehydrogenase is u ...
at the junction of
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
and the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prot ...
requires five organic cofactors and one metal ion: loosely bound
thiamine pyrophosphate Thiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. Thiamine pyrophosphate is a cofactor that is present in all liv ...
(TPP), covalently bound
lipoamide Lipoamide is a trivial name for 6,8-dithiooctanoic amide. It is the functional form of lipoic acid, i.e the carboxyl group is attached to protein via an amine with an amide linkage. Illustrative of the biochemical role of lipoamide is in the conv ...
and
flavin adenine dinucleotide Flavin may refer to: Placename * Flavin, Aveyron, a commune in southern France Surname * Adrian Flavin (born 1979), a professional rugby player * Christopher Flavin, president of the Worldwatch Institute * Dan Flavin (1933–1996), a minimalis ...
(FAD), cosubstrates
nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
(NAD+) and
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
(CoA), and a metal ion (Mg2+). Organic cofactors are often
vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
s or made from vitamins. Many contain the
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
adenosine monophosphate Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine; it is an ester of phosphoric acid and the nucleoside adenosine. As a substit ...
(AMP) as part of their structures, such as ATP,
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
, FAD, and NAD+. This common structure may reflect a common evolutionary origin as part of
ribozyme Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demons ...
s in an ancient
RNA world The RNA world is a hypothetical stage in the evolutionary history of life on Earth, in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existen ...
. It has been suggested that the AMP part of the molecule can be considered to be a kind of "handle" by which the enzyme can "grasp" the coenzyme to switch it between different catalytic centers.


Classification

Cofactors can be divided into two major groups: organic cofactors, such as flavin or
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
; and inorganic cofactors, such as the metal ions Mg2+, Cu+, Mn2+ and iron–sulfur clusters. Organic cofactors are sometimes further divided into ''coenzymes'' and ''
prosthetic group A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein. Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
s''. The term coenzyme refers specifically to enzymes and, as such, to the functional properties of a protein. On the other hand, "prosthetic group" emphasizes the nature of the binding of a cofactor to a protein (tight or covalent) and, thus, refers to a structural property. Different sources give slightly different definitions of coenzymes, cofactors, and prosthetic groups. Some consider tightly bound organic molecules as prosthetic groups and not as coenzymes, while others define all non-protein organic molecules needed for enzyme activity as coenzymes, and classify those that are tightly bound as coenzyme prosthetic groups. These terms are often used loosely. A 1980 letter in ''Trends in Biochemistry Sciences'' noted the confusion in the literature and the essentially arbitrary distinction made between prosthetic groups and coenzymes group and proposed the following scheme. Here, cofactors were defined as an additional substance apart from protein and substrate that is required for enzyme activity and a prosthetic group as a substance that undergoes its whole
catalytic cycle In chemistry, a catalytic cycle is a multistep reaction mechanism that involves a catalyst. The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, bioinorganic chemistry, materials s ...
attached to a single enzyme molecule. However, the author could not arrive at a single all-encompassing definition of a "coenzyme" and proposed that this term be dropped from use in the literature.


Inorganic cofactors


Metal ions

Metal A metal (from ancient Greek, Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electrical resistivity and conductivity, e ...
ions are common cofactors. The study of these cofactors falls under the area of
bioinorganic chemistry Bioinorganic chemistry is a field that examines the role of metals in biology. Bioinorganic chemistry includes the study of both natural phenomena such as the behavior of metalloproteins as well as artificially introduced metals, including those t ...
. In
nutrition Nutrition is the biochemical and physiological process by which an organism uses food to support its life. It provides organisms with nutrients, which can be metabolized to create energy and chemical structures. Failure to obtain sufficient ...
, the list of essential
trace element __NOTOC__ A trace element, also called minor element, is a chemical element whose concentration (or other measure of amount) is very low (a "trace amount"). They are classified into two groups: essential and non-essential. Essential trace elements ...
s reflects their role as cofactors. In humans this list commonly includes
iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in ...
,
magnesium Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ...
,
manganese Manganese is a chemical element with the Symbol (chemistry), symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of ...
,
cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...
,
copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pink ...
,
zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
, and
molybdenum Molybdenum is a chemical element with the symbol Mo and atomic number 42 which is located in period 5 and group 6. The name is from Neo-Latin ''molybdaenum'', which is based on Ancient Greek ', meaning lead, since its ores were confused with lead ...
. Although
chromium Chromium is a chemical element with the symbol Cr and atomic number 24. It is the first element in group 6. It is a steely-grey, lustrous, hard, and brittle transition metal. Chromium metal is valued for its high corrosion resistance and hard ...
deficiency causes
impaired glucose tolerance Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesit ...
, no human enzyme that uses this metal as a cofactor has been identified.
Iodine Iodine is a chemical element with the Symbol (chemistry), symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , ...
is also an essential trace element, but this element is used as part of the structure of
thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 386 25 ...
s rather than as an enzyme cofactor.
Calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
is another special case, in that it is required as a component of the human diet, and it is needed for the full activity of many enzymes, such as
nitric oxide synthase Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and perist ...
, protein phosphatases, and
adenylate kinase Adenylate kinase ( ECbr>2.7.4.3 (also known as ADK or myokinase) is a phosphotransferase enzyme that catalyzes the interconversion of the various adenosine phosphates (ATP, ADP, and AMP). By constantly monitoring phosphate nucleotide levels inside ...
, but calcium activates these enzymes in
allosteric regulation In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric sit ...
, often binding to these enzymes in a complex with
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bin ...
. Calcium is, therefore, a
cell signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
molecule, and not usually considered a cofactor of the enzymes it regulates. Other organisms require additional metals as enzyme cofactors, such as
vanadium Vanadium is a chemical element with the symbol V and atomic number 23. It is a hard, silvery-grey, malleable transition metal. The elemental metal is rarely found in nature, but once isolated artificially, the formation of an oxide layer ( pass ...
in the
nitrogenase Nitrogenases are enzymes () that are produced by certain bacteria, such as cyanobacteria (blue-green bacteria) and rhizobacteria. These enzymes are responsible for the reduction of nitrogen (N2) to ammonia (NH3). Nitrogenases are the only fa ...
of the nitrogen-fixing bacteria of the genus ''
Azotobacter ''Azotobacter'' is a genus of usually motile, oval or spherical bacteria that form thick-walled cysts (and also has hard crust) and may produce large quantities of capsular slime. They are aerobic, free-living soil microbes that play an impo ...
'',
tungsten Tungsten, or wolfram, is a chemical element with the symbol W and atomic number 74. Tungsten is a rare metal found naturally on Earth almost exclusively as compounds with other elements. It was identified as a new element in 1781 and first isol ...
in the
aldehyde ferredoxin oxidoreductase In enzymology, an aldehyde ferredoxin oxidoreductase () is an enzyme that catalyzes the chemical reaction :an aldehyde + H2O + 2 oxidized ferredoxin an acid + 2 H+ + 2 reduced ferredoxin This enzyme belongs to the family of oxidoreductases, sp ...
of the thermophilic
archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...
n ''
Pyrococcus furiosus ''Pyrococcus furiosus'' is a heterotrophic, strictly anaerobic, extremophilic, model species of archaea. It is classified as a hyperthermophile because it thrives best under extremely high temperatures, and is notable for having an optimum gr ...
'', and even
cadmium Cadmium is a chemical element with the Symbol (chemistry), symbol Cd and atomic number 48. This soft, silvery-white metal is chemically similar to the two other stable metals in group 12 element, group 12, zinc and mercury (element), mercury. Li ...
in the
carbonic anhydrase The carbonic anhydrases (or carbonate dehydratases) () form a family of enzymes that catalyze the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid (i.e. bicarbonate and hydrogen ions). The active sit ...
from the marine
diatom A diatom ( Neo-Latin ''diatoma''), "a cutting through, a severance", from el, διάτομος, diátomos, "cut in half, divided equally" from el, διατέμνω, diatémno, "to cut in twain". is any member of a large group comprising se ...
''
Thalassiosira weissflogii ''Thalassiosira weissflogii'' is a species of centric diatoms, a unicellular microalga. It is found in marine environments and also in inland waters in many parts of the world. It is actively studied because it may use C4-plant style strategies ...
''. In many cases, the cofactor includes both an inorganic and organic component. One diverse set of examples is the
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
proteins, which consist of a
porphyrin Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
ring coordinated to
iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in ...
.


Iron–sulfur clusters

Iron–sulfur clusters are complexes of iron and sulfur atoms held within proteins by cysteinyl residues. They play both structural and functional roles, including electron transfer, redox sensing, and as structural modules.


Organic

Organic cofactors are small organic molecules (typically a molecular mass less than 1000 Da) that can be either loosely or tightly bound to the enzyme and directly participate in the reaction. In the latter case, when it is difficult to remove without denaturing the enzyme, it can be called a
prosthetic group A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein. Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
. It is important to emphasize that there is no sharp division between loosely and tightly bound cofactors. Indeed, many such as NAD+ can be tightly bound in some enzymes, while it is loosely bound in others. Another example is
thiamine pyrophosphate Thiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. Thiamine pyrophosphate is a cofactor that is present in all liv ...
(TPP), which is tightly bound in
transketolase Transketolase (abbreviated as TK) is an enzyme that is encoded by the TKT gene. It participates in both the pentose phosphate pathway in all organisms and the Calvin cycle of photosynthesis. Transketolase catalyzes two important reactions, whic ...
or
pyruvate decarboxylase Pyruvate decarboxylase is an enzyme () that catalyses the decarboxylation of pyruvic acid to acetaldehyde. It is also called 2-oxo-acid carboxylase, alpha-ketoacid carboxylase, and pyruvic decarboxylase. In anaerobic conditions, this enzyme is ...
, while it is less tightly bound in
pyruvate dehydrogenase Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate. Pyruvate dehydrogenase is u ...
. Other coenzymes,
flavin adenine dinucleotide Flavin may refer to: Placename * Flavin, Aveyron, a commune in southern France Surname * Adrian Flavin (born 1979), a professional rugby player * Christopher Flavin, president of the Worldwatch Institute * Dan Flavin (1933–1996), a minimalis ...
(FAD),
biotin Biotin (or vitamin B7) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. The name ''biotin'', bo ...
, and
lipoamide Lipoamide is a trivial name for 6,8-dithiooctanoic amide. It is the functional form of lipoic acid, i.e the carboxyl group is attached to protein via an amine with an amide linkage. Illustrative of the biochemical role of lipoamide is in the conv ...
, for instance, are tightly bound. Tightly bound cofactors are, in general, regenerated during the same reaction cycle, while loosely bound cofactors can be regenerated in a subsequent reaction catalyzed by a different enzyme. In the latter case, the cofactor can also be considered a substrate or cosubstrate.
Vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
s can serve as precursors to many organic cofactors (e.g., vitamins B1, B2, B6, B12,
niacin Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variet ...
,
folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...
) or as coenzymes themselves (e.g.,
vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...
). However, vitamins do have other functions in the body. Many organic cofactors also contain a
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
, such as the electron carriers NAD and FAD, and
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
, which carries
acyl In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...
groups. Most of these cofactors are found in a huge variety of species, and some are universal to all forms of life. An exception to this wide distribution is a group of unique cofactors that evolved in
methanogen Methanogens are microorganisms that produce methane as a metabolic byproduct in hypoxic conditions. They are prokaryotic and belong to the domain Archaea. All known methanogens are members of the archaeal phylum Euryarchaeota. Methanogens are c ...
s, which are restricted to this group of
archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...
.


Vitamins and derivatives


Non-vitamins


Cofactors as metabolic intermediates

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 In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the r ...
s. 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 the loosely bound organic cofactors, often called coenzymes. Each class of group-transfer reaction is carried out by a particular cofactor, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. An example of this are the
dehydrogenase A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as ...
s that use
nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
(NAD+) as a cofactor. Here, hundreds of separate types of enzymes remove electrons from their substrates and reduce NAD+ to NADH. This reduced cofactor is then a substrate for any of the
reductase A reductase is an enzyme that catalyzes a reduction reaction. Examples * 5α-Reductase * 5β-Reductase * Dihydrofolate reductase * HMG-CoA reductase * Methemoglobin reductase * Ribonucleotide reductase * Thioredoxin reductase * ''E. coli' ...
s in the cell that require electrons to reduce their substrates. Therefore, these cofactors are continuously recycled as part of
metabolism Metabolism (, from 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 ...
. As an example, the total quantity of ATP in the human body is about 0.1  mole. This ATP is constantly being broken down into ADP, and then converted back into ATP. Thus, at any given time, the total amount of ATP + ADP remains fairly constant. The energy used by human cells requires the
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...
of 100 to 150 moles of ATP daily, which is around 50 to 75 kg. In typical situations, humans use up their body weight of ATP over the course of the day. This means that each ATP molecule is recycled 1000 to 1500 times daily.


Evolution

Organic cofactors, such as ATP and
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
, are present in all known forms of life and form a core part of
metabolism Metabolism (, from 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 ...
. Such universal
conservation Conservation is the preservation or efficient use of resources, or the conservation of various quantities under physical laws. Conservation may also refer to: Environment and natural resources * Nature conservation, the protection and manageme ...
indicates that these molecules evolved very early in the development of living things. At least some of the current set of cofactors may, therefore, have been present in the
last universal ancestor The last universal common ancestor (LUCA) is the most recent population from which all organisms now living on Earth share common descent—the most recent common ancestor of all current life on Earth. This includes all cellular organisms; th ...
, which lived about 4 billion years ago. Organic cofactors may have been present even earlier in the
history of life The history of life on Earth traces the processes by which living and fossil organisms evolved, from the earliest emergence of life to present day. Earth formed about 4.5 billion years ago (abbreviated as ''Ga'', for ''gigaannum'') and evide ...
on Earth. The nucleotide
adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside building ...
is present in cofactors that catalyse many basic metabolic reactions such as methyl, acyl, and phosphoryl group transfer, as well as
redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...
reactions. This ubiquitous chemical scaffold has, therefore, been proposed to be a remnant of the
RNA world The RNA world is a hypothetical stage in the evolutionary history of life on Earth, in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existen ...
, with early
ribozyme Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demons ...
s evolving to bind a restricted set of nucleotides and related compounds. Adenosine-based cofactors are thought to have acted as interchangeable adaptors that allowed enzymes and ribozymes to bind new cofactors through small modifications in existing adenosine-binding
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function ** Natural domain of a partial function **Domain of holomorphy of a function * ...
s, which had originally evolved to bind a different cofactor. This process of adapting a pre-evolved structure for a novel use is known as ''
exaptation Exaptation and the related term co-option describe a shift in the function of a trait during evolution. For example, a trait can evolve because it served one particular function, but subsequently it may come to serve another. Exaptations are common ...
''. A computational method, IPRO, recently predicted mutations that experimentally switched the cofactor specificity of Candida boidinii xylose reductase from NADPH to NADH.


History

The first organic cofactor to be discovered was NAD+, which was identified by Arthur Harden and William Young 1906. They noticed that adding boiled and filtered
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constit ...
extract greatly accelerated alcoholic fermentation in unboiled yeast extracts. They called the unidentified factor responsible for this effect a ''coferment''. Through a long and difficult purification from yeast extracts, this heat-stable factor was identified as a
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
sugar phosphate by
Hans von Euler-Chelpin Hans Karl August Simon von Euler-Chelpin (15 February 1873 – 6 November 1964) was a German-born Swedish biochemist. He won the Nobel Prize in Chemistry in 1929 with Arthur Harden for their investigations on the fermentation of sugar and enzy ...
. Other cofactors were identified throughout the early 20th century, with ATP being isolated in 1929 by Karl Lohmann, and coenzyme A being discovered in 1945 by
Fritz Albert Lipmann Fritz Albert Lipmann (; June 12, 1899 – July 24, 1986) was a German-American biochemist and a co-discoverer in 1945 of coenzyme A. For this, together with other research on coenzyme A, he was awarded the Nobel Prize in Physiology or Medicine in ...
. The functions of these molecules were at first mysterious, but, in 1936, Otto Heinrich Warburg identified the function of NAD+ in hydride transfer. This discovery was followed in the early 1940s by the work of
Herman Kalckar Herman Moritz Kalckar (26 March 1908 – 17 May 1991) was a Danish biochemist who pioneered the study of cellular respiration. Kalckar made a number of significant contributions to the development of 20th century biochemistry including: * a founder ...
, who established the link between the oxidation of sugars and the generation of ATP. This confirmed the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941. Later, in 1949, Morris Friedkin and
Albert L. Lehninger Albert Lester Lehninger (February 17, 1917 – March 4, 1986) was an American biochemist in the field of bioenergetics. He made fundamental contributions to the current understanding of metabolism at a molecular level. In 1948, he discovered, wit ...
proved that NAD+ linked metabolic pathways such as the citric acid cycle and the synthesis of ATP.


Protein-derived cofactors

In a number of enzymes, the moiety that acts as a cofactor is formed by post-translational modification of a part of the protein sequence. This often replaces the need for an external binding factor, such as a metal ion, for protein function. Potential modifications could be oxidation of aromatic residues, binding between residues, cleavage or ring-forming. These alterations are distinct from other post-translation protein modifications, such as
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
, methylation, or glycosylation in that the amino acids typically acquire new functions. This increases the functionality of the protein; unmodified amino acids are typically limited to acid-base reactions, and the alteration of resides can give the protein electrophilic sites or the ability to stabilize free radicals. Examples of cofactor production include tryptophan tryptophylquinone (TTQ), derived from two tryptophan side chains, and 4-methylidene-imidazole-5-one (MIO), derived from an Ala-Ser-Gly motif. Characterization of protein-derived cofactors is conducted using
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
and mass spectroscopy; structural data is necessary because sequencing does not readily identify the altered sites.


Non-enzymatic cofactors

The term is used in other areas of biology to refer more broadly to non-protein (or even protein) molecules that either activate, inhibit, or are required for the protein to function. For example,
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
such as
hormones A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
that bind to and activate receptor proteins are termed cofactors or coactivators, whereas molecules that inhibit receptor proteins are termed corepressors. One such example is the G protein-coupled receptor family of receptors, which are frequently found in sensory neurons. Ligand binding to the receptors activates the G protein, which then activates an enzyme to activate the effector. In order to avoid confusion, it has been suggested that such proteins that have ligand-binding mediated activation or repression be referred to as coregulators.


See also

*
Enzyme catalysis Enzyme catalysis is the increase in the rate of a process by a biological molecule, an " enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, cal ...
*
Inorganic chemistry Inorganic chemistry deals with synthesis and behavior of inorganic and organometallic compounds. This field covers chemical compounds that are not carbon-based, which are the subjects of organic chemistry. The distinction between the two disci ...
*
Organometallic chemistry Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and s ...
* Bioorganometallic chemistry * Cofactor engineering


References


Further reading

*


External links


Cofactors lecture
(Powerpoint file) *
The CoFactor Database
{{DEFAULTSORT:Cofactor (Biochemistry) Enzymes