{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:14:06Z","timestamp":1790730846871,"version":"4.1.0"},"reference-count":43,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,3,15]]},"abstract":"<jats:p>Peptidases of parasitic protozoans are emerging as novel virulence factors and therapeutic targets in parasitic infections. A trypanosome-derived aminopeptidase that exclusively hydrolysed substrates with Glp (pyroglutamic acid) in P1 was purified 9248-fold from the plasma of rats infected with Trypanosoma brucei brucei. The enzyme responsible was cloned from a T. brucei brucei genomic DNA library and identified as type I PGP (pyroglutamyl peptidase), belonging to the C15 family of cysteine peptidases. We showed that PGP is expressed in all life cycle stages of T. brucei brucei and is expressed in four other blood-stream-form African trypanosomes. Trypanosome PGP was optimally active and stable at bloodstream pH, and was insensitive to host plasma cysteine peptidase inhibitors. Native purified and recombinant hyper-expressed trypanosome PGP removed the N-terminal Glp blocking groups from TRH (thyrotrophin-releasing hormone) and GnRH (gonadotropin-releasing hormone) with a kcat\/Km value of 0.5 and 0.1\u00a0s\u22121\u00b7\u03bcM\u22121 respectively. The half-life of TRH and GnRH was dramatically reduced in the plasma of trypanosome-infected rats, both in vitro and in vivo. Employing an activity-neutralizing anti-trypanosome PGP antibody, and pyroglutamyl diazomethyl ketone, a specific inhibitor of type I PGP, we demonstrated that trypanosome PGP is entirely responsible for the reduced plasma half-life of TRH, and partially responsible for the reduced plasma half-life of GnRH in a rodent model of African trypanosomiasis. The abnormal degradation of TRH and GnRH, and perhaps other neuropeptides N-terminally blocked with a pyroglutamyl moiety, by trypanosome PGP, may contribute to some of the endocrine lesions observed in African trypanosomiasis.<\/jats:p>","DOI":"10.1042\/bj20051593","type":"journal-article","created":{"date-parts":[[2006,3,2]],"date-time":"2006-03-02T09:11:08Z","timestamp":1141290668000},"page":"635-645","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Pyroglutamyl peptidase type I from <i>Trypanosoma brucei<\/i>: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts"],"prefix":"10.1042","volume":"394","author":[{"given":"Rory\u00a0E.","family":"Morty","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University Hospital Giessen and Marburg, Aulweg 123, D-35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Bulau","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital Giessen and Marburg, Aulweg 123, D-35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Pell\u00e9","sequence":"additional","affiliation":[{"name":"International Livestock Research Institute, P.O. Box 30709, Nairobi, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherwin","family":"Wilk","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Abe","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co. Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2006,2,24]]},"reference":[{"key":"2021112214065393600_B1","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/S0140-6736(03)14694-6","article-title":"The trypanosomiases","volume":"362","author":"Barrett","year":"2003","journal-title":"Lancet"},{"key":"2021112214065393600_B2","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1128\/mr.42.4.664-681.1978","article-title":"Biologically active products from African trypanosomes","volume":"42","author":"Tizard","year":"1978","journal-title":"Microbiol. Rev."},{"key":"2021112214065393600_B3","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/0304-4165(90)90102-3","article-title":"Study of proteolytic activities released by incubation of trypanosomes (Trypanosoma brucei brucei) in pH\u00a05.5 and pH\u00a07.0 phosphate\/glucose buffers","volume":"1035","author":"Boutignon","year":"1990","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112214065393600_B4","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1017\/S0031182000057747","article-title":"Peptidase in the plasma of mice infected with Trypanosoma brucei brucei","volume":"95","author":"Knowles","year":"1987","journal-title":"Parasitology"},{"key":"2021112214065393600_B5","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1399-3011.1993.tb00125.x","article-title":"Unusual cleavage of peptidic hormones generated by trypanosome enzymes released in infested rat serum","volume":"41","author":"Tetaert","year":"1993","journal-title":"Int. J. Pept. Protein Res."},{"key":"2021112214065393600_B6","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S0361-9230(97)00305-5","article-title":"Plasma luteinizing hormone levels in response to gonadotropin-releasing hormone agonist and clonidine in Trypanosoma congolense-infected female goats","volume":"44","author":"Ng'wena","year":"1997","journal-title":"Brain Res. Bull."},{"key":"2021112214065393600_B7","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1055\/s-0029-1211225","article-title":"Experimental \u2018chronic\u2019 African trypanosomiasis: endocrine dysfunctions generated by parasitic components released during the tryptanolytic phase in rats","volume":"101","author":"Soudan","year":"1993","journal-title":"Exp. Clin. Endocrinol."},{"key":"2021112214065393600_B8","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1111\/j.1432-1033.1996.0728w.x","article-title":"Proteases from Trypanosoma brucei brucei. Purification, characterisation and interactions with host regulatory molecules","volume":"238","author":"Troeberg","year":"1996","journal-title":"Eur. J. Biochem."},{"key":"2021112214065393600_B9","doi-asserted-by":"crossref","first-page":"26149","DOI":"10.1074\/jbc.274.37.26149","article-title":"Oligopeptidase B from Trypanosoma brucei, a new member of an emerging subgroup of serine oligopeptidases","volume":"274","author":"Morty","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112214065393600_B10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1042\/BJ20041049","article-title":"Molecular, functional and structural properties of the prolyl oligopeptidase of Trypanosoma cruzi (POP Tc80), which is required for parasite entry into mammalian cells","volume":"388","author":"Bastos","year":"2005","journal-title":"Biochem. J."},{"key":"2021112214065393600_B11","doi-asserted-by":"crossref","first-page":"10925","DOI":"10.1074\/jbc.M410066200","article-title":"Oligopeptidase B from Trypanosoma evansi: a parasite peptidase that inactivates atrial natriuretic factor in the bloodstream of infected hosts","volume":"280","author":"Morty","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112214065393600_B12","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1128\/IAI.69.4.2757-2761.2001","article-title":"Trypanosome-derived oligopeptidase B is released into the plasma of infected rodents, where it persists and retains full catalytic activity","volume":"69","author":"Morty","year":"2001","journal-title":"Infect. Immun."},{"key":"2021112214065393600_B13","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/0006-291X(85)90468-1","article-title":"Pyroglutamyl diazomethyl ketone: potent inhibitor of mammalian pyroglutamyl peptide hydrolase","volume":"130","author":"Wilk","year":"1985","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112214065393600_B14","doi-asserted-by":"crossref","first-page":"14658","DOI":"10.1021\/bi051035k","article-title":"Tropolysin: a new oligopeptidase from African trypanosomes","volume":"44","author":"Morty","year":"2005","journal-title":"Biochemistry"},{"key":"2021112214065393600_B15","doi-asserted-by":"crossref","first-page":"3308","DOI":"10.1128\/jb.178.11.3308-3313.1996","article-title":"Mutational analysis of the active site of Pseudomonas fluorescens pyrrolidone carboxyl peptidase","volume":"178","author":"Le\u00a0Saux","year":"1996","journal-title":"J. Bacteriol."},{"key":"2021112214065393600_B16","doi-asserted-by":"crossref","first-page":"26057","DOI":"10.1074\/jbc.M202779200","article-title":"Cloning and characterization of a leucyl aminopeptidase from three pathogenic Leishmania species","volume":"277","author":"Morty","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021112214065393600_B17","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1023\/A:1015875824238","article-title":"Kinetics and pattern of degradation of thyrotropin-releasing hormone (TRH) in human plasma","volume":"7","author":"M\u00f8ss","year":"1990","journal-title":"Pharm. Res."},{"key":"2021112214065393600_B18","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1248\/bpb.26.1528","article-title":"Hydrolysis of synthetic substrate, L-pyroglutamyl p-nitroanilide is catalyzed solely by pyroglutamyl aminopeptidase I in rat liver cytosol","volume":"26","author":"Abe","year":"2003","journal-title":"Biol. Pharm. Bull."},{"key":"2021112214065393600_B19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/j.1423-0410.1972.tb03818.x","article-title":"Fractionation of plasma with polyethylene glycol","volume":"23","author":"Polson","year":"1972","journal-title":"Vox Sang."},{"key":"2021112214065393600_B20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-4838(98)00248-9","article-title":"Pyroglutamyl peptidase: an overview of the three known enzymatic forms","volume":"1429","author":"Cummins","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112214065393600_B21","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1042\/bj2900921","article-title":"Identification of the thyrotropin-releasing-hormone-degrading ectoenzyme as a metallopeptidase","volume":"290","author":"Czekay","year":"1993","journal-title":"Biochem. J."},{"key":"2021112214065393600_B22","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S1046-5928(02)00632-0","article-title":"Pyroglutamyl-peptidase I: cloning, sequencing, and characterisation of the recombinant human enzyme","volume":"28","author":"Dando","year":"2003","journal-title":"Protein Expr. Purif."},{"key":"2021112214065393600_B23","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/oxfordjournals.jbchem.a124005","article-title":"Pyroglutamyl peptidase gene from Bacillus amyloliquefaciens: cloning, sequencing, expression, and crystallization of the expressed enzyme","volume":"113","author":"Yoshimoto","year":"1993","journal-title":"J. Biochem. (Tokyo)"},{"key":"2021112214065393600_B24","doi-asserted-by":"crossref","first-page":"18557","DOI":"10.1074\/jbc.M011724200","article-title":"The mechanism of substrate recognition of pyroglutamyl-peptidase I from Bacillus amyloliquefaciens as determined by X-ray crystallography and site-directed mutagenesis","volume":"276","author":"Ito","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112214065393600_B25","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/1357-2725(96)00034-9","article-title":"Bovine brain pyroglutamyl aminopeptidase (type-1): purification and characterisation of a neuropeptide-inactivating peptidase","volume":"28","author":"Cummins","year":"1996","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2021112214065393600_B26","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1177\/153537020322801114","article-title":"Clinical follow-up in the rat experimental model of African trypanosomiasis","volume":"228","author":"Darsaud","year":"2003","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"2021112214065393600_B27","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1210\/jcem-48-3-377","article-title":"Plasma clearance and plasma half-disappearance time of exogenous thyrotropin-releasing hormone and pyroglutamyl-N3im-methyl-histidyl prolineamide","volume":"48","author":"Morley","year":"1979","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021112214065393600_B28","doi-asserted-by":"crossref","first-page":"16746","DOI":"10.1074\/jbc.M910386199","article-title":"Kinetic investigation of the specificity of porcine brain thyrotropin-releasing hormone-degrading ectoenzyme for thyrotropin-releasing hormone-like peptides","volume":"275","author":"Kelly","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112214065393600_B29","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1046\/j.1432-1327.1999.00753.x","article-title":"Human TRH-degrading ectoenzyme cDNA cloning, functional expression, genomic structure and chromosomal assignment","volume":"265","author":"Schomburg","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"2021112214065393600_B30","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1046\/j.1432-1033.2002.02768.x","article-title":"Purification and characterization of the thyrotropin-releasing hormone (TRH)-degrading serum enzyme and its identification as a product of liver origin","volume":"269","author":"Schmitmeier","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"2021112214065393600_B31","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/0006-291X(85)91201-X","article-title":"The effect of inhibitors of prolyl endopeptidase and pyroglutamyl peptide hydrolase on TRH degradation in rat serum","volume":"132","author":"Friedman","year":"1985","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112214065393600_B32","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1111\/j.1471-4159.1986.tb00643.x","article-title":"Delineation of a particulate thyrotropin-releasing hormone-degrading enzyme in rat brain by the use of specific inhibitors of prolyl endopeptidase and pyroglutamyl peptide hydrolase","volume":"46","author":"Friedman","year":"1986","journal-title":"J. Neurochem."},{"key":"2021112214065393600_B33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0167-0115(81)90001-X","article-title":"Degradation of luteinizing hormone-releasing hormone by serum and plasma in vitro","volume":"2","author":"McDermott","year":"1981","journal-title":"Regul. Pept."},{"key":"2021112214065393600_B34","first-page":"439","article-title":"Inhibition of endopeptidase 24.15 slows the in vivo degradation of luteinizing hormone-releasing hormone","volume":"251","author":"Lasdun","year":"1989","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021112214065393600_B35","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1042\/bj2880875","article-title":"A comparison of the zinc contents and substrate specificities of the endothelial and testicular forms of porcine angiotensin converting enzyme and the preparation of isoenzyme-specific antisera","volume":"288","author":"Williams","year":"1992","journal-title":"Biochem. J."},{"key":"2021112214065393600_B36","doi-asserted-by":"crossref","first-page":"47078","DOI":"10.1074\/jbc.M106017200","article-title":"Trypanosoma cruzi prolyl oligopeptidase Tc80 is involved in nonphagocytic mammalian cell invasion by trypomastigotes","volume":"276","author":"Grellier","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112214065393600_B37","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0166-6851(92)90158-G","article-title":"Identification of a 33-kilodalton immunodominant antigen of Trypanosoma congolense as a cysteine protease","volume":"56","author":"Authi\u00e9","year":"1992","journal-title":"Mol. Biochem. Parasitol."},{"key":"2021112214065393600_B38","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1210\/jcem-43-4-882","article-title":"Radioimmunoassay and chromatographic similarity of circulating endogenous gonadotropin releasing hormone and hypothalamic extracts in man","volume":"43","author":"Mortimer","year":"1976","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021112214065393600_B39","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1507\/endocrj1954.27.371","article-title":"Fluctuation of the plasma TRH level in normal subjects in a 4-hour observation period","volume":"27","author":"Azukizawa","year":"1980","journal-title":"Endocrinol. Jpn."},{"key":"2021112214065393600_B40","first-page":"5","article-title":"Reproductive disorders in African trypanosomiasis: a review","volume":"45","author":"Ikede","year":"1988","journal-title":"Acta Trop."},{"key":"2021112214065393600_B41","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1111\/j.1749-6632.1998.tb09619.x","article-title":"Neuroendocrine dysfunction in African trypanosomiasis. The role of cytokines","volume":"840","author":"Reincke","year":"1998","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2021112214065393600_B42","first-page":"172","article-title":"Impairment in the pituitary-thyroid axis of the Camelus dromedarius infected with Trypanosoma evansi","volume":"108","author":"al-Qarawi","year":"2001","journal-title":"Dtsch. Tierarztl. Wochenschr."},{"key":"2021112214065393600_B43","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1530\/acta.0.1270086","article-title":"Decrease of testosterone level during an experimental African trypanosomiasis: involvement of a testicular LH receptor desensitization","volume":"127","author":"Soudan","year":"1992","journal-title":"Acta Endocrinol. (Copenhagen)"}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/394\/3\/635\/641082\/bj3940635.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/394\/3\/635\/641082\/bj3940635.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T16:29:56Z","timestamp":1637598596000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/394\/3\/635\/44052\/Pyroglutamyl-peptidase-type-I-from-Trypanosoma"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,2,24]]},"references-count":43,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2006,3,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20051593","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,2,24]]}}}