Current Protein & Peptide Science

Ben M. Dunn  
Department of Biochemistry and Molecular Biology University of Florida
College of Medicine, P.O. Box 100245, Gainesville
Florida, FL 32610-0245
USA

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Structure-based Drug Design Targeting Biosynthesis of Isoprenoids: A Crystallographic State of the Art of the Involved Enzymes

Author(s): J. de Ruyck and J. Wouters

Affiliation: Laboratoire de Chimie Biologique Structurale, University of Namur, 61 rue de Bruxelles 5000 Namur, Belgium.

Abstract:

Biosynthesis of the universal terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), from three acetyl CoA moieties through mevalonate was studied extensively in the 1950s. For several decades, the mevalonate paradigm reigned supreme and a mevalonate origin was attributed to a growing number of natural products, in many cases erroneously. Besides this biosynthetic pathway, the existence of a second one leading to IPP and DMAPP through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered more recently in plants and some eubacteria. This pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis or Helicobacter pylori and is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of methods including comparative genomics, enzymology, advanced NMR technology and crystallography. The present crystallographic review of enzymes involved in isoprenoid biosynthesis will be useful for understanding the various catalytic mechanisms and could potentially help for structure-based drug design.

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Article Details

VOLUME: 9
ISSUE: 2
Page: [117 - 137]
Pages: 21
DOI: 10.2174/138920308783955261
Price: $58