Record number :
1257145
Title of article :
The Structural Basis of Chain Length Control in Rv1086
Author/Authors :
Wenjian Wang، نويسنده , , Changjiang Dong، نويسنده , , Michael McNeil، نويسنده , , Devinder Kaur، نويسنده , , Sebabrata Mahapatra، نويسنده , , Dean C. Crick، نويسنده , , James H. Naismith، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2008
Pages :
12
From page :
129
To page :
140
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 (C50) 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.
Keywords :
X-ray crystallography , Inhibitors , Drug Design , enzyme mechanism , Tuberculosis
Journal title :
Journal of Molecular Biology
Link To Document :