Editing Enzyme (section)

== Biological function ==

Enzymes serve a wide variety of [[function (biology)|functions]] inside living organisms. They are indispensable for [[signal transduction]] and cell regulation, often via [[kinase]]s and [[phosphatase]]s.<ref>{{cite journal | vauthors = Hunter T | title = Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling | journal = Cell | volume = 80 | issue = 2 | pages = 225–236 | date = January 1995 | pmid = 7834742 | doi = 10.1016/0092-8674(95)90405-0 | s2cid = 13999125 | doi-access = free }}</ref> They also generate movement, with [[myosin]] hydrolyzing [[adenosine triphosphate]] (ATP) to generate [[muscle contraction]], and also transport cargo around the cell as part of the [[cytoskeleton]].<ref>{{cite journal | vauthors = Berg JS, Powell BC, Cheney RE | title = A millennial myosin census | journal = Molecular Biology of the Cell | volume = 12 | issue = 4 | pages = 780–794 | date = April 2001 | pmid = 11294886 | pmc = 32266 | doi = 10.1091/mbc.12.4.780 }}</ref> Other [[ATPase]]s in the cell membrane are [[ion pump (biology)|ion pumps]] involved in [[active transport]]. Enzymes are also involved in more exotic functions, such as [[luciferase]] generating light in [[fireflies]].<ref>{{cite journal | vauthors = Meighen EA | title = Molecular biology of bacterial bioluminescence | journal = Microbiological Reviews | volume = 55 | issue = 1 | pages = 123–142 | date = March 1991 | pmid = 2030669 | pmc = 372803 | doi = 10.1128/MMBR.55.1.123-142.1991 }}</ref> [[Virus]]es can also contain enzymes for infecting cells, such as the [[HIV integrase]] and [[reverse transcriptase]], or for viral release from cells, like the [[influenza]] virus [[neuraminidase]].<ref name="pmid12370077">{{cite journal | vauthors = De Clercq E | title = Highlights in the development of new antiviral agents | journal = Mini Reviews in Medicinal Chemistry | volume = 2 | issue = 2 | pages = 163–175 | date = April 2002 | pmid = 12370077 | doi = 10.2174/1389557024605474 }}</ref>

An important function of enzymes is in the [[digestive systems]] of animals. Enzymes such as [[amylase]]s and [[protease]]s break down large molecules ([[starch]] or [[protein]]s, respectively) into smaller ones, so they can be absorbed by the intestines. Starch molecules, for example, are too large to be absorbed from the intestine, but enzymes hydrolyze the starch chains into smaller molecules such as [[maltose]] and eventually [[glucose]], which can then be absorbed. Different enzymes digest different food substances. In [[ruminant]]s, which have [[herbivorous]] diets, microorganisms in the gut produce another enzyme, [[cellulase]], to break down the cellulose cell walls of plant fiber.<ref>{{cite journal | vauthors = Mackie RI, White BA | title = Recent advances in rumen microbial ecology and metabolism: potential impact on nutrient output | journal = Journal of Dairy Science | volume = 73 | issue = 10 | pages = 2971–2995 | date = October 1990 | pmid = 2178174 | doi = 10.3168/jds.S0022-0302(90)78986-2 | doi-access = free }}</ref>

===Metabolism===

[[Image:Glycolysis metabolic pathway.svg|thumb|upright=2|alt=Schematic diagram of the glycolytic metabolic pathway starting with glucose and ending with pyruvate via several intermediate chemicals. Each step in the pathway is catalyzed by a unique enzyme.|The [[metabolic pathway]] of [[glycolysis]] releases energy by converting [[glucose]] to [[pyruvate]] via a series of intermediate metabolites. Each chemical modification (red box) is performed by a different enzyme.]]

Several enzymes can work together in a specific order, creating [[metabolic pathway]]s.<ref name = "Stryer_2002" />{{rp|30.1}} In a metabolic pathway, one enzyme takes the product of another enzyme as a substrate. After the catalytic reaction, the product is then passed on to another enzyme. Sometimes more than one enzyme can catalyze the same reaction in parallel; this can allow more complex regulation: with, for example, a low constant activity provided by one enzyme but an inducible high activity from a second enzyme.<ref name="Rouzer_2009">{{cite journal | vauthors = Rouzer CA, Marnett LJ | title = Cyclooxygenases: structural and functional insights | journal = Journal of Lipid Research | volume = 50 | issue = Suppl | pages = S29–S34 | date = April 2009 | pmid = 18952571 | pmc = 2674713 | doi = 10.1194/jlr.R800042-JLR200  |doi-access=free }}</ref>

Enzymes determine what steps occur in these pathways. Without enzymes, metabolism would neither progress through the same steps and could not be regulated to serve the needs of the cell. Most central metabolic pathways are regulated at a few key steps, typically through enzymes whose activity involves the hydrolysis of ATP. Because this reaction releases so much energy, other reactions that are [[endothermic|thermodynamically unfavorable]] can be coupled to ATP hydrolysis, driving the overall series of linked metabolic reactions.<ref name = "Stryer_2002" />{{rp|30.1}}

=== Control of activity ===

There are five main ways that enzyme activity is controlled in the cell.<ref name = "Stryer_2002" />{{rp|30.1.1}}

====Regulation====
Enzymes can be either [[enzyme activator|activated]] or [[enzyme inhibitor|inhibited]] by other molecules. For example, the end product(s) of a metabolic pathway are often inhibitors for one of the first enzymes of the pathway (usually the first irreversible step, called committed step), thus regulating the amount of end product made by the pathways. Such a regulatory mechanism is called a [[negative feedback|negative feedback mechanism]], because the amount of the end product produced is regulated by its own concentration.<ref name = "Suzuki_2015_8"/>{{rp|141–48}} Negative feedback mechanism can effectively adjust the rate of synthesis of intermediate metabolites according to the demands of the cells. This helps with effective allocations of materials and energy economy, and it prevents the excess manufacture of end products. Like other [[homeostasis|homeostatic devices]], the control of enzymatic action helps to maintain a stable internal environment in living organisms.<ref name = "Suzuki_2015_8"/>{{rp|141}}

====Post-translational modification====
Examples of [[post-translational modification]] include [[phosphorylation]], [[myristoylation]] and [[glycosylation]].<ref name = "Suzuki_2015_8">{{cite book | author = Suzuki H | title = How Enzymes Work: From Structure to Function | publisher = CRC Press | location = Boca Raton, FL | year = 2015 | isbn = 978-981-4463-92-8 | chapter = Chapter 8: Control of Enzyme Activity | pages = 141–69 }}</ref>{{rp|149–69}} For example, in the response to [[insulin]], the [[phosphorylation]] of multiple enzymes, including [[glycogen synthase]], helps control the synthesis or degradation of [[glycogen]] and allows the cell to respond to changes in [[blood sugar]].<ref name = "Doble_2003">{{cite journal | vauthors = Doble BW, Woodgett JR | title = GSK-3: tricks of the trade for a multi-tasking kinase | journal = Journal of Cell Science | volume = 116 | issue = Pt 7 | pages = 1175–1186 | date = April 2003 | pmid = 12615961 | pmc = 3006448 | doi = 10.1242/jcs.00384 }}</ref> Another example of post-translational modification is the cleavage of the polypeptide chain. [[Chymotrypsin]], a digestive protease, is produced in inactive form as [[chymotrypsinogen]] in the [[pancreas]] and transported in this form to the [[stomach]] where it is activated. This stops the enzyme from digesting the pancreas or other tissues before it enters the gut. This type of inactive precursor to an enzyme is known as a [[zymogen]]<ref name = "Suzuki_2015_8"/>{{rp|149–53}} or proenzyme.

====Quantity====
Enzyme production ([[Transcription (genetics)|transcription]] and [[Translation (genetics)|translation]] of enzyme genes) can be enhanced or diminished by a cell in response to changes in the cell's environment. This form of [[regulation of gene expression|gene regulation]] is called [[enzyme induction]]. For example, bacteria may become [[antibiotic resistance|resistant to antibiotics]] such as [[penicillin]] because enzymes called [[beta-lactamase]]s are induced that hydrolyse the crucial [[Beta-lactam|beta-lactam ring]] within the penicillin molecule.<ref name="pmid8452343">{{cite journal | vauthors = Bennett PM, Chopra I | title = Molecular basis of beta-lactamase induction in bacteria | journal = Antimicrobial Agents and Chemotherapy | volume = 37 | issue = 2 | pages = 153–158 | date = February 1993 | pmid = 8452343 | pmc = 187630 | doi = 10.1128/aac.37.2.153 }}</ref> Another example comes from enzymes in the [[liver]] called [[cytochrome P450 oxidase]]s, which are important in [[drug metabolism]]. Induction or inhibition of these enzymes can cause [[drug interaction]]s.<ref name = "Skett_Gibson_2001">{{cite book |vauthors=Skett P, Gibson GG | title = Introduction to Drug Metabolism | date = 2001 | publisher = Nelson Thornes Publishers | location = Cheltenham, UK | isbn = 978-0748760114 | pages = 87–118 | edition = 3 | chapter = Chapter 3: Induction and Inhibition of Drug Metabolism }}</ref> Enzyme levels can also be regulated by changing the rate of enzyme [[catabolism|degradation]].<ref name="Stryer_2002" />{{rp|30.1.1}} The opposite of enzyme induction is [[enzyme repression]].

====Subcellular distribution====
Enzymes can be compartmentalized, with different metabolic pathways occurring in different [[cellular compartment]]s. For example, [[fatty acid]]s are synthesized by one set of enzymes in the [[cytosol]], [[endoplasmic reticulum]] and [[golgi apparatus|Golgi]] and used by a different set of enzymes as a source of energy in the [[mitochondrion]], through [[β-oxidation]].<ref>{{cite journal | vauthors = Faergeman NJ, Knudsen J | title = Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling | journal = The Biochemical Journal | volume = 323 | issue = Pt 1 | pages = 1–12 | date = April 1997 | pmid = 9173866 | pmc = 1218279 | doi = 10.1042/bj3230001 }}</ref> In addition, [[protein targeting|trafficking]] of the enzyme to different compartments may change the degree of [[protonation]] (e.g., the neutral [[cytoplasm]] and the acidic [[lysosome]]) or oxidative state (e.g., oxidizing [[periplasm]] or reducing [[cytoplasm]]) which in turn affects enzyme activity.<ref name = "Suzuki_2015_4">{{cite book | author = Suzuki H | title = How Enzymes Work: From Structure to Function | publisher = CRC Press | location = Boca Raton, FL | year = 2015 | isbn = 978-981-4463-92-8 | chapter = Chapter 4: Effect of pH, Temperature, and High Pressure on Enzymatic Activity | pages = 53–74 }}</ref> In contrast to partitioning into membrane bound organelles, enzyme subcellular localisation may also be altered through polymerisation of enzymes into macromolecular cytoplasmic filaments.<ref>{{cite journal | vauthors = Noree C, Sato BK, Broyer RM, Wilhelm JE | title = Identification of novel filament-forming proteins in Saccharomyces cerevisiae and Drosophila melanogaster | journal = The Journal of Cell Biology | volume = 190 | issue = 4 | pages = 541–551 | date = August 2010 | pmid = 20713603 | pmc = 2928026 | doi = 10.1083/jcb.201003001 }}</ref><ref>{{cite journal | vauthors = Aughey GN, Liu JL | title = Metabolic regulation via enzyme filamentation | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 51 | issue = 4 | pages = 282–293 | date = 2015 | pmid = 27098510 | pmc = 4915340 | doi = 10.3109/10409238.2016.1172555 }}</ref>

====Organ specialization====
In [[multicellular]] [[eukaryote]]s, cells in different [[organ (anatomy)|organs]] and [[tissue (biology)|tissues]] have different patterns of [[gene expression]] and therefore have different sets of enzymes (known as [[isozyme]]s) available for metabolic reactions. This provides a mechanism for regulating the overall metabolism of the organism. For example, [[hexokinase]], the first enzyme in the [[glycolysis]] pathway, has a specialized form called [[glucokinase]] expressed in the liver and [[pancreas]] that has a lower [[affinity (pharmacology)|affinity]] for glucose yet is more sensitive to glucose concentration.<ref>{{cite journal | vauthors = Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y | title = Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase | journal = Structure | volume = 12 | issue = 3 | pages = 429–438 | date = March 2004 | pmid = 15016359 | doi = 10.1016/j.str.2004.02.005 | doi-access = free }}</ref> This enzyme is involved in sensing [[blood sugar]] and regulating insulin production.<ref>{{cite journal | vauthors = Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P | title = Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus | journal = The New England Journal of Medicine | volume = 328 | issue = 10 | pages = 697–702 | date = March 1993 | pmid = 8433729 | doi = 10.1056/NEJM199303113281005 | doi-access = free }}</ref>

=== Involvement in disease ===
[[File:Phenylalanine hydroxylase mutations.svg|thumb|upright=2|alt= Ribbon diagram of phenylalanine hydroxylase with bound cofactor, coenzyme and substrate|In [[phenylalanine hydroxylase]] over 300 different mutations throughout the structure cause [[phenylketonuria]]. [[Phenylalanine]] substrate and [[tetrahydrobiopterin]] coenzyme in black, and [[Iron|Fe<sup>2+</sup>]] cofactor in yellow. ({{PDB|1KW0}})]]
[[File:Autosomal recessive inheritance for affected enzyme.png|thumb|upright=1.4|Hereditary defects in enzymes are generally inherited in an [[autosomal inheritance|autosomal]] fashion because there are more non-X chromosomes than X-chromosomes, and a [[recessive inheritance|recessive]] fashion because the enzymes from the unaffected genes are generally sufficient to prevent symptoms in carriers.]]
{{see also|Genetic disorder}}

Since the tight control of enzyme activity is essential for [[homeostasis]], any malfunction (mutation, overproduction, underproduction or deletion) of a single critical enzyme can lead to a genetic disease. The malfunction of just one type of enzyme out of the thousands of types present in the human body can be fatal. An example of a fatal genetic disease due to enzyme insufficiency is [[Tay–Sachs disease]], in which patients lack the enzyme [[hexosaminidase]].<ref>{{cite journal | vauthors = Okada S, O'Brien JS | title = Tay-Sachs disease: generalized absence of a beta-D-N-acetylhexosaminidase component | journal = Science | volume = 165 | issue = 3894 | pages = 698–700 | date = August 1969 | pmid = 5793973 | doi = 10.1126/science.165.3894.698 | s2cid = 8473726 | bibcode = 1969Sci...165..698O }}</ref><ref>{{cite web | title = Learning About Tay–Sachs Disease | url = http://www.genome.gov/10001220 | publisher = U.S. National Human Genome Research Institute | access-date = 1 March 2015 }}</ref>

One example of enzyme deficiency is the most common type of [[phenylketonuria]]. Many different single amino acid mutations in the enzyme [[phenylalanine hydroxylase]], which catalyzes the first step in the degradation of [[phenylalanine]], result in build-up of phenylalanine and related products. Some mutations are in the active site, directly disrupting binding and catalysis, but many are far from the active site and reduce activity by destabilising the protein structure, or affecting correct oligomerisation.<ref name=pmid10527663>{{cite journal | vauthors = Erlandsen H, Stevens RC | title = The structural basis of phenylketonuria | journal = Molecular Genetics and Metabolism | volume = 68 | issue = 2 | pages = 103–125 | date = October 1999 | pmid = 10527663 | doi = 10.1006/mgme.1999.2922 }}</ref><ref>{{cite journal | vauthors = Flatmark T, Stevens RC | title = Structural Insight into the Aromatic Amino Acid Hydroxylases and Their Disease-Related Mutant Forms | journal = Chemical Reviews | volume = 99 | issue = 8 | pages = 2137–2160 | date = August 1999 | pmid = 11849022 | doi = 10.1021/cr980450y }}</ref> This can lead to [[intellectual disability]] if the disease is untreated.<ref>{{cite book | title = Genes and Disease [Internet] | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK22253/ | chapter = Phenylketonuria | publisher = National Center for Biotechnology Information (US) | location = Bethesda (MD) | year = 1998–2015 }}</ref> Another example is [[pseudocholinesterase deficiency]], in which the body's ability to break down choline ester drugs is impaired.<ref>{{cite web | title = Pseudocholinesterase deficiency | url = http://ghr.nlm.nih.gov/condition/pseudocholinesterase-deficiency | publisher = U.S. National Library of Medicine | access-date = 5 September 2013 }}</ref>
Oral administration of enzymes can be used to treat some functional enzyme deficiencies, such as [[pancreatic insufficiency]]<ref>{{cite journal | vauthors = Fieker A, Philpott J, Armand M | title = Enzyme replacement therapy for pancreatic insufficiency: present and future | journal = Clinical and Experimental Gastroenterology | volume = 4 | pages = 55–73 | date = 2011 | pmid = 21753892 | pmc = 3132852 | doi = 10.2147/CEG.S17634 | doi-access = free }}</ref> and [[lactose intolerance]].<ref>{{cite journal | vauthors = Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M | title = Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment | journal = United European Gastroenterology Journal | volume = 1 | issue = 3 | pages = 151–159 | date = June 2013 | pmid = 24917953 | pmc = 4040760 | doi = 10.1177/2050640613484463 }}</ref>

Another way enzyme malfunctions can cause disease comes from [[germline mutation]]s in genes coding for [[DNA repair]] enzymes. Defects in these enzymes cause cancer because cells are less able to repair mutations in their [[genome]]s. This causes a slow accumulation of mutations and results in the [[carcinogenesis|development of cancers]]. An example of such a hereditary [[cancer syndrome]] is [[xeroderma pigmentosum]], which causes the development of [[skin cancer]]s in response to even minimal exposure to [[ultraviolet light]].<ref>{{cite journal | vauthors = Cleaver JE | title = Defective repair replication of DNA in xeroderma pigmentosum | journal = Nature | volume = 218 | issue = 5142 | pages = 652–656 | date = May 1968 | pmid = 5655953 | doi = 10.1038/218652a0 | s2cid = 4171859 | bibcode = 1968Natur.218..652C }}</ref><ref name="Andrews">{{cite book | vauthors = James WD, Elston D, Berger TG | title = Andrews' Diseases of the Skin: Clinical Dermatology | date = 2011 | publisher = Saunders/ Elsevier | location = London | isbn = 978-1437703146 | edition = 11th | page = 567 }}</ref>