Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate

Org Biomol Chem. 2004 Jun 21;2(12):1732-41. doi: 10.1039/b403619k. Epub 2004 May 25.

Abstract

3-Deazathiamin diphosphate (deazaTPP) and a second thiamin diphosphate (TPP) analogue having a benzene ring in place of the thiazolium ring have been synthesised. These compounds are both extremely potent inhibitors of pyruvate decarboxylase from Zymomonas mobilis; binding is competitive with TPP and is essentially irreversible even though no covalent linkage is formed. DeazaTPP binds approximately seven-fold faster than TPP and at least 25,000-fold more tightly (K(i) less than 14 pM). DeazaTPP is also a potent inhibitor of the E1 subunit of alpha-ketoglutarate dehydrogenase from E. coli and binds more than 70-fold faster than TPP. In this case slow reversal of the inhibition could be observed and a K(i) value of about 5 nM was calculated (ca. 500-fold tighter binding than TPP).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzene Derivatives / chemistry
  • Benzene Derivatives / metabolism
  • Benzene Derivatives / pharmacology
  • Binding Sites
  • Binding, Competitive
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / enzymology
  • Ketoglutarate Dehydrogenase Complex / antagonists & inhibitors*
  • Ketoglutarate Dehydrogenase Complex / chemistry
  • Kinetics
  • Models, Molecular
  • Pyruvate Decarboxylase / antagonists & inhibitors*
  • Pyruvate Decarboxylase / metabolism
  • Thiamine Pyrophosphate / analogs & derivatives*
  • Thiamine Pyrophosphate / chemical synthesis
  • Thiamine Pyrophosphate / metabolism
  • Thiamine Pyrophosphate / pharmacology*
  • Zymomonas / enzymology

Substances

  • Benzene Derivatives
  • Enzyme Inhibitors
  • Ketoglutarate Dehydrogenase Complex
  • Pyruvate Decarboxylase
  • Thiamine Pyrophosphate