Revisiting heme mechanisms. A perspective on the mechanisms of nitric oxide synthase (NOS), heme oxygenase (HO), and cytochrome P450s (CYP450s)

Yaoqiu Zhu, Richard B Silverman*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

84 Scopus citations

Abstract

Despite the essential biological importance of reactions that involve heme, mechanisms of heme reactions in enzymes like nitric oxide synthase (NOS), heme oxygenase (HO), and cytochrome P450s (CYP450s) are still not well-understood. This Perspective on NOS, HO, and CYP450 mechanisms is written from the point of view of the heme chemistry. Steps in the classical heme catalytic cycle are discussed based on the specific environment within each of these enzymes. Elucidation of the mechanisms of NOS inactivation by some substrate analogues provides important mechanistic clues to the NOS catalytic mechanism. On the basis of mechanistic studies of NOS inactivation by amidine analogues of L-arginine and other previous mechanistic results, a new mechanism for NOS-catalyzed L-arginine NG-hydroxylation (the first half of the catalytic reaction) is proposed in this Perspective. The key step in the second half of the NOS catalytic reaction, the internal electron transfer between the substrate and heme, is discussed on the basis of mechanistic results of NOS inactivation by NG-allyl-L-arginine and the structures of the substrate intermediates. Elucidation of the mechanism of NOS inactivation by amidines, which leads to heme degradation, also provides important mechanistic implications for heme oxygenase-catalyzed heme catabolism. Focusing on the meso-hydroxylation step during inactivation of NOS by amidines as well as the HO-catalyzed reaction, the essential nature of the heme-oxygen species responsible for porphyrin meso-hydroxylation is discussed. Finally, on the basis of the proposed heme degradation mechanism during NOS inactivation and the HO-catalyzed reaction, the mechanism for the formation of the monooxygenated heme species in P450-catalyzed reactions is discussed.

Original languageEnglish (US)
Pages (from-to)2231-2243
Number of pages13
JournalBiochemistry
Volume47
Issue number8
DOIs
StatePublished - Feb 26 2008

ASJC Scopus subject areas

  • Biochemistry

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