Contents
Overview
Peptidases and proteinases hydrolyse peptide bonds, and can be simply divided on the basis of whether terminal peptide bonds are cleaved (exopeptidases and exoproteinases) at the amino terminus (aminopeptidases) or carboxy terminus (carboxypeptidases). Non-terminal peptide bonds are cleaved by endopeptidases and endoproteinases, which are divided into serine endopeptidases (EC 3.4.21.-), cysteine endopeptidases (EC 3.4.22.-), aspartate endopeptidases (EC 3.4.23.-), metalloendopeptidases (EC 3.4.24.-) and threonine endopeptidases (EC 3.4.25.-).
Since it is beyond the scope of the Guide to list all peptidase and proteinase activities, this summary focuses on selected enzymes of significant pharmacological interest that have ligands (mostly small-molecules) directed against them. For those interested in detailed background we recommend the MEROPS database [1] (with whom we collaborate) as an information resource [2].
Subfamilies
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Further reading
* Key recommended reading is highlighted with an asterisk
Aiken A, Khokha R. (2010) Unraveling metalloproteinase function in skeletal biology and disease using genetically altered mice. Biochim. Biophys. Acta, 1803 (1): 121-32. [PMID:19616584]
Bindom SM, Lazartigues E. (2009) The sweeter side of ACE2: physiological evidence for a role in diabetes. Mol. Cell. Endocrinol., 302 (2): 193-202. [PMID:18948167]
Catania JM, Chen G, Parrish AR. (2007) Role of matrix metalloproteinases in renal pathophysiologies. Am. J. Physiol. Renal Physiol., 292 (3): F905-11. [PMID:17190907]
Charrier-Hisamuddin L, Laboisse CL, Merlin D. (2008) ADAM-15: a metalloprotease that mediates inflammation. FASEB J., 22 (3): 641-53. [PMID:17905725]
Clark IM, Swingler TE, Sampieri CL, Edwards DR. (2008) The regulation of matrix metalloproteinases and their inhibitors. Int. J. Biochem. Cell Biol., 40 (6-7): 1362-78. [PMID:18258475]
Danser AH, Batenburg WW, van den Meiracker AH, Danilov SM. (2007) ACE phenotyping as a first step toward personalized medicine for ACE inhibitors. Why does ACE genotyping not predict the therapeutic efficacy of ACE inhibition?. Pharmacol. Ther., 113 (3): 607-18. [PMID:17257685]
DasGupta S, Murumkar PR, Giridhar R, Yadav MR. (2009) Current perspective of TACE inhibitors: a review. Bioorg. Med. Chem., 17 (2): 444-59. [PMID:19095454]
Datta B. (2009) Roles of P67/MetAP2 as a tumor suppressor. Biochim. Biophys. Acta, 1796 (2): 281-92. [PMID:19716858]
Deiteren K, Hendriks D, Scharpé S, Lambeir AM. (2009) Carboxypeptidase M: Multiple alliances and unknown partners. Clin. Chim. Acta, 399 (1-2): 24-39. [PMID:18957287]
Demon D, Van Damme P, Vanden Berghe T, Vandekerckhove J, Declercq W, Gevaert K, Vandenabeele P. (2009) Caspase substrates: easily caught in deep waters?. Trends Biotechnol., 27 (12): 680-8. [PMID:19879007]
Devel L, Czarny B, Beau F, Georgiadis D, Stura E, Dive V. (2010) Third generation of matrix metalloprotease inhibitors: Gain in selectivity by targeting the depth of the S1' cavity. Biochimie, 92 (11): 1501-8. [PMID:20696203]
Drucker DJ. (2007) The role of gut hormones in glucose homeostasis. J. Clin. Invest., 117 (1): 24-32. [PMID:17200703]
Ferrario CM. (2011) ACE2: more of Ang-(1-7) or less Ang II?. Curr. Opin. Nephrol. Hypertens., 20 (1): 1-6. [PMID:21045683]
Ferrario CM, Varagic J. (2010) The ANG-(1-7)/ACE2/mas axis in the regulation of nephron function. Am. J. Physiol. Renal Physiol., 298 (6): F1297-305. [PMID:20375118]
Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol., 10 (3): 241-7. [PMID:19221555]
Gingras D, Béliveau R. (2010) Emerging concepts in the regulation of membrane-type 1 matrix metalloproteinase activity. Biochim. Biophys. Acta, 1803 (1): 142-50. [PMID:19409422]
Greenlee KJ, Werb Z, Kheradmand F. (2007) Matrix metalloproteinases in lung: multiple, multifarious, and multifaceted. Physiol. Rev., 87 (1): 69-98. [PMID:17237343]
Gupta SP. (2007) Quantitative structure-activity relationship studies on zinc-containing metalloproteinase inhibitors. Chem. Rev., 107 (7): 3042-87. [PMID:17622180]
Gyrd-Hansen M, Meier P. (2010) IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat. Rev. Cancer, 10 (8): 561-74. [PMID:20651737]
Hadler-Olsen E, Fadnes B, Sylte I, Uhlin-Hansen L, Winberg JO. (2011) Regulation of matrix metalloproteinase activity in health and disease. FEBS J., 278 (1): 28-45. [PMID:21087458]
Haroon N, Inman RD. (2010) Endoplasmic reticulum aminopeptidases: Biology and pathogenic potential. Nat Rev Rheumatol, 6 (8): 461-7. [PMID:20531381]
Hu J, Van den Steen PE, Sang QX, Opdenakker G. (2007) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov, 6 (6): 480-98. [PMID:17541420]
Hui KS. (2007) Brain-specific aminopeptidase: from enkephalinase to protector against neurodegeneration. Neurochem. Res., 32 (12): 2062-71. [PMID:17476590]
Imai Y, Kuba K, Penninger JM. (2007) Angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Cell. Mol. Life Sci., 64 (15): 2006-12. [PMID:17558469]
Janecka A, Staniszewska R, Gach K, Fichna J. (2008) Enzymatic degradation of endomorphins. Peptides, 29 (11): 2066-73. [PMID:18718496]
Kantari C, Walczak H. (2011) Caspase-8 and bid: caught in the act between death receptors and mitochondria. Biochim. Biophys. Acta, 1813 (4): 558-63. [PMID:21295084]
Kawanabe Y, Nauli SM. (2011) Endothelin. Cell. Mol. Life Sci., 68 (2): 195-203. [PMID:20848158]
Kirby M, Yu DM, O'Connor S, Gorrell MD. (2010) Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin. Sci., 118 (1): 31-41. [PMID:19780719]
Kirkby NS, Hadoke PW, Bagnall AJ, Webb DJ. (2008) The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?. Br. J. Pharmacol., 153 (6): 1105-19. [PMID:17965745]
Kuba K, Imai Y, Ohto-Nakanishi T, Penninger JM. (2010) Trilogy of ACE2: a peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters. Pharmacol. Ther., 128 (1): 119-28. [PMID:20599443]
Lambert DW, Clarke NE, Turner AJ. (2010) Not just angiotensinases: new roles for the angiotensin-converting enzymes. Cell. Mol. Life Sci., 67 (1): 89-98. [PMID:19763395]
Lambert DW, Hooper NM, Turner AJ. (2008) Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system. Biochem. Pharmacol., 75 (4): 781-6. [PMID:17897633]
López-Otín C, Matrisian LM. (2007) Emerging roles of proteases in tumour suppression. Nat. Rev. Cancer, 7 (10): 800-8. [PMID:17851543]
MacFadyen RJ. (2007) Can matrix metalloproteinase inhibitors provide a realistic therapy in cardiovascular medicine?. Curr Opin Pharmacol, 7 (2): 171-8. [PMID:17317319]
Mastroianni CM, Liuzzi GM. (2007) Matrix metalloproteinase dysregulation in HIV infection: implications for therapeutic strategies. Trends Mol Med, 13 (11): 449-59. [PMID:18029231]
Mogk A, Schmidt R, Bukau B. (2007) The N-end rule pathway for regulated proteolysis: prokaryotic and eukaryotic strategies. Trends Cell Biol., 17 (4): 165-72. [PMID:17306546]
Mucha A, Drag M, Dalton JP, Kafarski P. (2010) Metallo-aminopeptidase inhibitors. Biochimie, 92 (11): 1509-29. [PMID:20457213]
Murphy G. (2008) The ADAMs: signalling scissors in the tumour microenvironment. Nat. Rev. Cancer, 8 (12): 929-41. [PMID:19005493]
Murphy G, Nagase H. (2011) Localizing matrix metalloproteinase activities in the pericellular environment. FEBS J., 278 (1): 2-15. [PMID:21087456]
Norton GR, Brooksbank R, Woodiwiss AJ. (2010) Gene variants of the renin-angiotensin system and hypertension: from a trough of disillusionment to a welcome phase of enlightenment?. Clin. Sci., 118 (8): 487-506. [PMID:20088829]
O'Brien P, O'Connor BF. (2008) Seprase: an overview of an important matrix serine protease. Biochim. Biophys. Acta, 1784 (9): 1130-45. [PMID:18262497]
Ohnuma K, Dang NH, Morimoto C. (2008) Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends Immunol., 29 (6): 295-301. [PMID:18456553]
Okun I, Balakin KV, Tkachenko SE, Ivachtchenko AV. (2008) Caspase activity modulators as anticancer agents. Anticancer Agents Med Chem, 8 (3): 322-41. [PMID:18393791]
Page-McCaw A, Ewald AJ, Werb Z. (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol., 8 (3): 221-33. [PMID:17318226]
Pejler G, Knight SD, Henningsson F, Wernersson S. (2009) Novel insights into the biological function of mast cell carboxypeptidase A. Trends Immunol., 30 (8): 401-8. [PMID:19643669]
Pirard B. (2007) Insight into the structural determinants for selective inhibition of matrix metalloproteinases. Drug Discov. Today, 12 (15-16): 640-6. [PMID:17706545]
Pradelli LA, Bénéteau M, Ricci JE. (2010) Mitochondrial control of caspase-dependent and -independent cell death. Cell. Mol. Life Sci., 67 (10): 1589-97. [PMID:20151314]
Raizada MK, Ferreira AJ. (2007) ACE2: a new target for cardiovascular disease therapeutics. J. Cardiovasc. Pharmacol., 50 (2): 112-9. [PMID:17703127]
Ramos-Fernandez M, Bellolio MF, Stead LG. (2011) Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review. J Stroke Cerebrovasc Dis, 20 (1): 47-54. [PMID:21044610]
Rengel Y, Ospelt C, Gay S. (2007) Proteinases in the joint: clinical relevance of proteinases in joint destruction. Arthritis Res. Ther., 9 (5): 221. [PMID:18001502]
Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M, Foidart JM, Noel A, Cataldo D. (2008) Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie, 90 (2): 369-79. [PMID:17920749]
Rosell A, Lo EH. (2008) Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol, 8 (1): 82-9. [PMID:18226583]
Rosenberg GA. (2009) Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol, 8 (2): 205-16. [PMID:19161911]
Rudnicki M, Mayer G. (2009) Significance of genetic polymorphisms of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. Pharmacogenomics, 10 (3): 463-76. [PMID:19290794]
Schrader K, Huai J, Jöckel L, Oberle C, Borner C. (2010) Non-caspase proteases: triggers or amplifiers of apoptosis?. Cell. Mol. Life Sci., 67 (10): 1607-18. [PMID:20169397]
Schulz R. (2007) Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu. Rev. Pharmacol. Toxicol., 47: 211-42. [PMID:17129183]
Shi L, Mao C, Xu Z, Zhang L. (2010) Angiotensin-converting enzymes and drug discovery in cardiovascular diseases. Drug Discov. Today, 15 (9-10): 332-41. [PMID:20170743]
Shi YB, Fu L, Hasebe T, Ishizuya-Oka A. (2007) Regulation of extracellular matrix remodeling and cell fate determination by matrix metalloproteinase stromelysin-3 during thyroid hormone-dependent post-embryonic development. Pharmacol. Ther., 116 (3): 391-400. [PMID:17919732]
Taylor RC, Cullen SP, Martin SJ. (2008) Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol., 9 (3): 231-41. [PMID:18073771]
Tsukamoto T, Wozniak KM, Slusher BS. (2007) Progress in the discovery and development of glutamate carboxypeptidase II inhibitors. Drug Discov. Today, 12 (17-18): 767-76. [PMID:17826690]
Tveita A, Rekvig OP, Zykova SN. (2008) Glomerular matrix metalloproteinases and their regulators in the pathogenesis of lupus nephritis. Arthritis Res. Ther., 10 (6): 229. [PMID:19090960]
Vakifahmetoglu-Norberg H, Zhivotovsky B. (2010) The unpredictable caspase-2: what can it do?. Trends Cell Biol., 20 (3): 150-9. [PMID:20061149]
van Endert P. (2011) Post-proteasomal and proteasome-independent generation of MHC class I ligands. Cell. Mol. Life Sci., 68 (9): 1553-67. [PMID:21390545]
Verma RP, Hansch C. (2007) Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg. Med. Chem., 15 (6): 2223-68. [PMID:17275314]
Vincenti MP, Brinckerhoff CE. (2007) Signal transduction and cell-type specific regulation of matrix metalloproteinase gene expression: can MMPs be good for you?. J. Cell. Physiol., 213 (2): 355-64. [PMID:17654499]
Wilson TJ, Singh RK. (2008) Proteases as modulators of tumor-stromal interaction: primary tumors to bone metastases. Biochim. Biophys. Acta, 1785 (2): 85-95. [PMID:18082147]
Wolfe MS. (2009) Intramembrane proteolysis. Chem. Rev., 109 (4): 1599-612. [PMID:19226105]
Xu P, Sriramula S, Lazartigues E. (2011) ACE2/ANG-(1-7)/Mas pathway in the brain: the axis of good. Am. J. Physiol. Regul. Integr. Comp. Physiol., 300 (4): R804-17. [PMID:21178125]
Yan C, Boyd DD. (2007) Regulation of matrix metalloproteinase gene expression. J. Cell. Physiol., 211 (1): 19-26. [PMID:17167774]
Yazbeck R, Howarth GS, Abbott CA. (2009) Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease?. Trends Pharmacol. Sci., 30 (11): 600-7. [PMID:19837468]
Zolkiewska A. (2008) ADAM proteases: ligand processing and modulation of the Notch pathway. Cell. Mol. Life Sci., 65 (13): 2056-68. [PMID:18344021]
References
1. Rawlings et al.. MEROPS. Accessed on 03/02/2016. Modified on 03/02/2016. MEROPS, https://merops.sanger.ac.uk/
2. Rawlings ND, Barrett AJ, Finn R. (2016) Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res., 44 (D1): D343-50. [PMID:26527717]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Anthony J. Turner (Chairperson)
Arnaud Chatonnet
David Fairlie
Christopher M. Overall
Neil Rawlings
Christopher Southan |
How to cite this family page
Database page citation:
Arnaud Chatonnet, David Fairlie, Christopher M. Overall, Neil Rawlings, Christopher Southan, Anthony J. Turner. Peptidases and proteinases. Accessed on 09/12/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=759.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Enzymes. Br J Pharmacol. 176 Issue S1: S297-S396.
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