Exploring the subsite specificity of Schistosoma mansoni aspartyl hemoglobinase through comparative molecular modelling.

Abstract:

:Blood flukes of the genus Schistosoma currently infect millions of people in tropical and subtropical countries. An enzyme playing a major role in hemoglobin (Hb) degradation by Schistosoma mansoni has been cloned and shown to be highly similar to the human cathepsin D aspartyl proteinase, although presenting a distinct substrate specificity from the latter. Investigating the structural features responsible for this difference has a major application in the design of selective anti-schistosomal drugs. In order to achieve this goal a homology model for the S. mansoni aspartyl hemoglobinase was constructed and then used to simulate the complexes formed with two transition state analogues of Hb-derived octapeptide substrates. Comparison with human cathepsin D showed that different pocket volumes and surface electrostatic potentials arise from substitutions in residues comprising the S4, S3, S2 and S3' subsites. Since the primary specificity of the S. mansoni enzyme resembles that of HIV-1 protease, we have discussed the applicability of current retroviral protease inhibitors as leads for the design of new anti-schistosomal drugs.

journal_name

FEBS Lett

journal_title

FEBS letters

authors

Silva FP Jr,Ribeiro F,Katz N,Giovanni-De-Simone S

doi

10.1016/s0014-5793(02)02270-6

keywords:

subject

Has Abstract

pub_date

2002-03-13 00:00:00

pages

141-8

issue

2-3

eissn

0014-5793

issn

1873-3468

pii

S0014579302022706

journal_volume

514

pub_type

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