A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogenesis.

Most metalloproteases require zinc, but some use cobalt. The metal ion is coordinated to the protein via three ligands.

• In coordination chemistry, a ligand^{[ The word ligand comes from Latin ligare, to bind/tie. It is pronounced either /ˈlaɪɡənd/ or /ˈlɪɡənd/; both are very common.]} 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 electron pairs often through Lewis Bases.^{[Burdge, J., & Overby, J. (2020). Chemistry – Atoms first (4th ed.). New York, NY: McGrawHill. doi:9781260571349]} 
• The nature of metal–ligand bonding can range from covalent to ionic. Furthermore, the metal–ligand bond order can range from one to three. Ligands are viewed as Lewis bases, although rare cases are known to involve Lewis acidic “ligands”.^{[Cotton, Frank Albert; Geoffrey Wilkinson; Carlos A. Murillo (1999). Advanced Inorganic Chemistry. Wiley-Interscience. p. 1355. ISBN 978-0471199571.][Miessler, Gary L.; Paul J. Fischer; Donald Arthur Tarr (2013). Inorganic Chemistry. Prentice Hall. p. 696. ISBN 978-0321811059.]}
  • A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any species that has a filled orbital containing an electron pair which is not involved in bonding but may form a dative bond with a Lewis acid to form a Lewis adduct. For example, NH₃ is a Lewis base, because it can donate its lone pair of electrons. Trimethylborane (Me₃B) is a Lewis acid as it is capable of accepting a lone pair. In a Lewis adduct, the Lewis acid and base share an electron pair furnished by the Lewis base, forming a dative bond.^{[IUPAC, Compendium of Chemical Terminology, 2nd ed. (the “Gold Book”) (1997). Online corrected version: (2006–) “Lewis acid“. doi:10.1351/goldbook.L03508]} In the context of a specific chemical reaction between NH₃ and Me₃B, a lone pair from NH₃ will form a dative bond with the empty orbital of Me₃B to form an adduct NH₃•BMe₃. The terminology refers to the contributions of Gilbert N. Lewis.^{[Lewis, Gilbert Newton (1923). Valence and the Structure of Atoms and Molecules. American chemical society. Monograph series. New York, New York, U.S.A.: Chemical Catalog Company. p. 142. ISBN9780598985408. From p. 142: “We are inclined to think of substances as possessing acid or basic properties, without having a particular solvent in mind. It seems to me that with complete generality we may say that a basic substance is one which has a lone pair of electrons which may be used to complete the stable group of another atom, and that an acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. In other words, the basic substance furnishes a pair of electrons for a chemical bond, the acid substance accepts such a pair.”]}
  • The terms nucleophile and electrophile are more or less interchangeable with Lewis base and Lewis acid, respectively. However, these terms, especially their abstract noun forms nucleophilicity and electrophilicity, emphasize the kinetic aspect of reactivity, while the Lewis basicity and Lewis acidity emphasize the thermodynamic aspect of Lewis adduct formation.^{[ Anslyn, Eric V. (2006). Modern physical organic chemistry. Dougherty, Dennis A., 1952-. Sausalito, CA: University Science. ISBN 1891389319. OCLC 55600610.[page needed]]}

• Metals and metalloids are bound to ligands in almost all circumstances, although gaseous “naked” metal ions can be generated in a high vacuum.
  • A metalloid is a type of chemical element which has a preponderance of properties in between, or that are a mixture of, those of metals and nonmetals. There is no standard definition of a metalloid and no complete agreement on which elements are metalloids. Despite the lack of specificity, the term remains in use in the literature of chemistry.
  • The six commonly recognised metalloids are boron, silicon, germanium, arsenic, antimony, and tellurium. Five elements are less frequently so classified: carbon, aluminium, selenium, polonium, and astatine. On a standard periodic table, all eleven elements are in a diagonal region of the p-block extending from boron at the upper left to astatine at lower right. Some periodic tables include a dividing line between metals and nonmetals, and the metalloids may be found close to this line.
  • Typical metalloids have a metallic appearance, but they are brittle and only fair conductors of electricity. Chemically, they behave mostly as nonmetals. They can form alloys with metals. Most of their other physical properties and chemical properties are intermediate in nature. Metalloids are usually too brittle to have any structural uses. They and their compounds are used in alloys, biological agents, catalysts, flame retardants, glasses, optical storage and optoelectronics, pyrotechnics, semiconductors, and electronics.
  • The electrical properties of silicon and germanium enabled the establishment of the semiconductor industry in the 1950s and the development of solid-state electronics from the early 1960s.^{[ Chedd 1969, pp. 58, 78; National Research Council 1984, p. 43]}
  • The term metalloid originally referred to nonmetals. Its more recent meaning, as a category of elements with intermediate or hybrid properties, became widespread in 1940–1960. Metalloids are sometimes called semimetals, a practice that has been discouraged,^{[ Atkins et al. 2010, p. 20]} as the term semimetal has a different meaning in physics than in chemistry. In physics, it refers to a specific kind of electronic band structure of a substance. In this context, only arsenic and antimony are semimetals, and commonly recognised as metalloids.

• Ligands in a complex dictate the reactivity of the central atom, including ligand substitution rates, the reactivity of the ligands themselves, and redox. Ligand selection requires critical consideration in many practical areas, including bioinorganic and medicinal chemistry, homogeneous catalysis, and environmental chemistry.
• Ligands are classified in many ways, including: charge, size (bulk), the identity of the coordinating atom(s), and the number of electrons donated to the metal (denticity or hapticity). The size of a ligand is indicated by its cone angle.
• The composition of coordination complexes have been known since the early 1800s, such as Prussian blue and copper vitriol. The key breakthrough occurred when Alfred Werner reconciled formulas and isomers. He showed, among other things, that the formulas of many cobalt(III) and chromium(III) compounds can be understood if the metal has six ligands in an octahedral geometry. The first to use the term “ligand” were Alfred Werner and Carl Somiesky, in relation to silicon chemistry. The theory allows one to understand the difference between coordinated and ionic chloride in the cobalt ammine chlorides and to explain many of the previously inexplicable isomers. He resolved the first coordination complex called hexol into optical isomers, overthrowing the theory that chirality was necessarily associated with carbon compounds.^{[ Jackson, W. Gregory; Josephine A. McKeon; Silvia Cortez (1 October 2004). “Alfred Werner’s Inorganic Counterparts of Racemic and Mesomeric Tartaric Acid: A Milestone Revisited”. Inorganic Chemistry. 43 (20): 6249–6254. doi:10.1021/ic040042e. PMID15446870][Bowman-James, Kristin (2005). “Alfred Werner Revisited: The Coordination Chemistry of Anions”. Accounts of Chemical Research. 38 (8): 671–678. doi:10.1021/ar040071t. PMID 16104690.]}
• See also
  • Bridging carbonyl
  • Coordination complex
  • Crystal field theory
  • DNA binding ligand
  • Inorganic chemistry
  • Josiphos ligands
  • Ligand dependent pathway
  • Ligand field theory
  • Ligand isomerism
  • Spectrochemical series
  • Tanabe–Sugano diagram

The ligands coordinating the metal ion can vary with histidine, glutamate, aspartate, lysine, and arginine.^{[clarification needed]} (I need notes but these may require individual pages)

• Histidine
  • Histidine (symbol His or H)^{[ “Nomenclature and Symbolism for Amino Acids and Peptides”. IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.]} is an essential α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH₃⁺ form under biological conditions), a carboxylic acid group (which is in the deprotonated –COO⁻ form under biological conditions), and an imidazole side chain (which is partially protonated), classifying it as a positively charged amino acid at physiological pH. Initially thought essential only for infants, it has now been shown in longer-term studies to be essential for adults also.^{[Kopple, J D; Swendseid, M E (1975). “Evidence that histidine is an essential amino acid in normal and chronically uremic man”. Journal of Clinical Investigation. 55 (5): 881–91. doi:10.1172/JCI108016. PMC 301830. PMID 1123426]} It is encoded by the codons CAU and CAC.
  • HISTORY: Histidine was first isolated by German physician Albrecht Kossel and Sven Gustaf Hedin in 1896.^{[Vickery, Hubert Bradford; Leavenworth, Charles S. (1928-08-01). “On the Separation of Histidine and Arginine” (PDF). Journal of Biological Chemistry. 78 (3): 627–635. doi:10.1016/S0021-9258(18)83967-9. ISSN 0021-9258]} It is also a precursor to histamine, a vital inflammatory agent in immune responses. The acyl radical is histidyl.
  • LIGAND: Histidine forms complexes with many metal ions. The imidazole sidechain of the histidine residue commonly serves as a ligand in metalloproteins. One example is the axial base attached to Fe in myoglobin and hemoglobin. Poly-histidine tags (of six or more consecutive H residues) are utilized for protein purification by binding to columns with nickel or cobalt, with micromolar affinity.^{[Bornhorst, J. A.; Falke, J. J. (2000). “Purification of proteins using polyhistidine affinity tags”. Methods in Enzymology. 326: 245–254. doi:10.1016/s0076-6879(00)26058-8. ISSN 0076-6879. PMC 2909483. PMID 11036646]} 
    • Natural poly-histidine peptides, found in the venom of the viper Atheris squamigera have been shown to bind Zn(2+), Ni(2+) and Cu(2+) and affect the function of venom metalloproteases.^{[Watly, Joanna; Simonovsky, Eyal; Barbosa, Nuno; Spodzieja, Marta; Wieczorek, Robert; Rodziewicz-Motowidlo, Sylwia; Miller, Yifat; Kozlowski, Henryk (2015-08-17). “African Viper Poly-His Tag Peptide Fragment Efficiently Binds Metal Ions and Is Folded into an α-Helical Structure”. Inorganic Chemistry. 54 (16): 7692–7702. doi:10.1021/acs.inorgchem.5b01029. ISSN 1520-510X. PMID 26214303.]}
  • Glutamate
    • Glutamic acid (symbol Glu or E;^{[ “Nomenclature and Symbolism for Amino Acids and Peptides”. IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.]} the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is non-essential in humans, meaning that the body can synthesize it. It is also the most abundant excitatory neurotransmitter in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABA-ergic neurons.
    • Its molecular formula is C₅H₉NO₄. Glutamic acid exists in three optically isomeric forms; the dextrorotatory l-form is usually obtained by hydrolysis of gluten or from the waste waters of beet-sugar manufacture or by fermentation.^{[Webster’s Third New International Dictionary of the English Language Unabridged, Third Edition, 1971.]} Its molecular structure could be idealized as HOOC−CH(NH₂)−(CH₂)₂−COOH, with two carboxyl groups −COOH and one amino group −NH₂.
    • However, in the solid state and mildly acidic water solutions, the molecule assumes an electrically neutral zwitterion structure ⁻OOC−CH(NH⁺₃)−(CH₂)₂−COOH. It is encoded by the codons GAA or GAG.
    • The acid can lose one proton from its second carboxyl group to form the conjugate base, the singly-negative anion glutamate ⁻OOC−CH(NH⁺₃)−(CH₂)₂−COO⁻. This form of the compound is prevalent in neutral solutions. The glutamate neurotransmitter plays the principal role in neural activation.^{[Robert Sapolsky (2005), Biology and Human Behavior: The Neurological Origins of Individuality (2nd edition); The Teaching Company. pp. 19–20 of the Guide Book.]} This anion creates the savory umami flavor of foods and is found in glutamate flavorings such as MSG. In Europe it is classified as food additive E620. In highly alkaline solutions the doubly negative anion ⁻OOC−CH(NH₂)−(CH₂)₂−COO⁻ prevails. The radical corresponding to glutamate is called glutamyl.
    • HISTORY: Although they occur naturally in many foods, the flavor contributions made by glutamic acid and other amino acids were only scientifically identified early in the 20th century. The substance was discovered and identified in the year 1866 by the German chemist Karl Heinrich Ritthausen, who treated wheat gluten (for which it was named) with sulfuric acid.^{[R. H. A. Plimmer (1912) [1908]. R. H. A. Plimmer; F. G. Hopkins (eds.). The Chemical Constitution of the Protein. Monographs on biochemistry. Vol. Part I. Analysis (2nd ed.). London: Longmans, Green and Co. p. 114. Retrieved June 3, 2012.]} In 1908, Japanese researcher Kikunae Ikeda of the Tokyo Imperial University identified brown crystals left behind after the evaporation of a large amount of kombu broth as glutamic acid. These crystals, when tasted, reproduced the ineffable but undeniable flavor he detected in many foods, most especially in seaweed. Professor Ikeda termed this flavor umami. He then patented a method of mass-producing a crystalline salt of glutamic acid, monosodium glutamate.^{[Renton, Alex (2005-07-10). “If MSG is so bad for you, why doesn’t everyone in Asia have a headache?”. The Guardian. Retrieved 2008-11-21.][ “Kikunae Ikeda Sodium Glutamate”. Japan Patent Office. 2002-10-07. Archived from the original on 2007-10-28. Retrieved 2008-11-21.]}
      • Main article: Glutamic acid (flavor)
  • Aspartate
    • Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the protonated –NH⁺₃ form under physiological conditions, while its α-carboxylic acid group is deprotonated −COO⁻ under physiological conditions. Aspartic acid has an acidic side chain (CH₂COOH) which reacts with other amino acids, enzymes and proteins in the body. Under physiological conditions (pH 7.4) in proteins the side chain usually occurs as the negatively charged aspartate form, −COO⁻.^{[G., Voet, Judith; W., Pratt, Charlotte (2016-02-29). Fundamentals of biochemistry : life at the molecular level. ISBN 9781118918401. OCLC 910538334.]} It is a non-essential amino acid in humans, meaning the body can synthesize it as needed. It is encoded by the codons GAU and GAC.
    • D-Aspartate is one of two D-amino acids commonly found in mammals.^{[Haynes, William M., ed. (2016). CRC Handbook of Chemistry and Physics (97th ed.). CRC Press. pp. 5–89. ISBN 978-1498754286.]}
    • In proteins aspartate sidechains are often hydrogen bonded to form asx turns or asx motifs, which frequently occur at the N-termini of alpha helices.
    • The L-isomer of Asp is one of the 22 proteinogenic amino acids, i.e., the building blocks of proteins. Aspartic acid, like glutamic acid, is classified as an acidic amino acid, with a pK_a of 3.9, however in a peptide this is highly dependent on the local environment, and could be as high as 14. Asp is pervasive in biosynthesis.
    • In plants and microorganisms, aspartate is the precursor to several amino acids, including four that are essential for humans: methionine, threonine, isoleucine, and lysine. The conversion of aspartate to these other amino acids begins with reduction of aspartate to its “semialdehyde”, O₂CCH(NH₂)CH₂CHO.^[11] 
    • Asparagine is derived from aspartate via transamidation:-O₂CCH(NH₂)CH₂CO₂– + GC(O)NH₃+ O₂CCH(NH₂)CH₂CONH₃+ + GC(O)O (where GC(O)NH₂ and GC(O)OH are glutamine and glutamic acid, respectively)
    • There are two forms or enantiomers of aspartic acid. The name “aspartic acid” can refer to either enantiomer or a mixture of two.^{[“Nomenclature and symbolism for amino acids and peptides (IUPAC-IUB Recommendations 1983)”, Pure Appl. Chem., 56 (5): 595–624, 1984, doi:10.1351/pac198456050595.]} Of these two forms, only one, “L-aspartic acid”, is directly incorporated into proteins. The biological roles of its counterpart, “D-aspartic acid” are more limited. Where enzymatic synthesis will produce one or the other, most chemical syntheses will produce both forms, “DL-aspartic acid”, known as a racemic mixture.^{[citation needed]}
    • In the human body, aspartate is most frequently synthesized through the transamination of oxaloacetate. The biosynthesis of aspartate is facilitated by an aminotransferase enzyme: the transfer of an amine group from another molecule such as alanine or glutamine yields aspartate and an alpha-keto acid.^{[G., Voet, Judith; W., Pratt, Charlotte (2016-02-29). Fundamentals of biochemistry : life at the molecular level. ISBN 9781118918401. OCLC 910538334.]}
    • Aspartate also plays an important role in the urea cycle.^{[citation needed]}
    • In the urea cycle, aspartate and ammonia donate amino groups leading to the formation of urea.^{[“Biochemistry – Biochemistry”. www.varsitytutors.com. Retrieved 2022-02-18.]}
    • HISTORY: Aspartic acid was first discovered in 1827 by Auguste-Arthur Plisson and Étienne Ossian Henry^{[ Berzelius JJ, Öngren OG (1839). Traité de chimie (in French). Vol. 3. Brussels: A. Wahlen et Cie. p. 81. Retrieved 25 August 2015.]} by hydrolysis of asparagine, which had been isolated from asparagus juice in 1806.^{[Plimmer R (1912) [1908]. Plimmer R, Hopkins F (eds.). The chemical composition of the proteins. Monographs on Biochemistry. Vol. Part I. Analysis (2nd ed.). London: Longmans, Green and Co. p. 112. Retrieved January 18, 2010.]} Their original method used lead hydroxide, but various other acids or bases are now more commonly used instead.^{[citation needed]}
  • • Aspartate has many other biochemical roles. It is a metabolite in the urea cycle and participates in gluconeogenesis. It carries reducing equivalents in the malate-aspartate shuttle, which utilizes the ready interconversion of aspartate and oxaloacetate, which is the oxidized (dehydrogenated) derivative of malic acid. Aspartate donates one nitrogen atom in the biosynthesis of inosine, the precursor to the purine bases. In addition, aspartic acid acts as a hydrogen acceptor in a chain of ATP synthase. Dietary L-aspartic acid has been shown to act as an inhibitor of Beta-glucuronidase, which serves to regulate enterohepatic circulation of bilirubin and bile acids.^{[Kreamer, Siegel, & Gourley (Oct 2001). “A novel inhibitor of beta-glucuronidase: L-aspartic acid”. Pediatric Research. 50 (4): 460–466. doi:10.1203/00006450-200110000-00007. PMID 11568288.]}
    • Aspartate (the conjugate base of aspartic acid) stimulates NMDA receptors, though not as strongly as the amino acid neurotransmitter L-glutamate does.^{[hen PE, Geballe MT, Stansfeld PJ, Johnston AR, Yuan H, Jacob AL, Snyder JP, Traynelis SF, Wyllie DJ (May 2005). “Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling”. Molecular Pharmacology. 67 (5): 1470–84. doi:10.1124/mol.104.008185. PMID 15703381. S2CID 13505187]}
    • In 2014, the global market for aspartic acid was 39.3 thousand short tons (35.7 thousand tonnes)^{[ “Global Aspartic Acid Market By Application”. Grand View Research. Retrieved November 30, 2019.]} or about $117 million annually^{[Evans J (2014). Commercial Amino Acids. BCC Research. pp. 101–103.]} with potential areas of growth accounting for an addressable market^{[clarification needed]} of $8.78 billion (Bn).^{[ Transparency Market Research. Superabsorbent polymers market – global industry analysis, size, share, growth, trends and forecase, 2014-2020. (2014).]} The three largest market segments include the U.S., Western Europe, and China. Current applications include biodegradable polymers (polyaspartic acid), low calorie sweeteners (aspartame), scale and corrosion inhibitors, and resins.^{[citation needed]}
    • One area of aspartic acid market growth is biodegradable superabsorbent polymers (SAP), and hydrogels. ^{[Adelnia, Hossein; Blakey, Idriss; Little, Peter J.; Ta, Hang T. (2019). “Hydrogels Based on Poly(aspartic acid): Synthesis and Applications”. Frontiers in Chemistry. 7: 755. Bibcode:2019FrCh….7..755A. doi:10.3389/fchem.2019.00755. ISSN 2296-2646. PMC 6861526. PMID 31799235.]} The superabsorbent polymers market is anticipated to grow at a compound annual growth rate of 5.5% from 2014 to 2019 to reach a value of $8.78Bn globally.^{[Transparency Market Research. Superabsorbent polymers market – global industry analysis, size, share, growth, trends and forecase, 2014-2020. (2014).]} Around 75% of superabsorbent polymers are used in disposable diapers and an additional 20% is used for adult incontinence and feminine hygiene products. Polyaspartic acid, the polymerization product of aspartic acid, is a biodegradable substitute to polyacrylate.^{[Adelnia, Hossein; Blakey, Idriss; Little, Peter J.; Ta, Hang T. (2019). “Hydrogels Based on Poly(aspartic acid): Synthesis and Applications”. Frontiers in Chemistry. 7: 755. Bibcode:2019FrCh….7..755A. doi:10.3389/fchem.2019.00755. ISSN 2296-2646. PMC 6861526. PMID 31799235.][Adelnia, Hossein; Tran, Huong D.N.; Little, Peter J.; Blakey, Idriss; Ta, Hang T. (2021-06-14). “Poly(aspartic acid) in Biomedical Applications: From Polymerization, Modification, Properties, Degradation, and Biocompatibility to Applications”. ACS Biomaterials Science & Engineering. 7 (6): 2083–2105. doi:10.1021/acsbiomaterials.1c00150. hdl:10072/404497. PMID 33797239. S2CID 232761877][Alford DD, Wheeler AP, Pettigrew CA (1994). “Biodegradation of thermally synthesized polyaspartate”. J Environ Polym Degr. 2 (4): 225–236. doi:10.1007/BF02071970]} The polyaspartate market comprises a small fraction (est. < 1%) of the total SAP market.^{[citation needed]}
    • In addition to SAP, aspartic acid has applications in the $19Bn fertilizer industry, where polyaspartate improves water retention and nitrogen uptake;^{[Kelling K (2001). Crop Responses to Amisorb in the North Central Region. University of Wisconsin-Madison.]} the $1.1Bn (2020) concrete floor coatings market, where polyaspartic is a low VOC, low energy alternative to traditional epoxy resins;^{[Global concrete floor coatings market will be worth US$1.1Bn by 2020. Transparency Market Research (2015).]} and lastly the >$5Bn scale and corrosion inhibitors market.^{[Corrosion inhibitors market analysis by product, by application, by end-use industry, and segment forecasts to 2020. Grand View Research (2014)]}
  • Lysine
    • Lysine (symbol Lys or K)^[2] is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated −NH₃⁺ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO⁻ form under biological conditions), and a side chain lysyl ((CH₂)₄NH₂), classifying it as a basic, charged (at physiological pH), aliphatic amino acid. It is encoded by the codons AAA and AAG.
    • Like almost all other amino acids, the α-carbon is chiral and lysine may refer to either enantiomer or a racemic mixture of both. For the purpose of this article, lysine will refer to the biologically active enantiomer L-lysine, where the α-carbon is in the S configuration.
    • The human body cannot synthesize lysine. It is essential in humans and must therefore be obtained from the diet. In organisms that synthesise lysine, two main biosynthetic pathways exist, the diaminopimelate and α-aminoadipate pathways, which employ distinct enzymes and substrates and are found in diverse organisms. Lysine catabolism occurs through one of several pathways, the most common of which is the saccharopine pathway.
    • Lysine plays several roles in humans, most importantly proteinogenesis, but also in the crosslinking of collagen polypeptides, uptake of essential mineral nutrients, and in the production of carnitine, which is key in fatty acid metabolism. Lysine is also often involved in histone modifications, and thus, impacts the epigenome. The ε-amino group often participates in hydrogen bonding and as a general base in catalysis. The ε-ammonium group (NH₃⁺) is attached to the fourth carbon from the α-carbon, which is attached to the carboxyl (C=OOH) group.^{[ Lysine. The Biology Project, Department of Biochemistry and Molecular Biophysics, University of Arizona]}
    • Due to its importance in several biological processes, a lack of lysine can lead to several disease states including defective connective tissues, impaired fatty acid metabolism, anaemia, and systemic protein-energy deficiency. In contrast, an overabundance of lysine, caused by ineffective catabolism, can cause severe neurological disorders.
    • HISTORY: Lysine was first isolated by the German biological chemist Ferdinand Heinrich Edmund Drechsel in 1889 from the protein casein in milk.^{[Drechsel E (1889). “Zur Kenntniss der Spaltungsprodukte des Caseïns” [[Contribution] to [our] knowledge of the cleavage products of casein]. Journal für Praktische Chemie. 2nd series (in German). 39: 425–429. doi:10.1002/prac.18890390135. On p. 428, Drechsel presented an empirical formula for the chloroplatinate salt of lysine – C₈H₁₆N₂O₂Cl₂•PtCl₄ + H₂O – but he later admitted that this formula was wrong because the salt’s crystals contained ethanol instead of water. See: Drechsel E (1891). “Der Abbau der Eiweissstoffe” [The disassembly of proteins]. Archiv für Anatomie und Physiologie (in German): 248–278.; Drechsel E (1877). “Zur Kenntniss der Spaltungsproducte des Caseïns” [Contribution] to [our] knowledge of the cleavage products of casein] (in German): 254–260. From p. 256:] ” … die darin enthaltene Base hat die Formel C₆H₁₄N₂O₂. Der anfängliche Irrthum ist dadurch veranlasst worden, dass das Chloroplatinat nicht, wie angenommen ward, Krystallwasser, sondern Krystallalkohol enthält, … “ ( … the base [that’s] contained therein has the [empirical] formula C₆H₁₄N₂O₂. The initial error was caused by the chloroplatinate containing not water in the crystal (as was assumed), but ethanol … )]} He named it “lysin“.^[5] In 1902, the German chemists Emil Fischer and Fritz Weigert determined lysine’s chemical structure by synthesizing it.^{[Fischer E, Weigert F (1902). “Synthese der α,ε – Diaminocapronsäure (Inactives Lysin)” [Synthesis of α,ε-diaminohexanoic acid ([optically] inactive lysine)]. Berichte der Deutschen Chemischen Gesellschaft (in German). 35 (3): 3772–3778. doi:10.1002/cber.190203503211]}
      • Wikipedia makes a point of differentiating between Lysin and Lysine with “not to be confused with” messages at the top of all relevant pages.
      • Lysins, also known as endolysins or murein hydrolases, are hydrolytic enzymes produced by bacteriophages in order to cleave the host’s cell wall during the final stage of the lytic cycle. Lysins are highly evolved enzymes that are able to target one of the five bonds in peptidoglycan (murein), the main component of bacterial cell walls, which allows the release of progeny virions from the lysed cell. Cell-wall-containing Archaea are also lysed by specialized pseudomurein-cleaving lysins,^{[Visweswaran GR, Dijkstra BW, Kok J (November 2010). “Two major archaeal pseudomurein endoisopeptidases: PeiW and PeiP”. Archaea. 2010: 480492. doi:10.1155/2010/480492. PMC 2989375. PMID 21113291]} while most archaeal viruses employ alternative mechanisms.^{[Quemin ER, Quax TE (5 June 2015). “Archaeal viruses at the cell envelope: entry and egress”. Frontiers in Microbiology. 6: 552. doi:10.3389/fmicb.2015.00552. PMC 4456609. PMID 26097469]} Similarly, not all bacteriophages synthesize lysins: some small single-stranded DNA and RNA phages produce membrane proteins that activate the host’s autolytic mechanisms such as autolysins.^{[Young R (September 1992). “Bacteriophage lysis: mechanism and regulation”. Microbiological Reviews. 56 (3): 430–81. doi:10.1128/mr.56.3.430-481.1992. PMC 372879. PMID 1406491.]}
        • Lysins are being used as antibacterial agents due to their high effectiveness and specificity in comparison with antibiotics, which are susceptible to bacterial resistance.^{[Fischetti VA (Oct 2008). “Bacteriophage lysins as effective antibacterials”. Current Opinion in Microbiology. 11 (5): 393–400. doi:10.1016/j.mib.2008.09.012. PMC 2597892. PMID 18824123]}
        • One of the most problematic aspects of the use of phage lysins as antimicrobial agents is the potential immunogenicity of these enzymes. Unlike most antibiotics, proteins are prone to antibody recognition and binding, which means that lysins could be ineffective when treating bacterial infections or even dangerous, potentially leading to a systemic immune response or a cytokine storm. Nonetheless, experimental data from immunologically-rich rabbit serum showed that hyperimmune serum slows down but does not block the activity of pneumococcal lysin Cpl-1.^{[ Loeffler JM, Djurkovic S, Fischetti VA (Nov 2003). “Phage lytic enzyme Cpl-1 as a novel antimicrobial for pneumococcal bacteremia”. Infection and Immunity. 71 (11): 6199–204. doi:10.1128/IAI.71.11.6199-6204.2003. PMC 219578. PMID 14573637.]}
      • The term lysin may refer to any protein that causes cell lysis, such as:
        • Most commonly, phage lysins, also known as endolysins
        • Autolysin
        • Cytolysin
        • Egg lysin
        • Hemolysin
        • NK-lysin
        • Streptolysin
      • See also:
        • Cell lysis
        • Toxin

• The 1993 film Jurassic Park (based on the 1990 Michael Crichton novel of the same name) features dinosaurs that were genetically altered so that they could not produce lysine, an example of engineered auxotrophy.^{[Coyne JA (10 October 1999). “The Truth Is Way Out There”. The New York Times. Retrieved 6 April 2008.]} This was known as the “lysine contingency” and was supposed to prevent the cloned dinosaurs from surviving outside the park, forcing them to be dependent on lysine supplements provided by the park’s veterinary staff. In reality, no animals are capable of producing lysine (it is an essential amino acid).^{[Wu G (May 2009). “Amino acids: metabolism, functions, and nutrition”. Amino Acids. 37 (1): 1–17. doi:10.1007/s00726-009-0269-0. PMID 19301095. S2CID 1870305.]}
  • • In 1996, lysine became the focus of a price-fixing case, the largest in United States history. The Archer Daniels Midland Company paid a fine of US$100 million, and three of its executives were convicted and served prison time. Also found guilty in the price-fixing case were two Japanese firms (Ajinomoto, Kyowa Hakko) and a South Korean firm (Sewon).^{[Connor JM (2008). Global Price Fixing (2nd ed.). Heidelberg: Springer-Verlag. ISBN 978-3-540-78669-6.]} Secret video recordings of the conspirators fixing lysine’s price can be found online or by requesting the video from the U.S. Department of Justice, Antitrust Division. This case served as the basis of the movie The Informant!, and a book of the same title.^{[ Eichenwald K (2000). The Informant: a true story. New York: Broadway Books. ISBN 978-0-7679-0326-4.]}
  • Arginine
    • Arginine is the amino acid with the formula (H₂N)(HN)CN(H)(CH₂)₃CH(NH₂)CO₂H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO₂⁻) and both the amino and guanidino groups are protonated, resulting in a cation. Only the l-arginine (symbol Arg or R) enantiomer is found naturally.^[1] Arg residues are common components of proteins. It is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG. ^[2] 
    • The guanidine group in arginine is the precursor for the biosynthesis of nitric oxide.^{[Ignarro LJ (2000-09-13). Nitric Oxide: Biology and Pathobiology. Academic Press. p. 189. ISBN 978-0-08-052503-7.]}
    • HISTORY: Arginine was first isolated in 1886 from yellow lupin seedlings by the German chemist Ernst Schulze and his assistant Ernst Steiger.^{[Apel F (July 2015). “Biographie von Ernst Schulze” (PDF). Archived from the original (PDF) on 17 November 2015. Retrieved 2017-11-06.][Schulze E, Steiger E (1887). “Ueber das Arginin” [On arginine]. Zeitschrift für Physiologische Chemie. 11 (1–2): 43–65.]} 
      • He named it from the Greek árgyros (ἄργυρος) meaning “silver” due to the silver-white appearance of arginine nitrate crystals.^{[“BIOETYMOLOGY: ORIGIN IN BIO-MEDICAL TERMS: arginine (Arg R)”. Retrieved 25 July 2019.]} 
      • In 1897, Schulze and Ernst Winterstein (1865–1949) determined the structure of arginine.^{[Schulze E, Winterstein E (September 1897). “Ueber ein Spaltungs-product des Arginins” [On a cleavage product of arginine]. Berichte der Deutschen Chemischen Gesellschaft (in German). 30 (3): 2879–2882. doi:10.1002/cber.18970300389. The structure for arginine is presented on p. 2882.]} 
    • Schulze and Winterstein synthesized arginine from ornithine and cyanamide in 1899,^{[Schulze E, Winterstein E (October 1899). “Ueber die Constitution des Arginins” [On the constitution of arginine]. Berichte der Deutschen Chemischen Gesellschaft (in German). 32 (3): 3191–3194. doi:10.1002/cber.18990320385]} but some doubts about arginine’s structure lingered^{[Cohen JB (1919). Organic Chemistry for Advanced Students, Part 3 (2nd ed.). New York, New York, USA: Longmans, Green & Co. p. 140.]} until Sørensen’s synthesis of 1910.^{[Sölrensen SP (January 1910). “Über die Synthese des dl-Arginins (α-Amino-δ-guanido-n-valeriansäure) und der isomeren α-Guanido-δ-amino-n-valeriansäure” [On the synthesis of racemic arginine (α-amino-δ-guanido-n-valeric acid) and of the isomeric α-guanido-δ-amino-n-valeric acid]. Berichte der Deutschen Chemischen Gesellschaft (in German). 43 (1): 643–651. doi:10.1002/cber.191004301109.]}
      STRUCTURE: The amino acid side-chain of arginine consists of a 3-carbon aliphatic straight chain, the distal end of which is capped by a guanidinium group, which has a pK_a of 13.8,^{[Fitch CA, Platzer G, Okon M, et al. (May 2015). “Arginine: Its pKa value revisited”. Protein Science. 24 (5): 752–61. doi:10.1002/pro.2647. PMC 4420524. PMID 25808204.]} and is therefore always protonated and positively charged at physiological pH. Because of the conjugation between the double bond and the nitrogen lone pairs, the positive charge is delocalized, enabling the formation of multiple hydrogen bonds.
    • It is traditionally obtained by hydrolysis of various cheap sources of protein, such as gelatin.^{[Brand E, Sandberg M (1932). “d-Arginine Hydrochloride”. Org. Synth. 12: 4. doi:10.15227/orgsyn.012.0004]} 
    • It is obtained commercially by fermentation. In this way, 25-35 g/liter can be produced, using glucose as a carbon source.^{[Drauz K, Grayson I, Kleemann A, et al. (2006). “Amino Acids”. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a02_057.pub2]}
    • Arginine is synthesized from citrulline in the urea cycle by the sequential action of the cytosolic enzymes argininosuccinate synthetase and argininosuccinate lyase. This is an energetically costly process, because for each molecule of argininosuccinate that is synthesized, one molecule of adenosine triphosphate (ATP) is hydrolyzed to adenosine monophosphate (AMP), consuming two ATP equivalents.
    • The pathways linking arginine, glutamine, and proline are bidirectional. Thus, the net use or production of these amino acids is highly dependent on cell type and developmental stage.
    • Arginine plays an important role in cell division, wound healing, removing ammonia from the body, immune function,^{[Mauro C, Frezza C (2015-07-13). The Metabolic Challenges of Immune Cells in Health and Disease. Frontiers Media SA. p. 17. ISBN 9782889196227.]} and the release of hormones.^{[Tapiero H, Mathé G, Couvreur P, Tew KD (November 2002). “L-Arginine”. (review). Biomedicine & Pharmacotherapy. 56 (9): 439–445. doi:10.1016/s0753-3322(02)00284-6. PMID 12481980.][Stechmiller JK, Childress B, Cowan L (February 2005). “Arginine supplementation and wound healing”. (review). Nutrition in Clinical Practice. 20 (1): 52–61. doi:10.1177/011542650502000152. PMID 16207646][Witte MB, Barbul A (2003). “Arginine physiology and its implication for wound healing”. (review). Wound Repair and Regeneration. 11 (6): 419–23. doi:10.1046/j.1524-475X.2003.11605.x. PMID 14617280. S2CID 21239136]} 
    • It is a precursor for the synthesis of nitric oxide (NO),^{[Andrew PJ, Mayer B (August 1999). “Enzymatic function of nitric oxide synthases”. (review). Cardiovascular Research. 43 (3): 521–31. doi:10.1016/S0008-6363(99)00115-7. PMID 10690324]} making it important in the regulation of blood pressure.^{[Gokce N (October 2004). “L-arginine and hypertension”. The Journal of Nutrition. 134 (10 Suppl): 2807S–2811S, discussion 2818S–2819S. doi:10.1093/jn/134.10.2807S. PMID 15465790][Kibe R, Kurihara S, Sakai Y, et al. (2014). “Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice”. Scientific Reports. 4 (4548): 4548. Bibcode:2014NatSR…4E4548K. doi:10.1038/srep04548. PMC 4070089. PMID 24686447]} 
    • Arginine is necessary for T-Cells to function in the body, and can lead to their deregulation if depleted.^{[Banerjee, Kasturi; Chattopadhyay, Agnibha; Banerjee, Satarupa (2022-07-01). “Understanding the association of stem cells in fetal development and carcinogenesis during pregnancy”. Advances in Cancer Biology – Metastasis. 4: 100042. doi:10.1016/j.adcanc.2022.100042. ISSN 2667-3940. S2CID 248485831.][Rodriguez, Paulo C.; Quiceno, David G.; Ochoa, Augusto C. (2006-10-05). “l-arginine availability regulates T-lymphocyte cell-cycle progression”. Blood. 109 (4): 1568–1573. doi:10.1182/blood-2006-06-031856. ISSN 0006-4971. PMC 1794048. PMID 17023580.]}
    • See also
    • Arginine glutamate
    • AAKG
    • Canavanine and canaline are toxic analogs of arginine and ornithine.
      • Canavanine
        • L-(+)-(S)-Canavanine is a non-proteinogenic amino acid found in certain leguminous plants. It is structurally related to the proteinogenic α-amino acid L–arginine, the sole difference being the replacement of a methylene bridge (-CH₂– unit) in arginine with an oxa group (i.e., an oxygen atom) in canavanine. Canavanine is accumulated primarily in the seeds of the organisms which produce it, where it serves both as a highly deleterious defensive compound against herbivores (due to cells mistaking it for arginine) and a vital source of nitrogen for the growing embryo.^{[citation needed]} The related L–canaline is similar to ornithine.
        • The mechanism of canavanine’s toxicity is that organisms that consume it typically mistakenly incorporate it into their own proteins in place of L-arginine, thereby producing structurally aberrant proteins that may not function properly. Cleavage by arginase also produces canaline, a potent insecticide.
        • The toxicity of canavanine may be enhanced under conditions of protein starvation,^{[Akaogi, Jun; Barker, Tolga; Kuroda, Yoshiki; Nacionales, Dina C.; Yamasaki, Yoshioki; Stevens, Bruce R.; Reeves, Westley H.; Satoh, Minoru (2006). “Role of non-protein amino acid l-canavanine in autoimmunity”. Autoimmunity Reviews. 5 (6): 429–35. doi:10.1016/j.autrev.2005.12.004. PMID 16890899]} 
        • and canavanine toxicity, resulting from consumption of Hedysarum alpinum seeds with a concentration of 1.2% canavanine weight/weight, has been implicated in the death of a malnourished Christopher McCandless.^{[Krakauer, J., et al. (2015). “Presence of l-canavanine in Hedysarum alpinum seeds and its potential role in the death of Christopher McCandless.” Wilderness & Environmental Medicine. doi:10.1016/j.wem.2014.08.014]} (McCandless was the subject of Jon Krakauer‘s book (and subsequent movie) Into the Wild).
        • NZB/W F1, NZB, and DBA/2 mice fed L-canavanine develop a syndrome similar to systemic lupus erythematosus,^{[Akaogi, Jun; Barker, Tolga; Kuroda, Yoshiki; Nacionales, Dina C.; Yamasaki, Yoshioki; Stevens, Bruce R.; Reeves, Westley H.; Satoh, Minoru (2006). “Role of non-protein amino acid l-canavanine in autoimmunity”. Autoimmunity Reviews. 5 (6): 429–35. doi:10.1016/j.autrev.2005.12.004. PMID 16890899]} while BALB/c mice fed a steady diet of protein containing 1% canavanine showed no change in lifespan.^{[Brown, Dan L (2005). “Canavanine-induced longevity in mice may require diets with greater than 15.7% protein”. Nutrition & Metabolism. 2 (1): 7. doi:10.1186/1743-7075-2-7. PMC 554090. PMID 15733319]}
        • Alfalfa seeds and sprouts contain L-canavanine. The L-canavanine in alfalfa has been linked to lupus-like symptoms in primates, including humans, and other auto-immune diseases. Often stopping consumption reverses the problem.^{[Montanaro, A; Bardana Jr, E. J. (1991). “Dietary amino acid-induced systemic lupus erythematosus”. Rheumatic Disease Clinics of North America. 17 (2): 323–32. doi:10.1016/S0889-857X(21)00573-1. PMID 1862241.][Herbert, V; Kasdan, T. S. (1994). “Alfalfa, vitamin E, and autoimmune disorders”. The American Journal of Clinical Nutrition. 60 (4): 639–40. doi:10.1093/ajcn/60.4.639. PMID 8092103][6]}
      • Canaline
        • l-Canaline (IUPAC name 2-amino-4-(aminooxy)butyric acid)) is a non-proteinogenic amino acid. The compound is found in legumes that contain canavanine, from which it is produced by the action of arginase. The most common-used source for this amino acid is the jack bean, Canavalia ensiformis.
        • l-Canaline is the only naturally occurring amino acid known that has an O-alkyl hydroxylamine functionality in the side chain. This amino acid is structurally related to ornithine (it is the 5-oxa derivative) and is a potent insecticide. Tobacco hornworm larvae fed a diet containing 2.5 mM canaline showed massive developmental aberrations, and most larvae so treated died at the pupal stage. It also exhibits potent neurotoxic effects in the moth.
        • Its toxicity stems primarily from the fact that it readily forms oximes with keto acids and aldehydes, especially the pyridoxal phosphate cofactor of many vitamin B₆-dependent enzymes. It inhibits ornithine aminotransferase at concentrations as low as 10 nM.
        • PLANT NUTRITION: l-Canaline is a substrate for ornithine aminotransferase resulting in the synthesis of l-ureidohomoserine (the corresponding analog of l-citrulline). In turn, the latter forms l-canavaninosuccinic acid in a reaction mediated by argininosuccinic acid synthetase. l-Canavaninosuccinic acid is cleaved to form l-canavanine by argininosuccinic acid synthetase. By these sequential reactions, the canaline-urea cycle (analogous to the ornithine-urea cycle) is formed. Every time a canavanine molecule runs through the canaline-urea cycle, the two terminal nitrogen atoms are released as urea. Urea is an important by-product of this reaction sequence because it makes ammonicial ammonia (urease-mediated) that is available to support intermediary nitrogen metabolism. l-Canaline can be reductively cleaved to l-homoserine, a non-protein amino acid of great importance in the formation of a host of essential amino acids. In this way, the third nitrogen atom of canavanine enters into the reactions of nitrogen metabolism of the plant. As homoserine, its carbon skeleton also finds an important use.

The fourth coordination position is taken up by a labile water molecule. (Lability refers to something that is constantly undergoing change or is likely to undergo change.)

• Lability in Biochemistry
  • This is an important concept as far as kinetics is concerned in metalloproteins. This can allow for the rapid synthesis and degradation of substrates in biological systems.
• Lability in Biology
  • CELLS: Labile cells refer to cells that constantly divide by entering and remaining in the cell cycle.^{[ “Regeneration and Repair”. usc.edu. Archived from the original on 2008-11-28.]} These are contrasted with “stable cells” and “permanent cells”. An important example of this is in the epithelium of the cornea, where cells divide at the basal level and move upwards, and the topmost cells die and fall off.
  • PROTEINS: In medicine, the term “labile” means susceptible to alteration or destruction. For example, a heat-labile protein is one that can be changed or destroyed at high temperatures. The opposite of labile in this context is “stable”.^{[Jackson, C. J.; Fox, A. J.; Jones, D. M.; Wareing, D. R.; Hutchinson, D. N (August 1998). “Associations between heat-stable (O) and heat-labile (HL) serogroup antigens of Campylobacter jejuni: evidence for interstrain relationships within three O/HL serovars”. Journal of Clinical Microbiology. 36 (8): 2223–2228. doi:10.1128/JCM.36.8.2223-2228.1998. PMC 105019. PMID 9665996.]}
  • SOILS: Compounds or materials that are easily transformed (often by biological activity) are termed labile. For example, labile phosphate is that fraction of soil phosphate that is readily transformed into soluble or plant-available phosphate.^{[Mattingly, G. E. G. (1975). “Labile phosphate in soils”. Soil Science. 119 (5): 369. Bibcode:1975SoilS.119..369M. doi:10.1097/00010694-197505000-00007. S2CID 93102505.]} Labile organic matter is the soil organic matter that is easily decomposed by microorganisms.^{[ “Can simple measures of labile soil organic matter predict corn performance?”. ScienceDaily.com. Retrieved 29 August 2014.]}
• Lability in Chemistry
  • The term is used to describe a transient chemical species. As a general example, if a molecule exists in a particular conformation for a short lifetime, before adopting a lower energy conformation (structural arrangement), the former molecular structure is said to have ‘high lability’ (such as C₂₅, a 25-carbon fullerene spheroid). The term is sometimes also used in reference to reactivity – for example, a complex that quickly reaches equilibrium in solution is said to be labile (with respect to that solution). Another common example is the cis effect in organometallic chemistry, which is the labilization of CO ligands in the cis position of octahedral transition metal complexes.
• For the psychological term, see Labile affect.

Treatment with chelating agents such as EDTA leads to complete inactivation. EDTA is a metal chelator that removes zinc, which is essential for activity. They are also inhibited by the chelator orthophenanthroline.

Classification

There are two subgroups of metalloproteinases:

• Exopeptidases, metalloexopeptidases (EC number: 3.4.17).
  • An exopeptidase is any peptidase that catalyzes the cleavage of the terminal (or the penultimate) peptide bond; the process releases a single amino acid, dipeptide or a tripeptide from the peptide chain.^{[ Škárka, Bohumil (1992). Biochémia (in Slovak). Bratislava: Alfa. pp. 360, 688. ISBN 80-05-01076-1.]} Depending on whether the amino acid is released from the amino or the carboxy terminal (N-terminus or C-terminus), an exopeptidase is further classified as an aminopeptidase or a carboxypeptidase, respectively. Thus, an aminopeptidase, an enzyme in the brush border of the small intestine, will cleave a single amino acid from the amino terminal, whereas carboxypeptidase, which is a digestive enzyme present in pancreatic juice, will cleave a single amino acid from the carboxylic end of the peptide.
  • Some examples of exopeptidases include:
    • Carboxypeptidase A – cleaves C-terminal Phe, Tyr, Trp, or Leu
    • Carboxypeptidase B – cleaves C-terminal Lys or Arg
    • Aminopeptidase – cleaves any N-terminal amino acid
    • Prolinase – cleaves N-terminal Pro from dipeptides^{[ “Definition of prolinase | Dictionary.com”. www.dictionary.com. Retrieved 2022-04-09.]}
    • Prolidase – cleaves C-terminal Pro from dipeptides^{[ Namiduru, E. S. (2016). “Prolidase”. Bratislavske Lekarske Listy. 117 (8): 480–485. doi:10.4149/bll_2016_093. ISSN 0006-9248. PMID 27546702.]}
  • A metalloexopeptidase is a type of enzyme that acts as a metalloproteinase exopeptidase. These enzymes have a catalytic mechanism involving a metal, often zinc. They function in molecular biology as agents that cut the terminal (or penultimate) peptide bonds ending peptide chains. Analogous to slicing the end off a loaf of bread, the process releases a single amino acid (or dipeptide) for use.
  • The terms “metallo carboxypeptidase”, “metallo-carboxypeptidase” and “metallocarboxypeptidase” are used to describe a metalloexopeptidase carboxypeptidase. These peptidases specifically target the C-terminus, the unbound carboxyl group (-COOH) at one distinct end of the amino acid chain (cutting one side from a loaf of bread rather than the end).
  • Using the Enzyme Commission number (EC number) system, metallocarboxypeptidases fall under EC 3.4.17.^{[ “ENZYME: 3.4.17.-“. enzyme.expasy.org. Retrieved 2016-05-21.]} Examples of these compounds in the human genome include AGBL1 and AGBL2, known also as ATP/GTP Binding Protein-Like 1 and 2, respectively. The former resides in Chromosome 15 and is made up of 951,392 base pairs (bases) while the latter resides in Chromosome 11 and is made up of 56,221 bases.^{[ “AGBL1”. www.genecards.org. Retrieved 2016-05-21.][“AGBL2”. www.genecards.org. Retrieved 2016-05-21.]}

• Endopeptidases, metalloendopeptidases (3.4.24). Well known metalloendopeptidases include ADAM proteins and matrix metalloproteinases, and M16 metalloproteinases such as Insulin Degrading Enzyme and Presequence Protease^[1][2]
  • Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids.^{[ “endopeptidase”. Merriam-Webster. Archived from the original on 18 January 2017. Retrieved 18 January 2017.]} 
    • For this reason, endopeptidases cannot break down peptides into monomers, while exopeptidases can break down proteins into monomers. A particular case of endopeptidase is the oligopeptidase, whose substrates are oligopeptides instead of proteins.
    • They are usually very specific for certain amino acids. Examples of endopeptidases include:
      • Trypsin – cuts after Arg or Lys, unless followed by Pro. Very strict. Works best at pH 8.
      • Chymotrypsin – cuts after Phe, Trp, or Tyr, unless followed by Pro. Cuts more slowly after His, Met or Leu. Works best at pH 8.
      • Elastase – cuts after Ala, Gly, Ser, or Val, unless followed by Pro.
      • Thermolysin – cuts before Ile, Met, Phe, Trp, Tyr, or Val, unless preceded by Pro. Sometimes cuts after Ala, Asp, His or Thr. Heat stable.
      • Pepsin – cuts before Leu, Phe, Trp or Tyr, unless preceded by Pro. Also others, quite nonspecific; works best at pH 2.
      • Glutamyl endopeptidase – cuts after Glu. Works best at pH 8.
      • Neprilysin
    • Grab the map – The Proteolysis Map
  • A metalloendopeptidase is an enzyme that functions as a metalloproteinase endopeptidase.^{[Glucksman MJ, Orlowski M, Roberts JL (April 1992). “Structural and functional studies of the metalloendopeptidase (EC 3.4.24.15) involved in degrading gonadotropin releasing hormone”. Biophysical Journal. 62 (1): 119–122. Bibcode:1992BpJ….62..119G. doi:10.1016/S0006-3495(92)81798-8. PMC 1260504. PMID 1318098]}

In the MEROPS database peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate – these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.

Metalloproteases are the most diverse of the four main protease types, with more than 50 families classified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are histidine, glutamate, aspartate or lysine and at least one other residue is required for catalysis, which may play an electrophilic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site.^[3] The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as ‘abXHEbbHbc’, where ‘a’ is most often valine or threonine and forms part of the S1′ subsite in thermolysin and neprilysin, ‘b’ is an uncharged residue, and ‘c’ a hydrophobic residue.^[4] Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases.^[3]

Metallopeptidases from family M48 are integral membrane proteins associated with the endoplasmic reticulum and Golgi, binding one zinc ion per subunit. These endopeptidases include CAAX prenyl protease 1, which proteolytically removes the C-terminal three residues of farnesylated proteins.^{[citation needed]}

Metalloproteinase inhibitors are found in numerous marine organisms, including fish, cephalopods, mollusks, algae and bacteria.^[5]

Members of the M50 metallopeptidase family include: mammalian sterol-regulatory element binding protein (SREBP) site 2 protease and Escherichia coli protease EcfE, stage IV sporulation protein FB.

See also

• Matrix metalloproteinase
• The Proteolysis Map

References

1. ^ Shen, Yuequan; Joachimiak, Andrzej; Rosner, Marsha Rich; Tang, Wei-Jen (2006-10-19). “Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism”. Nature. 443 (7113): 870–874. Bibcode:2006Natur.443..870S. doi:10.1038/nature05143. ISSN 1476-4687. PMC 3366509. PMID 17051221.
2. ^ King, John V.; Liang, Wenguang G.; Scherpelz, Kathryn P.; Schilling, Alexander B.; Meredith, Stephen C.; Tang, Wei-Jen (2014-07-08). “Molecular basis of substrate recognition and degradation by human presequence protease”. Structure. 22 (7): 996–1007. doi:10.1016/j.str.2014.05.003. ISSN 1878-4186. PMC 4128088. PMID 24931469.
3. ^ Jump up to:^a b Rawlings ND, Barrett AJ (1995). Evolutionary families of metallopeptidases. Methods in Enzymology. Vol. 248. pp. 183–228. doi:10.1016/0076-6879(95)48015-3. ISBN 978-0-12-182149-4. PMID 7674922.
4. ^ Minde DP, Maurice MM, Rüdiger SG (2012). “Determining biophysical protein stability in lysates by a fast proteolysis assay, FASTpp”. PLOS ONE. 7 (10): e46147. Bibcode:2012PLoSO…746147M. doi:10.1371/journal.pone.0046147. PMC 3463568. PMID 23056252.
5. ^ Thomas NV, Kim SK (2010). “Metalloproteinase inhibitors: status and scope from marine organisms”. Biochemistry Research International. 2010: 845975. doi:10.1155/2010/845975. PMC 3004377. PMID 21197102.

External links

• The MEROPS online database for peptidases and their inhibitors: Metallo Peptidases
• Metalloproteases at the US National Library of Medicine Medical Subject Headings (MeSH)
• Proteopedia: Metalloproteases

This article incorporates text from the public domain Pfam and InterPro: IPR008915

Proteases: metalloendopeptidases (EC 3.4.24)

Enzymes

Portal:

 Biology

Categories: 

• EC 3.4.24
• EC 3.4.17
• Protein families
• Proteases

From Wikipedia where the main page was last updated April 2, 2022