Document Detail

Active site contribution to specificity of the aspartic proteases plasmepsins I and II.
MedLine Citation:
PMID:  12189138     Owner:  NLM     Status:  MEDLINE    
Plasmepsins I and II (PM I and II) are aspartic proteases involved in the initial steps of Plasmodium hemoglobin degradation. They are attractive targets for antimalarial drug development. The two enzymes are 73% identical, yet have different substrate and inhibitor specificities. The x-ray structures of proform and mature PM II have been determined, but models of PM I do not adequately explain the selectivity of the two proteases. To better understand the basis of these recognition differences, we have identified nine residues of PM II that are in proximity to the inhibitor pepstatin in the crystal structure and differ in PM I. We mutated these residues in PM II to the cognate amino acids of PM I. Kinetic parameters for substrate and inhibitors for the PM II-mutant were similar to those of PM II-wild type (WT). Cleavage specificity was assessed using hemoglobin or a random decamer peptide library as substrate. Again, PM II-mutant behaved like PM II-WT rather than PM I-WT. These results indicate that differences in plasmepsin specificity depend more on conformational differences from distant sites than on specific active site variation.
Pilaiwan Siripurkpong; Jirundon Yuvaniyama; Prapon Wilairat; Daniel E Goldberg
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2002-08-19
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Oct 
Date Detail:
Created Date:  2002-10-25     Completed Date:  2002-12-09     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  41009-13     Citation Subset:  IM    
Department of Biochemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand.
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MeSH Terms
Aspartic Acid Endopeptidases / antagonists & inhibitors,  chemistry,  genetics,  metabolism*
Base Sequence
Binding Sites
Chromatography, High Pressure Liquid
DNA Primers
Hemoglobins / metabolism
Models, Molecular
Mutagenesis, Site-Directed
Protozoan Proteins
Recombinant Proteins / antagonists & inhibitors,  chemistry,  genetics,  metabolism
Substrate Specificity
Grant Support
Reg. No./Substance:
0/DNA Primers; 0/Hemoglobins; 0/Protozoan Proteins; 0/Recombinant Proteins; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC; EC II

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