TAILIEUCHUNG - Báo cáo khoa học: Enzymatic properties of the lactate dehydrogenase enzyme from Plasmodium falciparum

The lactate dehydrogenase enzyme fromPlasmodium falciparum(PfLDH) is a target for antimalarial compounds owing to structural and functional differences from the human isozymes. The plasmodial enzyme possesses a five-residue insertion in the substrate-specificity loop and exhibits less marked substrate inhibition than its mammalian counterparts. | ễFEBS Journal Enzymatic properties of the lactate dehydrogenase enzyme from Plasmodium falciparum Deborah K. Shoemark1 Matthew J. Cliff2 Richard B. Sessions1 and Anthony R. Clarke1 1 Department of Biochemistry University of Bristol UK 2 Molecular Biology and Biotechnology Department University of Sheffield UK Keywords kinetic lactate dehydrogenase malaria mechanism Plasmodium falciparum Correspondence D. K. Shoemark Department of Biochemistry School of Medical Sciences University Walk Clifton BristolBS8 1TD UK Fax 44 117 9288274 Tel 44 117 9288595 E-mail Received 24 January 2007 revised 13 March 2007 accepted 23 March 2007 doi The lactate dehydrogenase enzyme from Plasmodium falciparum PfLDH is a target for antimalarial compounds owing to structural and functional differences from the human isozymes. The plasmodial enzyme possesses a five-residue insertion in the substrate-specificity loop and exhibits less marked substrate inhibition than its mammalian counterparts. Here we provide a comprehensive kinetic analysis of the enzyme by steady-state and transient kinetic methods. The mechanism deduced by product inhibition studies proves that PfLDH shares a common mechanism with the human LDHs that of an ordered sequential bireactant system with coenzyme binding first. Transient kinetic analysis reveals that the major rate-limiting step is the closure of the substrate-specificity loop prior to hydride transfer in line with other LDHs. The five-residue insertion in this loop markedly increases substrate specificity compared with the human muscle and heart isoforms. The lactate dehydrogenase enzyme from the parasite causing cerebral malaria Plasmodium falciparum is currently the subject of efforts to find alternatives to established drug regimens which suffer increasingly from problems of resistance and side-effects 1 . This enzyme PfLDH catalyses the final step in the glycolytic pathway upon which the parasite .

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