Synthesis and evaluation of 1-deoxy-D-xylulose 5-phosphoric acid analogues as alternate substrates for methylerythritol phosphate synthase

J Org Chem. 2005 Mar 18;70(6):1978-85. doi: 10.1021/jo048022h.

Abstract

[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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Aldose-Ketose Isomerases / chemistry*
  • Catalysis
  • Erythritol / analogs & derivatives*
  • Erythritol / chemical synthesis
  • Molecular Conformation
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / chemistry*
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / chemistry*
  • Pentosephosphates / chemical synthesis*
  • Pentosephosphates / chemistry
  • Pentosephosphates / pharmacology
  • Sugar Phosphates / chemical synthesis

Substances

  • 1-deoxylulose 5-phosphate
  • 2-C-methylerythritol 4-phosphate
  • Multienzyme Complexes
  • Pentosephosphates
  • Sugar Phosphates
  • Oxidoreductases
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases
  • Erythritol