Studies on the inhibition of sphingosine-1-phosphate lyase by stabilized reaction intermediates and stereodefined azido phosphates

Eur J Med Chem. 2016 Nov 10;123:905-915. doi: 10.1016/j.ejmech.2016.08.008. Epub 2016 Aug 6.

Abstract

Two kinds of inhibitors of the PLP-dependent enzyme sphingosine-1-phosphate lyase have been designed and tested on the bacterial (StS1PL) and the human (hS1PL) enzymes. Amino phosphates 1, 12, and 32, mimicking the intermediate aldimines of the catalytic process, were weak inhibitors on both enzyme sources. On the other hand, a series of stereodefined azido phosphates, resulting from the replacement of the amino group of the natural substrates with an azido group, afforded competitive inhibitors in the low micromolar range on both enzyme sources. This similar behavior represents an experimental evidence of the reported structural similarities for both enzymes at their active site level. Interestingly, the anti-isomers of the non-natural enantiomeric series where the most potent inhibitors on hS1PL.

Keywords: Enzyme inhibitor; Sphingolipids; Sphingosine lyase; Stereocontrolled; Synthesis.

MeSH terms

  • Aldehyde-Lyases / antagonists & inhibitors*
  • Aldehyde-Lyases / chemistry
  • Aldehyde-Lyases / metabolism
  • Azides / chemistry*
  • Drug Stability
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Phosphates / chemistry*
  • Phosphates / metabolism
  • Phosphates / pharmacology*
  • Protein Conformation
  • Stereoisomerism

Substances

  • Azides
  • Enzyme Inhibitors
  • Phosphates
  • Aldehyde-Lyases
  • sphingosine 1-phosphate lyase (aldolase)