749858-60-4Relevant articles and documents
Hydrogen tunneling steps in cyclooxygenase-2 catalysis
Danish, Husain H.,Doncheva, Irina S.,Roth, Justine P.
, p. 15846 - 15849 (2011)
Cyclooxygenases-1 and -2 are tyrosyl radical (Y?)-utilizing hemoproteins responsible for the biosynthesis of lipid-derived autocoids. COX-2, in particular, is a primary mediator of inflammation and believed to be up-regulated in many forms of cancer. Described here are first-of-a-kind studies of COX-2-catalyzed oxidation of the substrate analogue linoleic acid. Very large (≥20) temperature-independent deuterium kinetic isotope effects (KIEs) on the rate constant for enzyme turnover were observed, due to hydrogen atom abstraction from the bisallylic C-H(D) of the fatty acid. The magnitude of the KIE depends on the O2 concentration, consistent with reversible H/D tunneling mediated by the catalytic Y?. At physiological levels of O 2, retention of the hydrogen initially abstracted by the catalytic tyrosine results in strongly temperature-dependent KIEs on O-H(D) homolysis, also characteristic of nuclear tunneling.
