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Oligopeptidase
Oligopeptidase is an enzyme that cleaves peptides but not proteins, a property that is due to its structure: the active site of this enzyme is located at the end of a narrow cavity which can only be reached by peptides. These oligopeptides, peptides, predominantely smaller than 30 amino acids in length, play essential roles as hormones, in the surveillance against pathogens, and in neurological activities. Therefore these molecules constantly need to be specifically generated and inactivated, which is the role of the oligopeptidases. Oligopeptidase is a term coined in 1979 to designate a sub-group of the endopeptidases,〔(ACM, Caldo H, Reis ML (1979) Susceptibility of a peptide derived from bradykinin to hydrolysis by brain endo-oligopeptidases and pancreatic proteinases. J Biol Chem 254, 5304-5307. PMID 447650 )〕〔(AJ and Rawlings ND (1992). Oligopeptidases, and the emergence of the prolyl oligopeptidase family. Chem Hoppe-Seyler 373, 353-360. PMID 1515061 )〕 which are not involved in the digestion nor in the processing of proteins like the pancreatic enzymes, proteasomes, cathepsins among many others. The prolyl-oligopeptidase or prolyl endopeptidase (POP) is a good example of how an oligopeptidase interacts with and metabolizes an oligopeptide. The peptide has first to penetrate into a 4 Å hole on the surface of the enzyme in order to reach an 8,500Å3 internal cavity, where the active site is located.〔(V, Böcskei Z, Polgár L (1998). Prolyl oligopeptidase: an unusual beta propeller domain regulates proteolysis. Cell 94, 161-170. PMID 9695945 )〕〔(M, Chen C, Davies DR, Chiu TK (2010). Induced-fit mechanism for prolyl endopeptidase. J Biol Chem 285, 21487-21495. ) 〕 Even though the size of the peptide is crucial for its docking, the flexibility of both enzyme and ligand seems to play an essential role in determining whether a peptide bond will be hydrolyzed or not.〔(SG, Gomes MD, Juliano L, Camargo ACM (1998). A comparative conformational analysis of thimet oligopeptidase (EC 3.5.2.4.15) substrates. J Pept Res 51, 452-459. PMID 9650720 )〕〔(F, Gomes MD, Cabrera A et al (1999). Thimet oligopeptidase and the stability of MHC class I epitopes in macrophage cytosol. Biochem. Biophys. Res. Cmmun. 255, 596-601. ) 〕 This contrasts with the classical specificity of proteolytic enzymes, which derives from the chemical features of the amino acid side chains around the scissile bond.〔(I, Berger A (1967). On the size of the active site in proteases I. Papain. Biochem Biophys Res Commun 27, 157-162. ) 〕 A number of enzymatic studies supports this conclusion.〔〔(ACM, Gomes MD, Reichl AP, Jacchieri SG, Juliano L (1997) Structural features which make oligopeptides susceptible to hydrolysis by recombinant endooligopeptidase 24.15 (EC 3.4.24.15). Biochem J 324, 517-522 )〕 This peculiar specificity suggests that the concept of conformational melding of the peptides used to explain the interaction between T-cell receptor and its epitopes,〔Backer BM, Scott DR, Blevins SJ, Hawse WF (2012). Structural and dynamic control of T-cell receptor specificity, cross-reactivity, and binding mechanism. Imunn Rev 250, 10-31.] 〕 seems more likely to describe the enzymatic specificity of the oligopeptidases. Another important feature of the oligopeptidases is their sensitivity to the oxidation-reduction (redox) state of the environment.〔(ACM, Shapanka R, Greene LJ (1973). Preparation, assay and partial characterization of a neutral endopeptidase from rabbit brain. Biochemistry 12, 1838-1844, 1973. PMID 4699240 )〕〔(EB, Martins AR, Camargo ACM. 1976. Isolation of brain endopeptidases: Influence of size and sequence of substrates structurally related to bradykinin. Biochemistry 15, 1967-1974. PMID 5120 )〕 An "on-off" switch provides a qualitative change in peptide binding and/or degradation activity. However, the redox state only exerts strong influence on cytosolic enzymes (TOP〔(CN, Glucksman MJ, Lew RA et al. (1997). Thiol activation of endopeptidase (EC 3.4.24.15). A novel mechanism for the regulation of the catalytic activity. J Biol Chem 272, 17395-17399 ) 〕〔(K, Hines CS, Coll-Rodriguez J, Rodgers DW (2004). Crystal structure of human thimet oligopeptidase provides insight into substrate recognition, regulation, and localization. J Biol Chem 279, 20480-20489 ) 〕 neurolysin〔(A, Sugiura N et al. (1997). Targeting of endopeptidase 24.16 to different subcellular compartments by alternative promoter usage. J Biol Chem 272, 15313-15322 ) 〕〔(KL, Vento MA et al (2013). The effects of para-chloromercuribenzoic acid and different oxidative and sulfhydryl agents on a novel, non-AT1, non-AT2 angiotensin binding site identified as neurolysin. Regul Pept. 184,104-114 ) 〕 POP〔(V, Szeltner Z, Polgár L (2000). Catalysis of serine oligopeptidases is controlled by a gating filter mechanism. EMBO Rep 1, 277-281 ) 〕 and Ndl-1 oligopeptidase,〔(MD, Juliano L et al (1993). Dynorphin-derived peptides reveal the presence of a critical cysteine for the activity of brain endo-oligopeptidase A. Biochem Biophys Res Commun 197, 501-507 )〕〔(MA, Portaro FC, Bastos MF et al. (2005). Inhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1. Proc. Natl. Acad. Sci 102 (10): 3828-3833. ) 〕 not on cytoplasmic membrane oligopeptidases (angiotensin-converting enzyme and neprilysin). Thus, the redox state of the intracellular environment very likely modulates the activity of the thiol-sensitive oligopeptidases, thereby contributing to define the fate of proteasome products, driving them to complete hydrolysis, or, alternatively, converting them into bioactive peptides, such as the MHC-Class I peptides.〔〔(JH, Khan S, Seifert U et al. (2011) Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nature Immunology- http://www.nature.com/ni/journal/v12/n1/full/ni.1974.html )〕〔(CL, Portaro FCV, Bonato VLD et al (1999). Thimet Oligopeptidase (EC.3.4.24.15) is a novel protein on the route of MHC class I antigen presentation. Biochem Biophys Res Commun 255, 591-595. ) 〕
==Historical Background==
Autolysis:Proteins are essential macromolecules of living organisms. They are continuously being degraded into their constituent amino acids which can be reused in the synthesis of new proteins. Every cellular protein has its own half-life time. In humans, for instance, 50% of the liver and plasma proteins are replaced in 10 days, whereas in muscles it takes 180 days. In average, every 80 days about 50% of our proteins are totally replaced. Although the regulation of the protein degradation is as important as their synthesis to keep each cell protein concentration at the optimum level, this research area remained neglected until the end of the 1970s. Up to this time, lysosomes, discovered in the 1950s by the Belgian cytologist Christian de Duve were held responsible for the complete digestion of intra- and extracellular proteins by the lysosomal hydrolytic enzymes.
Limited proteolysis: Between the 1970s and 1980s, this view drastically changed. New experimental evidences showed that, under physiological conditions, non-lysosomal proteases were responsible for limited proteolysis of intra- and/or extracellular proteins, a concept originally conceived by Linderstᴓm-Lang in 1950. Endogenous or exogenous proteins are processed by non-lysosomal proteases into intermediate-sized polypeptides, which display gene and metabolic regulation, neurologic, endocrine, and immunological roles, whose dysfunction might explain a number of pathologies. Consequently, protein degradation did not represent anymore the end of the biological function of proteins, but rather the beginning of a yet unexplored side of the biology of the cells. A number of intra- or extracellular proteases release protein fragments endowed with essential biological activities. These hydrolytic processes could be carried out by proteases such as Proteasomes, Proprotein Convertases, Caspases, Rennin and Kallikreins. Among the products released by the non-lysosomal proteases are the bioactive oligopeptides such as hormones, neuropeptides and epitopes that, once released, could be modulated in their biological activities by specific peptidases, which promote the trimming, conversion and/or inactivation of the bioactive oligopeptides.
The history of oligopeptidases originates in the late 1960s, when the rabbit brain was searched for enzymes that cause inactivation of the nonapeptide bradykinin.〔Camargo ACM, Graeff F (1969).Subcellular distribution and properties of the bradykinin inactivation system in rabbit brain homogenates. Biochem Pharmacol 18, 548-549. PMID 5778163〕 In the early and mid 1970s two thiol-activated endopeptidases, responsible for more than 90% of bradykinin inactivation, were isolated from cytosol of rabbit brain, and characterized.〔〔 They correspond to EOPA (endooligopeptidase A, EC 3.4.22.19), and Prolyl endopeptidase or Prolyl oligopeptidase (POP) (EC 3.4.21.26). Since their activities are restricted to oligopeptides (usually from 8-13 amino acid residues), and do not hydrolyze proteins or large peptides (>30 amino acid residues), they were designated oligopeptidases.〔 In the early and mid 1980s other oligopeptidases, mostly metallopeptidases, were described in the cytosol of mammalian tissues, such as the TOP (thimet oligopeptidase, EC 3.4.24.15),〔(M, Michaud C, Chu TG (1983). A soluble metalloendopeptidase from rat brain. Purification of the enzyme and determination of specificity with synthetic and natural peptides. Eur J Biochem 135, 81–88. ) 〕 and the neurolysin (EC 3.4.24.16).〔(F, Vincent JP, Kitabgi P (1983). Degradation of neurotensin by synaptic membranes: involvement of a thermolysin-like metalloendopeptidase (enkephalinase), angiotensin-converting enzyme and other unidentified peptidases. J Neurochem 41, 375-384. PMID 6308159 )〕 Earlier on, the ACE (angiotensin-converting enzyme, EC 3.4.15.1), and the NEP (neprilysin, EC 3.4.24.11), had been described, at the end of the 1960s,〔()〕 and in 1973,〔(MA, Kenny AJ (1974). The purification and specificity of a neutral endopeptidase from rabbit kidney brush border. Biochem J 137, 477–488. PMID 4423492 )〕 respectively.
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