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Synthesis, inhibitory and activation properties of prenyldiphosphate mimics for aromatic prenylations with ubiA-prenyl transferase

2004; ARKAT USA, Inc.; Volume: 2004; Issue: 13 Linguagem: Inglês

10.3998/ark.5550190.0005.d10

1551-7012

Svetlana Zakharova, Michael Fulhorst, L. LUCZAK, Ludger A. Wessjohann,

Chemical Synthesis and Analysis

4-Hydroxybenzoate oligoprenyl transferase from E. coli (ubiA-prenyl transferase) is a crucial enzyme for ubiquinone biosynthesis.It catalyzes the formation of 3-oligoprenyl-4-hydroxybenzoates like geranyl hydroxybenzoate (GHB, 23) from geranyl pyrophosphate (GPP, 22).Several analogues and mimics of geranyl pyrophosphate have been prepared for an examination of their ability to inhibit the enzyme.7,11-Dimethyl-3-oxododeca-6,10-dienoic acid (2), 3-hydroxy-7,11-dimethyldodeca-6,10-dienoic acid (3), 2-hydroxy-4,8-dimethyl-3,7-nonadienylphosphonic acid (4), and tripotassium [[(4E)-5,9-dimethyldeca-4,8-dienyl]phosphinato](difluoro)methylphosphonate (5) were synthesized from geraniol.ω-2,ω-1-Dihydroxylated farnesyl diphosphate 6 was prepared from trans,trans-farnesol.All compounds were tested for enzyme inhibition in a competitive assay with natural substrate.The effect of these compounds on ubiA-prenyltransferase activity varied substantially, ranging from almost full inhibition to, surprisingly, enhanced enzymatic activity at low concentrations by some compounds.A special, EDTAmodifyable magnesium effect is discussed as potential reason.