The structural basis of chain length control in Rv1086

Wenjian Wang, Changjiang Dong, Michael McNeil, Devinder Kaur, Sebabrata Mahapatra, Dean C. Crick, James H. Naismith

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

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-famesyl 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-famesyl 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. (C) 2008 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)129-140
Number of pages12
JournalJournal of Molecular Biology
Volume381
Issue number1
DOIs
Publication statusPublished - 1 Aug 2008

Keywords

  • drug design
  • enzyme mechanism
  • tuberculosis
  • x-ray crystallography
  • inhibitors
  • UNDECAPRENYL DIPHOSPHATE SYNTHASE
  • MYCOBACTERIUM-TUBERCULOSIS
  • BIOSYNTHESIS
  • COMPLEXES

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