A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2.

A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2. Research Abstract Details 

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A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2. Abstract Text:

Ajay Singh,K Jordan Walker,Puran S Sijwali,Anthony L Lau,Philip J Rosenthal,

The cysteine proteases falcipain-2 and falcipain-3 are hemoglobinases and potential targets for chemotherapy directed against Plasmodium falciparum, the most important human malaria parasite. Most in vivo evaluations of candidate antimalarials are conducted in murine malaria models, and falcipain homologs from rodent malaria parasites differ importantly from falcipain-2 and falcipain-3. We expressed berghepain-2, the single homolog of falcipain-2 and falcipain-3 of the rodent parasite P. berghei, in Escherichia coli, and characterized the refolded active enzyme. Berghepain-2 was biochemically very similar to the previously characterized rodent plasmodial protease vinckepain-2, but differed from falcipain-2 and falcipain-3 in its fine substrate and inhibitor specificity. We then used homology modeling and evolutionary trace analysis to predict key amino acids that mediate functional differences between falcipain-2 and berghepain-2. Thirteen amino acids were sequentially altered to replace berghepain-2 residues with those in falcipain-2. Mutant enzymes varied in activity and sensitivity to inhibitors. A berghepain-2 mutant with eight substitutions retained good activity and demonstrated fine substrate and inhibitor sensitivity more similar to that of falcipain-2 than berghepain-2. These results suggest that, to facilitate drug discovery, we can produce mutant animal model malaria parasites with biochemical properties more like those of the key drug target, P. falciparum.

A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2. Publishing Authors By Initials

A Singh,KJ Walker,PS Sijwali,AL Lau,PJ Rosenthal,

For similar proteins: protozoan proteins research abstracts see: proteins: protozoan proteins research

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A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Protein engineering, design & selection : PEDS

VOLUME: 20

Page Numbers: 171-7

Journal Abbreviation: Protein Eng. Des. Sel.

ISSN: 1741-0126

DAY: 12

MONTH: 04

YEAR: 2007

A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101186484

A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2. Keywords Mesh Terms:

KEYWORDS: Protozoan Proteins

MESH TERMS: genetics

Chemical & Substance for Abstract: A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2. Information

Substance Name: falcipain 2

Registry Number: EC 3.4.22.-

Grant and Affiliation Information for A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2.

AFFILIATION: Department of Medicine, San Francisco General Hospital, University of California, CA 94143, USA.

Country: England

AGENCY: United States NCRR

GRANT: RR01081

ACRONYM: RR

MEDLINETA: Protein Eng Des Sel

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