Synthesis and evaluation of 1-deoxy-D-xylulose 5-phosphoric acid analogues as alternate substrates for methylerythritol phosphate synthase.
[structure: see text] Four deoxyxylulose phosphate (DXP) analogues were synthesized and evaluated as substrates/inhibitors for methylerythritol phosphate (MEP) synthase. In analogues CF(3)-DXP (1), CF(2)-DXP (2), and CF-DXP (3), the three methyl hydrogens at C1 of DXP were sequentially replaced by fluorine. In the fourth analogue, Et-DXP (4), the methyl group in DXP was replaced by an ethyl moiety. Analogues 1, 2, and 4 were not substrates for MEP synthase under normal catalytic conditions and were instead modest inhibitors with IC(50) values of 2.0, 3.4, and 6.2 mM, respectively. In contrast, 3 was a good substrate (k(cat) = 38 s(-)(1), K(m) = 227 muM) with a turnover rate similar to that of the natural substrate. These results are consistent with a retro-aldol/aldol mechanism rather than an alpha-ketol rearrangement for the enzyme-catalyzed conversion of DXP to MEP.
Fox
David T
DT
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
Poulter
C Dale
CD
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002384:Catalysis; D004896:Erythritol / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D008968:Molecular Conformation; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010428:Pentosephosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013403:Sugar Phosphates / Q000138:chemical synthesis
C109460:1-deoxylulose 5-phosphate; C114232:2-C-methylerythritol 4-phosphate; D009097:Multienzyme Complexes; D010428:Pentosephosphates; D013403:Sugar Phosphates; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases; D004896:Erythritol