Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism

Kristaps Jaudzems, Janis Kuka, Aleksandrs Gutsaits, Kirils Zinovjevs, Ivars Kalvinsh, Edgars Liepinsh, Edvards Liepinsh, Maija Dambrova

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Carnitine acetyltransferase (CrAT; EC 2.3.1.7) catalyzes the reversible transfer of acetyl groups between acetyl-coenzyme A (acetyl-CoA) and L-carnitine; it also regulates the cellular pool of CoA and the availability of activated acetyl groups. In this study, biochemical measurements, saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, and molecular docking were applied to give insights into the CrAT binding of a synthetic inhibitor, the cardioprotective drug mildronate (3-(2,2,2- trimethylhydrazinium)-propionate). The obtained results show that mildronate inhibits CrAT in a competitive manner through binding to the carnitine binding site, not the acetyl-CoA binding site. The bound conformation of mildronate closely resembles that of carnitine except for the orientation of the trimethylammonium group, which in the mildronate molecule is exposed to the solvent. The dissociation constant of the mildronate CrAT complex is approximately 0.1mM, and the Ki is 1.6mM. The results suggest that the cardioprotective effect of mildronate might be partially mediated by CrAT inhibition and concomitant regulation of cellular energy metabolism pathways.

Original languageEnglish
Pages (from-to)1269-1275
Number of pages7
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume24
Issue number6
DOIs
Publication statusPublished - Dec 2009
Externally publishedYes

Keywords

  • Acetyl-CoA
  • Carnitine acetyltransferase
  • Inhibition
  • Mildronate
  • STD NMR

Field of Science

  • 3.1 Basic medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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