The structural basis of chain length control in Rv1086

Wang, Wenjian, Dong, Changjiang, McNeil, Michael, Kaur, Devinder, Mahapatra, Sebabrata, Crick, Dean C and Naismith, James H (2008) The structural basis of chain length control in Rv1086. Journal of Molecular Biology, 381 (1). pp. 129-40. ISSN 0022-2836

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Abstract

In Mycobacterium tuberculosis, two related Z-prenyl diphosphate synthases, E,Z-farnesyl diphosphate synthase (Rv1086) and decaprenyl diphosphate synthase (Rv2361c), work in series to synthesize decaprenyl phosphate (C(50)) from isopentenyl diphosphate and E-geranyl diphosphate. Decaprenyl phosphate plays a central role in the biosynthesis of essential mycobacterial cell wall components, such as the mycolyl-arabinogalactan-peptidoglycan complex and lipoarabinomannan; thus, its synthesis has attracted considerable interest as a potential therapeutic target. Rv1086 is a unique prenyl diphosphate synthase in that it adds only one isoprene unit to geranyl diphosphate, generating the 15-carbon product (E,Z-farnesyl diphosphate). Rv2361c then adds a further seven isoprene units to E,Z-farnesyl diphosphate in a processive manner to generate the 50-carbon prenyl diphosphate, which is then dephosphorylated to generate a carrier for activated sugars. The molecular basis for chain-length discrimination by Rv1086 during synthesis is unknown. We also report the structure of apo Rv1086 with citronellyl diphosphate bound and with the product mimic E,E-farnesyl diphosphate bound. We report the structures of Rv2361c in the apo form, with isopentenyl diphosphate bound and with a substrate analogue, citronellyl diphosphate. The structures confirm the enzymes are very closely related. Detailed comparison reveals structural differences that account for chain-length control in Rv1086. We have tested this hypothesis and have identified a double mutant of Rv1086 that makes a range of longer lipid chains.

Item Type: Article
Uncontrolled Keywords: alkyl and aryl transferases,amino acid sequence,bacterial proteins,crystallography, x-ray,models, molecular,molecular sequence data,mutation,mycobacterium tuberculosis,protein binding,protein structure, quaternary,protein structure, tertiary,sequence alignment,sequence homology, amino acid,structural homology, protein,substrate specificity
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 17 Nov 2014 12:58
Last Modified: 10 Jun 2020 00:05
URI: https://ueaeprints.uea.ac.uk/id/eprint/50982
DOI: 10.1016/j.jmb.2008.05.060

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