Pyroglutamyl peptidase type I from Trypanosoma brucei: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts
- 24 February 2006
- journal article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 394 (3), 635-645
- https://doi.org/10.1042/bj20051593
Abstract
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 s−1·μM−1 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.Keywords
This publication has 46 references indexed in Scilit:
- Tropolysin, a New Oligopeptidase from African Trypanosomes,Biochemistry, 2005
- Cloning and Characterization of a Leucyl Aminopeptidase from Three Pathogenic Leishmania SpeciesPublished by Elsevier BV ,2002
- Trypanosoma cruzi Prolyl Oligopeptidase Tc80 Is Involved in Nonphagocytic Mammalian Cell Invasion by TrypomastigotesPublished by Elsevier BV ,2001
- Kinetic Investigation of the Specificity of Porcine Brain Thyrotropin-releasing Hormone-degrading Ectoenzyme for Thyrotropin-releasing Hormone-like PeptidesPublished by Elsevier BV ,2000
- Experimental “Chronic” African Trypanosomiasis: Endocrine Dysfunctions Generated by Parasitic Components Released during the Tryptanolytic Phase in RatsExperimental and Clinical Endocrinology & Diabetes, 1993
- Study of proteolytic activities released by incubation of trypanosomes (Trypanosoma brucei brucei) in pH 5.5 and pH 7.0 phosphate/glucose buffersBiochimica et Biophysica Acta (BBA) - General Subjects, 1990
- Peptidase in the plasma of mice infected withTrypanosoma brucei bruceiParasitology, 1987
- Delineation of a Particulate Thyrotropin‐Releasing Hormone‐Degrading Enzyme in Rat Brain by the Use of Specific Inhibitors of Prolyl Endopeptidase and Pyroglutamyl Peptide HydrolaseJournal of Neurochemistry, 1986
- The effect of inhibitors of prolyl endopeptidase and pyroglutamyl peptide hydrolase on TRH degradation in rat serumBiochemical and Biophysical Research Communications, 1985
- Pyroglutamyl diazomethyl ketone: Potent inhibitor of mammalian pyroglutamyl peptide hydrolaseBiochemical and Biophysical Research Communications, 1985