cofactor (biochemistry)

Cofactors can be divided into two major groups: organic cofactors, such as flavin or heme; 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 groups. 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 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.{{Cite journal |last=Bryce |date=March 1979 |title=SAM – semantics and misunderstandings |journal=Trends Biochem. Sci. |volume=4 |issue=3 |pages=N62–N63 |doi=10.1016/0968-0004(79)90255-X}}

{{Further|Metalloprotein}}

Metal ions are common cofactors.{{Cite web |url=http://vle.du.ac.in/mod/book/view.php?id=13511&chapterid=30165 |title=Biochemistry: Enzymes: Classification and catalysis (Cofactors) |website=vle.du.ac.in |access-date=2018-02-07 }}{{Dead link|date=July 2020 |bot=InternetArchiveBot |fix-attempted=yes }} The study of these cofactors falls under the area of bioinorganic chemistry. In nutrition, the list of essential trace elements reflects their role as cofactors. In humans this list commonly includes iron, magnesium, manganese, cobalt, copper, zinc, and molybdenum.{{Cite journal |vauthors=Aggett PJ |date=August 1985 |title=Physiology and metabolism of essential trace elements: an outline |journal=Clinics in Endocrinology and Metabolism |volume=14 |issue=3 |pages=513–43 |doi=10.1016/S0300-595X(85)80005-0 |pmid=3905079}} Although chromium deficiency causes impaired glucose tolerance, no human enzyme that uses this metal as a cofactor has been identified.{{Cite journal |vauthors=Stearns DM |year=2000 |title=Is chromium a trace essential metal? |journal=BioFactors |volume=11 |issue=3 |pages=149–62 |doi=10.1002/biof.5520110301 |pmid=10875302|s2cid=19417496 }}{{Cite journal |vauthors=Vincent JB |date=April 2000 |title=The biochemistry of chromium |journal=The Journal of Nutrition |volume=130 |issue=4 |pages=715–8 |doi=10.1093/jn/130.4.715 |pmid=10736319 |doi-access=free}} Iodine is also an essential trace element, but this element is used as part of the structure of thyroid hormones rather than as an enzyme cofactor.{{Cite journal |vauthors=Cavalieri RR |date=April 1997 |title=Iodine metabolism and thyroid physiology: current concepts |journal=Thyroid |volume=7 |issue=2 |pages=177–81 |doi=10.1089/thy.1997.7.177 |pmid=9133680}} Calcium 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, protein phosphatases, and adenylate kinase, but calcium activates these enzymes in allosteric regulation, often binding to these enzymes in a complex with calmodulin.{{Cite journal |vauthors=Clapham DE |year=2007 |title=Calcium signaling |journal=Cell |volume=131 |issue=6 |pages=1047–58 |doi=10.1016/j.cell.2007.11.028 |pmid=18083096|s2cid=15087548 |doi-access=free }} Calcium is, therefore, a cell signaling ion, and not usually considered a cofactor of the enzymes it regulates.{{Cite journal |vauthors=Niki I, Yokokura H, Sudo T, Kato M, Hidaka H |date=October 1996 |title=Ca2+ signaling and intracellular Ca2+ binding proteins |journal=Journal of Biochemistry |volume=120 |issue=4 |pages=685–98 |doi=10.1093/oxfordjournals.jbchem.a021466 |pmid=8947828}}

Other organisms require additional metals as enzyme cofactors, such as vanadium in the nitrogenase of the nitrogen-fixing bacteria of the genus Azotobacter,{{Cite journal |vauthors=Eady RR |date=July 1988 |title=The vanadium-containing nitrogenase of Azotobacter |journal=BioFactors |volume=1 |issue=2 |pages=111–6 |pmid=3076437}} tungsten in the aldehyde ferredoxin oxidoreductase of the thermophilic archaean Pyrococcus furiosus,{{Cite journal |vauthors=Chan MK, Mukund S, Kletzin A, Adams MW, Rees DC |date=March 1995 |title=Structure of a hyperthermophilic tungstopterin enzyme, aldehyde ferredoxin oxidoreductase |journal=Science |volume=267 |issue=5203 |pages=1463–9 |bibcode=1995Sci...267.1463C |doi=10.1126/science.7878465 |pmid=7878465|s2cid=20868012 }} and even cadmium in the carbonic anhydrase from the marine diatom Thalassiosira weissflogii.{{Cite journal |vauthors=Lane TW, Morel FM |date=April 2000 |title=A biological function for cadmium in marine diatoms |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=9 |pages=4627–31 |bibcode=2000PNAS...97.4627L |doi=10.1073/pnas.090091397 |pmc=18283 |pmid=10781068|doi-access=free }}{{Cite journal |vauthors=Lane TW, Saito MA, George GN, Pickering IJ, Prince RC, Morel FM |year=2005 |title=Biochemistry: a cadmium enzyme from a marine diatom |journal=Nature |volume=435 |issue=7038 |page=42 |bibcode=2005Natur.435...42L |doi=10.1038/435042a |pmid=15875011|s2cid=52819760 |doi-access=free }}

In many cases, the cofactor includes both an inorganic and organic component. One diverse set of examples is the heme proteins, which consist of a porphyrin ring coordinated to iron.{{Cite journal |vauthors=Li T, Bonkovsky HL, Guo JT |date=March 2011 |title=Structural analysis of heme proteins: implications for design and prediction |journal=BMC Structural Biology |volume=11 |pages=13 |doi=10.1186/1472-6807-11-13 |pmc=3059290 |pmid=21371326 |doi-access=free }}

File:2Fe2S.png

{{Further|Iron–sulfur protein}}

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.{{Cite journal |vauthors=Meyer J |date=February 2008 |title=Iron-sulfur protein folds, iron-sulfur chemistry, and evolution |journal=J. Biol. Inorg. Chem. |volume=13 |issue=2 |pages=157–70 |doi=10.1007/s00775-007-0318-7 |pmid=17992543|s2cid=21961142 }}

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.{{Cite book |last=Palmer |first=Trevor |url=https://archive.org/details/understandingenz0000palm |title=Understanding enzymes |publisher=Horwood |year=1981 |isbn=978-0-85312-307-1 |location=New York |name-list-style=vanc |url-access=registration}}{{Cite book |last1=Cox |first1=Michael |url=https://archive.org/details/lehningerprincip01lehn |title=Lehninger principles of biochemistry |last2=Lehninger |first2=Albert L |last3=Nelson |first3=David R. |publisher=Worth Publishers |year=2000 |isbn=978-1-57259-153-0 |edition=3rd |location=New York |name-list-style=vanc |url-access=registration}}{{Cite book |last1=Farrell |first1=Shawn O. |title=Biochemistry |last2=Campbell |first2=Mary K. |publisher=Brooks Cole |year=2009 |isbn=978-0-495-39041-1 |edition=6th |location=Pacific Grove |name-list-style=vanc}} In the latter case, when it is difficult to remove without denaturing the enzyme, it can be called a prosthetic group. There is no sharp division between loosely and tightly bound cofactors. Many such as NAD⁺ can be tightly bound in some enzymes, while it is loosely bound in others. Another example is thiamine pyrophosphate (TPP), which is tightly bound in transketolase or pyruvate decarboxylase, while it is less tightly bound in pyruvate dehydrogenase.{{Cite journal |vauthors=Morey AV, Juni E |date=June 1968 |title=Studies on the nature of the binding of thiamine pyrophosphate to enzymes |url=http://www.jbc.org/content/243/11/3009 |journal=The Journal of Biological Chemistry |volume=243 |issue=11 |pages=3009–19 |doi=10.1016/S0021-9258(18)93372-7 |pmid=4968184|doi-access=free }} Other coenzymes, flavin adenine dinucleotide (FAD), biotin, and lipoamide, for instance, are tightly bound.{{Cite journal |vauthors=Hanukoglu I |date=December 2017 |title=Conservation of the Enzyme–Coenzyme Interfaces in FAD and NADP Binding Adrenodoxin Reductase-A Ubiquitous Enzyme |journal=Journal of Molecular Evolution |volume=85 |issue=5–6 |pages=205–218 |bibcode=2017JMolE..85..205H |doi=10.1007/s00239-017-9821-9 |pmid=29177972|s2cid=7120148 }} 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.

Vitamins can serve as precursors to many organic cofactors (e.g., vitamins B₁, B₂, B₆, B₁₂, niacin, folic acid) or as coenzymes themselves (e.g., vitamin C). However, vitamins do have other functions in the body.{{Cite journal |vauthors=Bolander FF |year=2006 |title=Vitamins: not just for enzymes |journal=Curr Opin Investig Drugs |volume=7 |issue=10 |pages=912–5 |pmid=17086936}} Many organic cofactors also contain a nucleotide, such as the electron carriers NAD and FAD, and coenzyme A, which carries acyl 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 methanogens, which are restricted to this group of archaea.{{Cite journal |vauthors=Rouvière PE, Wolfe RS |date=June 1988 |title=Novel biochemistry of methanogenesis |journal=The Journal of Biological Chemistry |volume=263 |issue=17 |pages=7913–6 |doi=10.1016/S0021-9258(18)68417-0 |pmid=3131330 |doi-access=free }}

File:NAD oxidation reduction.svg reactions of nicotinamide adenine dinucleotide.]]

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.{{Cite journal |vauthors=Mitchell P |date=March 1979 |title=The Ninth Sir Hans Krebs Lecture. Compartmentation and communication in living systems. Ligand conduction: a general catalytic principle in chemical, osmotic and chemiosmotic reaction systems |journal=European Journal of Biochemistry |volume=95 |issue=1 |pages=1–20 |doi=10.1111/j.1432-1033.1979.tb12934.x |pmid=378655|doi-access=free }} This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.{{Cite journal |vauthors=Wimmer MJ, Rose IA |year=1978 |title=Mechanisms of enzyme-catalyzed group transfer reactions |journal=Annual Review of Biochemistry |volume=47 |pages=1031–78 |doi=10.1146/annurev.bi.47.070178.005123 |pmid=354490}} 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 dehydrogenases that use nicotinamide adenine dinucleotide (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 reductases in the cell that require electrons to reduce their substrates.{{Cite journal |vauthors=Pollak N, Dölle C, Ziegler M |year=2007 |title=The power to reduce: pyridine nucleotides—small molecules with a multitude of functions |journal=Biochem. J. |volume=402 |issue=2 |pages=205–18 |doi=10.1042/BJ20061638 |pmc=1798440 |pmid=17295611}}

Therefore, these cofactors are continuously recycled as part of metabolism. 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 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.{{Cite journal |vauthors=Di Carlo SE, Collins HL |year=2001 |title=Estimating ATP resynthesis during a marathon run: a method to introduce metabolism |url=http://advan.physiology.org/cgi/content/full/25/2/70 |journal=Advan. Physiol. Edu. |volume=25 |issue=2 |pages=70–1}} This means that each ATP molecule is recycled 1000 to 1500 times daily.

{{Further|Abiogenesis}}

Organic cofactors, such as ATP and NADH, are present in all known forms of life and form a core part of metabolism. Such universal conservation indicates that these molecules evolved very early in the development of living things.{{Cite journal |vauthors=Chen X, Li N, Ellington AD |year=2007 |title=Ribozyme catalysis of metabolism in the RNA world |journal=Chemistry & Biodiversity |volume=4 |issue=4 |pages=633–55 |doi=10.1002/cbdv.200790055 |pmid=17443876|s2cid=44873410 }} At least some of the current set of cofactors may, therefore, have been present in the last universal ancestor, which lived about 4 billion years ago.{{Cite book |title=How did bacteria come to be? |vauthors=Koch AL |series=Advances in Microbial Physiology |year=1998 |isbn=9780120277407 |volume=40 |pages=353–99 |doi=10.1016/S0065-2911(08)60135-6 |pmid=9889982}}{{Cite journal |vauthors=Ouzounis C, Kyrpides N |date=July 1996 |title=The emergence of major cellular processes in evolution |journal=FEBS Letters |volume=390 |issue=2 |pages=119–23 |doi=10.1016/0014-5793(96)00631-X |pmid=8706840|s2cid=39128865 |doi-access=free |bibcode=1996FEBSL.390..119O }}

Organic cofactors may have been present even earlier in the history of life on Earth.{{Cite journal |vauthors=White HB |date=March 1976 |title=Coenzymes as fossils of an earlier metabolic state |journal=Journal of Molecular Evolution |volume=7 |issue=2 |pages=101–4 |bibcode=1976JMolE...7..101W |doi=10.1007/BF01732468 |pmid=1263263|s2cid=22282629 }} The nucleotide adenosine is a cofactor for many basic metabolic enzymes such as transferases. It may be a remnant of the RNA world.{{Cite journal |vauthors=Saran D, Frank J, Burke DH |year=2003 |title=The tyranny of adenosine recognition among RNA aptamers to coenzyme A |journal=BMC Evol. Biol. |volume=3 |pages=26 |doi=10.1186/1471-2148-3-26 |pmc=317284 |pmid=14687414 |doi-access=free }}{{Cite journal |vauthors=Jadhav VR, Yarus M |year=2002 |title=Coenzymes as coribozymes |journal=Biochimie |volume=84 |issue=9 |pages=877–88 |doi=10.1016/S0300-9084(02)01404-9 |pmid=12458080}} Adenosine-based cofactors may have acted as adaptors that allowed enzymes and ribozymes to bind new cofactors through small modifications in existing adenosine-binding domains, which had originally evolved to bind a different cofactor.{{Cite journal |vauthors=Denessiouk KA, Rantanen VV, Johnson MS |date=August 2001 |title=Adenine recognition: a motif present in ATP-, CoA-, NAD-, NADP-, and FAD-dependent proteins |journal=Proteins |volume=44 |issue=3 |pages=282–91 |doi=10.1002/prot.1093 |pmid=11455601|s2cid=10848692 }} This process of adapting a pre-evolved structure for a novel use is known as exaptation.

Prebiotic origin of coenzymes. Like amino acids and nucleotides, certain vitamins and thus coenzymes can be created under early earth conditions. For instance, vitamin B3 can be synthesized with electric discharges applied to ethylene and ammonia.{{Cite journal |last1=Dowler |first1=M. J. |last2=Fuller |first2=W. D. |last3=Orgel |first3=L. E. |last4=Sanchez |first4=R. A. |date=1970-09-25 |title=Prebiotic synthesis of propiolaldehyde and nicotinamide |url=https://pubmed.ncbi.nlm.nih.gov/4247738 |journal=Science |volume=169 |issue=3952 |pages=1320–1321 |doi=10.1126/science.169.3952.1320 |issn=0036-8075 |pmid=4247738|bibcode=1970Sci...169.1320D }} Similarly, pantetheine (a vitamin B5 derivative), a precursor of coenzyme A and thioester-dependent synthesis, can be formed spontaneously under evaporative conditions.{{Cite journal |last1=Keefe |first1=A. D. |last2=Newton |first2=G. L. |last3=Miller |first3=S. L. |date=1995-02-23 |title=A possible prebiotic synthesis of pantetheine, a precursor to coenzyme A |url=https://pubmed.ncbi.nlm.nih.gov/7854449 |journal=Nature |volume=373 |issue=6516 |pages=683–685 |doi=10.1038/373683a0 |issn=0028-0836 |pmid=7854449|bibcode=1995Natur.373..683K }} Other coenzymes may have existed early on Earth, such as pterins (a derivative of vitamin B9), flavins (FAD, flavin mononucleotide = FMN), and riboflavin (vitamin B2).{{Cite journal |last1=Monteverde |first1=D. R. |last2=Gómez-Consarnau |first2=L. |last3=Suffridge |first3=C. |last4=Sañudo-Wilhelmy |first4=S. A. |date=January 2017 |title=Life's utilization of B vitamins on early Earth |url=https://onlinelibrary.wiley.com/doi/10.1111/gbi.12202 |journal=Geobiology |language=en |volume=15 |issue=1 |pages=3–18 |doi=10.1111/gbi.12202 |pmid=27477998 |bibcode=2017Gbio...15....3M |issn=1472-4677|url-access=subscription }}

Changes in coenzymes. A computational method, IPRO, recently predicted mutations that experimentally switched the cofactor specificity of Candida boidinii xylose reductase from NADPH to NADH.{{Cite journal |vauthors=Khoury GA, Fazelinia H, Chin JW, Pantazes RJ, Cirino PC, Maranas CD |date=October 2009 |title=Computational design of Candida boidinii xylose reductase for altered cofactor specificity |journal=Protein Science |volume=18 |issue=10 |pages=2125–38 |doi=10.1002/pro.227 |pmc=2786976 |pmid=19693930}}

Evolution of enzymes without coenzymes. If enzymes require a co-enzyme, how does the coenzyme evolve? The most likely scenario is that enzymes can function initially without their coenzymes and later recruit the coenzyme, even if the catalyzed reaction may not be as efficient or as fast. Examples are Alcohol Dehydrogenase (coenzyme: NAD⁺),{{Cite book |url=https://link.springer.com/book/10.1007/b100340 |title=Comprehensive Enzyme Kinetics |date=2004 |language=en |doi=10.1007/b100340|isbn=0-306-46712-7 }} Lactate Dehydrogenase (NAD⁺),{{Cite book |last1=Garrett |first1=R. |title=Biochemistry |last2=Grisham |first2=Charles M. |date=2010 |publisher=Brooks/Cole, Cengage Learning |isbn=978-0-495-10935-8 |edition=4th |location=Belmont, CA}} Glutathione Reductase (NADPH).{{Citation |last1=Carlberg |first1=Inger |title=Glutamate, Glutamine, Glutathione, and Related Compounds |date=1985 |series=Methods in Enzymology |volume=113 |pages=484–490 |url=https://linkinghub.elsevier.com/retrieve/pii/S0076687985130624 |access-date=2024-09-21 |publisher=Elsevier |language=en |doi=10.1016/s0076-6879(85)13062-4 |isbn=978-0-12-182013-8 |last2=Mannervik |first2=Bengt|chapter=Glutathione reductase |pmid=3003504 |url-access=subscription }}

{{Further|History of biochemistry}}

The first organic cofactor to be discovered was NAD⁺, which was identified by Arthur Harden and William Young 1906.{{Cite journal |vauthors=Harden A, Young WJ |date=24 October 1906 |title=The Alcoholic Ferment of Yeast-Juice |journal=Proceedings of the Royal Society B: Biological Sciences |volume=78 |issue=526 |pages=369–75 |doi=10.1098/rspb.1906.0070 |doi-access=free}} They noticed that adding boiled and filtered yeast 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 sugar phosphate by Hans von Euler-Chelpin.{{Cite web |url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1929/euler-chelpin-lecture.pdf |title=Fermentation of sugars and fermentative enzymes: Nobel Lecture, May 23, 1930 |publisher=Nobel Foundation |access-date=2007-09-30}} Other cofactors were identified throughout the early 20th century, with ATP being isolated in 1929 by Karl Lohmann,{{Cite journal |last=Lohmann K |date=August 1929 |title=Über die Pyrophosphatfraktion im Muskel |journal=Naturwissenschaften |volume=17 |issue=31 |pages=624–5 |bibcode=1929NW.....17..624. |doi=10.1007/BF01506215|s2cid=20328411 }} and coenzyme A being discovered in 1945 by Fritz Albert Lipmann.{{Cite journal |last=Lipmann F |date=1 September 1945 |title=Acetylation of sulfanilamide by liver homogenates and extracts |journal=J. Biol. Chem. |volume=160 |issue=1 |pages=173–90 |doi=10.1016/S0021-9258(18)43110-9 |doi-access=free }}

The functions of these molecules were at first mysterious, but, in 1936, Otto Heinrich Warburg identified the function of NAD⁺ in hydride transfer.{{Cite journal |vauthors=Warburg O, Christian W |year=1936 |title=Pyridin, the hydrogen-transferring component of the fermentation enzymes (pyridine nucleotide) |journal=Biochemische Zeitschrift |volume=287 |pages=E79–E88 |doi=10.1002/hlca.193601901199}} This discovery was followed in the early 1940s by the work of Herman Kalckar, who established the link between the oxidation of sugars and the generation of ATP.{{Cite journal |vauthors=Kalckar HM |date=November 1974 |title=Origins of the concept oxidative phosphorylation |journal=Molecular and Cellular Biochemistry |volume=5 |issue=1–2 |pages=55–63 |doi=10.1007/BF01874172 |pmid=4279328|s2cid=26999163 }} This confirmed the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941.{{Cite book |last=Lipmann F |title=A Source Book in Chemistry, 1900-1950 |chapter=Metabolic generation and utilization of phosphate bond energy |series=Adv Enzymol |year=1941 |isbn=9780674366701 |volume=1 |pages=99–162 |doi=10.4159/harvard.9780674366701.c141}} Later, in 1949, Morris Friedkin and Albert L. Lehninger proved that NAD⁺ linked metabolic pathways such as the citric acid cycle and the synthesis of ATP.{{Cite journal |vauthors=Friedkin M, Lehninger AL |year=1949 |title=Esterification of inorganic phosphate coupled to electron transport between dihydrodiphosphopyridine nucleotide and oxygen |url=http://www.jbc.org/cgi/reprint/178/2/611 |journal=J. Biol. Chem. |volume=178 |issue=2 |pages=611–23 |doi=10.1016/S0021-9258(18)56879-4 |pmid=18116985|doi-access=free }}

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.{{cite journal | vauthors = Davidson VL| title = Protein-Derived Cofactors. Expanding the Scope of Post-Translational Modifications† | journal = Biochemistry | volume = 46 | issue = 18 | pages = 5283–5292 | pmid = 17439161 | doi = 10.1021/bi700468t | year=2007}} These alterations are distinct from other post-translation protein modifications, such as phosphorylation, 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,{{cite journal | vauthors = Davidson VL, Wilmot CM | title = Posttranslational biosynthesis of the protein-derived cofactor tryptophan tryptophylquinone | journal = Annual Review of Biochemistry | volume = 82 | pages = 531–50 | year = 2013 | pmid = 23746262 | pmc = 4082410 | doi = 10.1146/annurev-biochem-051110-133601 }} and 4-methylidene-imidazole-5-one (MIO), derived from an Ala-Ser-Gly motif.{{cite journal | vauthors = Huang SX, Lohman JR, Huang T, Shen B | title = A new member of the 4-methylideneimidazole-5-one-containing aminomutase family from the enediyne kedarcidin biosynthetic pathway | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 20 | pages = 8069–74 | date = May 2013 | pmid = 23633564 | pmc = 3657804 | doi = 10.1073/pnas.1304733110 | bibcode = 2013PNAS..110.8069H | doi-access = free }} Characterization of protein-derived cofactors is conducted using X-ray crystallography and mass spectroscopy; structural data is necessary because sequencing does not readily identify the altered sites.

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 such as hormones 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.{{Cite book|last1=Lodish|first1=Harvey|last2=Berk|first2=Arnold|last3=Zipursky|first3=S. Lawrence|last4=Matsudaira|first4=Paul|last5=Baltimore|first5=David|last6=Darnell|first6=James |chapter=G Protein–Coupled Receptors and Their Effectors |date=2000-01-01|title=Molecular Cell Biology|url=https://www.ncbi.nlm.nih.gov/books/NBK21718/|edition=4th}} 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.{{cite journal | vauthors = O'Malley BW, McKenna NJ | title = Coactivators and corepressors: what's in a name? | journal = Molecular Endocrinology | volume = 22 | issue = 10 | pages = 2213–4 | date = October 2008 | pmid = 18701638 | pmc = 2582534 | doi = 10.1210/me.2008-0201 }}

• Enzyme catalysis
• Inorganic chemistry
• Organometallic chemistry
• Bioorganometallic chemistry
• Cofactor engineering
• Vitamin

{{Reflist|30em}}

• {{cite book |last=Bugg |first=Tim |name-list-style=vanc |title=An introduction to enzyme and coenzyme chemistry |publisher=Blackwell Science |location=Oxford |year=1997 |isbn=978-0-86542-793-8 |url-access=registration |url=https://archive.org/details/introductiontoen0000bugg }}

• [http://www.bio.mtu.edu/%7Ehlyoungs/BL4010/cofactors.ppt Cofactors lecture] {{Webarchive|url=https://web.archive.org/web/20161005230343/http://www.bio.mtu.edu/%7Ehlyoungs/BL4010/cofactors.ppt |date=2016-10-05 }} (Powerpoint file)
• {{MeshName|Enzyme+cofactors}}
• [http://www.ebi.ac.uk/thornton-srv/databases/CoFactor/ The CoFactor Database]

{{Enzymes}}

{{Enzyme cofactors}}

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{{DEFAULTSORT:Cofactor (Biochemistry)}}

Category:Enzymes