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].

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* 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]

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]

Subcommittee members: Anthony J. Turner (Chairperson) School of Molecular and Cellular Biology Faculty of Biological Sciences University of Leeds Leeds LS2 9JT U.K Arnaud Chatonnet Dynamique Musculaire et Métabolisme INRA Université de Montpellier UMR866 2 Place Viala 34060 Montpellier David Fairlie Institute for Molecular Bioscience Division of Chemistry and Structural Biology and Australian Infectious Diseases Research Centre School of Chemistry and Molecular Biosciences University of Queensland St. Lucia Queensland 4067, Australia Christopher M. Overall Department of Biochemistry and Molecular Biology University of British Columbia Vancouver British Columbia Canada Neil Rawlings The Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton Cambridgeshire CB10 1SA UK Christopher Southan (Curator) Centre for Discovery Brain Sciences Edinburgh Medical School: Biomedical Sciences Room 338 Hugh Robson Building George Square Edinburgh EH8 9XD