Graduate Thesis Or Dissertation
 

Studies of non-mevalonate isoprenoid biosynthesis : the 1-deoxy-D-xylulose-5-phosphate isomeroreductase (DXR) mediated reaction

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  • This dissertation details the investigation of an alternate pathway to isoprenoids that occurs in plants and microorganisms, the non-mevalonate pathway. This exploration of the pathway focuses on the second step, the conversion of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methylerythritol-4-phosphate (MEP) by the enzyme DXP isomeroreductase (DXR). These studies led to an appreciation of the stereochemical course of the enzymatic reduction step and to a better understanding of the structural requirements for inhibitors to have optimal interactions at the active site of the enzyme, DXR. The investigation of the reduction step mediated by DXR revealed that the C1 pro-S hydrogen in 2-C-methylerythritol-4-phosphate derives from C3 of DXP for the DXR from Synechocystis sp PCC6803. The pro-R hydrogen originates from NADPH. The pro-S hydride of NADPH is transferred to the re face of the proposed aldehyde intermediate, which designates DXR as a class B dehydrogenase. Based on the structural features of fosmidomycin, a known inhibitor of DXR, several analogs were synthesized and evaluated for their inhibitory activity against DXR. It was discovered that a polar head group with two ionizable groups, a suitable length of intervening carbons, and an N-acyl N-hydroxy moiety are important factors to demonstrate significant inhibition activity. These studies also provided information that is complementary to structural data obtained from recent X-ray crystal structures of DXR.
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