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Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2

Academic Article
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Overview

authors

  • Sansen, S.
  • Yano, J. K.
  • Reynald, R. L.
  • Schoch, G. A.
  • Griffin, K. J.
  • Stout, C. David
  • Johnson, Eric

publication date

  • May 2007

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Microsomal cytochrome P450 family 1 enzymes play prominent roles in xenobiotic detoxication and procarcinogen activation. P450 1A2 is the principal cytochrome P450 family 1 enzyme expressed in human liver and participates extensively in drug oxidations. This enzyme is also of great importance in the bioactivation of mutagens, including the N-hydroxylation of arylamines. P450-catalyzed reactions involve a wide range of substrates, and this versatility is reflected in a structural diversity evident in the active sites of available P450 structures. Here, we present the structure of human P450 1A2 in complex with the inhibitor alpha-naphthoflavone, determined to a resolution of 1.95 A. alpha-Naphthoflavone is bound in the active site above the distal surface of the heme prosthetic group. The structure reveals a compact, closed active site cavity that is highly adapted for the positioning and oxidation of relatively large, planar substrates. This unique topology is clearly distinct from known active site architectures of P450 family 2 and 3 enzymes and demonstrates how P450 family 1 enzymes have evolved to catalyze efficiently polycyclic aromatic hydrocarbon oxidation. This report provides the first structure of a microsomal P450 from family 1 and offers a template to study further structure-function relationships of alternative substrates and other cytochrome P450 family 1 members.

subject areas

  • Benzoflavones
  • Binding Sites
  • Crystallization
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Enzyme Inhibitors
  • Humans
  • Hydroxylation
  • Models, Molecular
  • Oxidation-Reduction
  • Protein Conformation
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M611692200

PubMed ID

  • 17311915
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Additional Document Info

start page

  • 14348

end page

  • 14355

volume

  • 282

issue

  • 19

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