Editing Enzyme (section)

==Inhibition==

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 | image1 = DHFR methotrexate inhibitor.svg
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 | image2 = Methotrexate vs folate 2.svg
 | alt2 = Two dimensional representations of the chemical structure of folic acid and methotrexate highlighting the differences between these two substances (amidation of pyrimidone and methylation of secondary amine).
 | caption2 = The coenzyme [[folic acid]] (left) and the anti-cancer drug [[methotrexate]] (right) are very similar in structure (differences show in green). As a result, methotrexate is a competitive inhibitor of many enzymes that use folates.
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{{main|Enzyme inhibitor}}

Enzyme reaction rates can be decreased by various types of enzyme inhibitors.<ref name = "Cornish-Bowden_2004">{{cite book | author = Cornish-Bowden A | title = Fundamentals of Enzyme Kinetics | date = 2004 | publisher = Portland Press | location = London | isbn = 1-85578-158-1 | edition = 3 }}</ref>{{rp|73–74}}

===Types of inhibition===

====Competitive====
A [[competitive inhibitor]] and substrate cannot bind to the enzyme at the same time.<ref name = "Price_1979">{{cite journal | vauthors = Price NC | year = 1979 | title = What is meant by 'competitive inhibition'? | journal = Trends in Biochemical Sciences | volume = 4 | issue=11 | pages = N272–N273 | doi = 10.1016/0968-0004(79)90205-6 }}</ref> Often competitive inhibitors strongly resemble the real substrate of the enzyme. For example, the drug [[methotrexate]] is a competitive inhibitor of the enzyme [[dihydrofolate reductase]], which catalyzes the reduction of [[folic acid|dihydrofolate]] to tetrahydrofolate.<ref name="Goodsell 340–341">{{cite journal | vauthors = Goodsell DS | title = The molecular perspective: methotrexate | journal = The Oncologist | volume = 4 | issue = 4 | pages = 340–341 | date = 1999-08-01 | pmid = 10476546 | doi = 10.1634/theoncologist.4-4-340 | doi-access = free }}</ref> The similarity between the structures of dihydrofolate and this drug are shown in the accompanying figure. This type of inhibition can be overcome with high substrate concentration. In some cases, the inhibitor can bind to a site other than the binding-site of the usual substrate and exert an [[#Allosteric modulation|allosteric effect]] to change the shape of the usual binding-site.<ref>{{cite journal | vauthors = Wu P, Clausen MH, Nielsen TE | title = Allosteric small-molecule kinase inhibitors | journal = Pharmacology & Therapeutics | volume = 156 | pages = 59–68 | date = December 2015 | pmid = 26478442 | doi = 10.1016/j.pharmthera.2015.10.002 | s2cid = 1550698 | url = https://backend.orbit.dtu.dk/ws/files/129911346/PT_Revised_Main_Manuscript_with_embedded_figures.pdf }}</ref>

====Non-competitive====
A [[non-competitive inhibition|non-competitive inhibitor]] binds to a site other than where the substrate binds. The substrate still binds with its usual affinity and hence K<sub>m</sub> remains the same. However the inhibitor reduces the catalytic efficiency of the enzyme so that V<sub>max</sub> is reduced. In contrast to competitive inhibition, non-competitive inhibition cannot be overcome with high substrate concentration.<ref name = "Cornish-Bowden_2004"/>{{rp|76–78}}

====Uncompetitive====
An [[uncompetitive inhibitor]] cannot bind to the free enzyme, only to the enzyme-substrate complex; hence, these types of inhibitors are most effective at high substrate concentration. In the presence of the inhibitor, the enzyme-substrate complex is inactive.<ref name = "Cornish-Bowden_2004"/>{{rp|78}} This type of inhibition is rare.<ref>{{cite journal | vauthors = Cornish-Bowden A | title = Why is uncompetitive inhibition so rare? A possible explanation, with implications for the design of drugs and pesticides | journal = FEBS Letters | volume = 203 | issue = 1 | pages = 3–6 | date = July 1986 | pmid = 3720956 | doi = 10.1016/0014-5793(86)81424-7 | bibcode = 1986FEBSL.203....3C | s2cid = 45356060 | author-link1 = Athel Cornish-Bowden }}</ref>

====Mixed====
A [[mixed inhibition|mixed inhibitor]] binds to an allosteric site and the binding of the substrate and the inhibitor affect each other. The enzyme's function is reduced but not eliminated when bound to the inhibitor. This type of inhibitor does not follow the Michaelis–Menten equation.<ref name = "Cornish-Bowden_2004"/>{{rp|76–78}}

====Irreversible====
An [[irreversible inhibitor]] permanently inactivates the enzyme, usually by forming a [[covalent bond]] to the protein.<ref>{{cite journal | vauthors = Strelow JM | title = A Perspective on the Kinetics of Covalent and Irreversible Inhibition | journal = SLAS Discovery | volume = 22 | issue = 1 | pages = 3–20 | date = January 2017 | pmid = 27703080 | doi = 10.1177/1087057116671509 | doi-access = free }}</ref> [[Penicillin]]<ref>{{cite journal | vauthors = Fisher JF, Meroueh SO, Mobashery S | title = Bacterial resistance to beta-lactam antibiotics: compelling opportunism, compelling opportunity | journal = Chemical Reviews | volume = 105 | issue = 2 | pages = 395–424 | date = February 2005 | pmid = 15700950 | doi = 10.1021/cr030102i }}</ref> and [[aspirin]]<ref name="Johnson">{{cite journal | vauthors = Johnson DS, Weerapana E, Cravatt BF | title = Strategies for discovering and derisking covalent, irreversible enzyme inhibitors | journal = Future Medicinal Chemistry | volume = 2 | issue = 6 | pages = 949–964 | date = June 2010 | pmid = 20640225 | pmc = 2904065 | doi = 10.4155/fmc.10.21 }}</ref> are common drugs that act in this manner.

===Functions of inhibitors===

In many organisms, inhibitors may act as part of a [[feedback]] mechanism. If an enzyme produces too much of one substance in the organism, that substance may act as an inhibitor for the enzyme at the beginning of the pathway that produces it, causing production of the substance to slow down or stop when there is sufficient amount. This is a form of [[negative feedback]]. Major metabolic pathways such as the [[citric acid cycle]] make use of this mechanism.<ref name = "Stryer_2002" />{{rp|17.2.2}}

Since inhibitors modulate the function of enzymes they are often used as drugs. Many such drugs are reversible competitive inhibitors that resemble the enzyme's native substrate, similar to [[methotrexate]] above; other well-known examples include [[statin]]s used to treat high [[cholesterol]],<ref name="Endo1992">{{cite journal | vauthors = Endo A | title = The discovery and development of HMG-CoA reductase inhibitors | journal = Journal of Lipid Research | volume = 33 | issue = 11 | pages = 1569–1582 | date = November 1992 | pmid = 1464741 | doi = 10.1016/S0022-2275(20)41379-3 | doi-access = free }}</ref> and [[protease inhibitors]] used to treat [[retroviral]] infections such as [[HIV]].<ref>{{cite journal | vauthors = Wlodawer A, Vondrasek J | title = Inhibitors of HIV-1 protease: a major success of structure-assisted drug design | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 27 | pages = 249–284 | date = 1998 | pmid = 9646869 | doi = 10.1146/annurev.biophys.27.1.249 | s2cid = 10205781 }}</ref> A common example of an irreversible inhibitor that is used as a drug is [[aspirin]], which inhibits the [[Cyclooxygenase|COX-1]] and [[Cyclooxygenase|COX-2]] enzymes that produce the [[inflammation]] messenger [[prostaglandin]].<ref name="Johnson" /> Other enzyme inhibitors are poisons. For example, the poison [[cyanide]] is an irreversible enzyme inhibitor that combines with the copper and iron in the active site of the enzyme [[cytochrome c oxidase]] and blocks [[cellular respiration]].<ref>{{cite journal | vauthors = Yoshikawa S, Caughey WS | title = Infrared evidence of cyanide binding to iron and copper sites in bovine heart cytochrome c oxidase. Implications regarding oxygen reduction | journal = The Journal of Biological Chemistry | volume = 265 | issue = 14 | pages = 7945–7958 | date = May 1990 | pmid = 2159465 | doi = 10.1016/S0021-9258(19)39023-4 | doi-access = free }}</ref>