A novel type of allosteric regulation: Functional cooperativity in monomeric proteins

Ilia G. Denisov, Stephen G. Sligar

Research output: Contribution to journalReview article

Abstract

Cooperative functional properties and allosteric regulation in cytochromes P450 play an important role in xenobiotic metabolism and define one of the main mechanisms of drug-drug interactions. Recent experimental results suggest that ability to bind simultaneously two or more small organic molecules can be the essential feature of cytochrome P450 fold, and often results in rich and complex pattern of allosteric behavior. Manifestations of non-Michaelis kinetics include homotropic and heterotropic activation and inhibition effects depending on the stoichiometric ratios of substrate and effector, changes in the regio- and stereospecificity of catalytic transformations, and often give rise to the clinically important drug-drug interactions. In addition, functional response of P450 systems is modulated by the presence of specific and non-specific effector molecules, metal ions, membrane incorporation, formation of homo- and hetero-oligomers, and interactions with the protein redox partners. In this article we briefly overview the main factors contributing to the allosteric effects in cytochromes P450 with the main focus on the sources of cooperative behavior in xenobiotic metabolizing monomeric heme enzymes with their conformational flexibility and extremely broad substrate specificity. The novel mechanism of functional cooperativity in P450 enzymes does not require substantial binding cooperativity, rather it implies the presence of one or more binding sites with higher affinity than the single catalytically active site in the vicinity of the heme iron.

Original languageEnglish (US)
Pages (from-to)91-102
Number of pages12
JournalArchives of Biochemistry and Biophysics
Volume519
Issue number2
DOIs
StatePublished - Mar 15 2012

Keywords

  • Allosteric effects
  • Cooperativity
  • Cytochrome P450
  • Drug-drug interactions
  • Heterotropic interactions
  • Substrate specificity

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Fingerprint Dive into the research topics of 'A novel type of allosteric regulation: Functional cooperativity in monomeric proteins'. Together they form a unique fingerprint.

  • Cite this