Ejection of Structural Zinc Leads to Inhibition of γ-butyrobetaine Hydroxylase

Bioorg Med Chem Lett. 2014 Nov 1;24(21):4954-7. doi: 10.1016/j.bmcl.2014.09.035. Epub 2014 Sep 19.

Abstract

γ-Butyrobetaine hydroxylase (BBOX) is a 2-oxoglutarate and Fe(II) dependent oxygenase that catalyses an essential step during carnitine biosynthesis in animals. BBOX is inhibited by ejection of structural zinc by a set of selenium containing analogues. Previous structural analyses indicated that an undisrupted N-terminal zinc binding domain of BBOX is required for catalysis. Ebselen is a relatively potent BBOX inhibitor, an observation which may in part reflect its cardioprotective properties.

Keywords: 2-Oxoglutarate dependent oxygenase; Carnitine; Ebselen; Zinc ejection; γ-Butyrobetaine hydroxylase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azoles / pharmacology*
  • Catalysis
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Organoselenium Compounds / pharmacology*
  • Oxidation-Reduction
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship
  • Zinc / metabolism*
  • gamma-Butyrobetaine Dioxygenase / antagonists & inhibitors*
  • gamma-Butyrobetaine Dioxygenase / metabolism

Substances

  • Azoles
  • Enzyme Inhibitors
  • Organoselenium Compounds
  • ebselen
  • gamma-Butyrobetaine Dioxygenase
  • Zinc