A malleable catalyst dominates the metabolism of drugs

@article{Guengerich2006AMC,
  title={A malleable catalyst dominates the metabolism of drugs},
  author={F. Peter Guengerich},
  journal={Proceedings of the National Academy of Sciences},
  year={2006},
  volume={103},
  pages={13565 - 13566}
}
  • F. Guengerich
  • Published 12 September 2006
  • Biology, Chemistry
  • Proceedings of the National Academy of Sciences
In this issue of PNAS, Ekroos and Sjogren (1) present new structures of a cytochrome P450 (P450, or “CYP”), in one case bound with two ligands. The results are of considerable importance not only in regard to the practical issues in drug development but also because they have general significance in consideration of the flexibility of enzymes in recognizing substrates. The concept of how some enzymes accommodate a broad variety of ligands and catalyze multiple, regioselective reactions on a… 

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The binding of substrates to P450s, which is usually viewed as the first step in the catalytic cycle, has been studied extensively via a variety of biochemical and biophysical approaches, and the techniques employed in the binding studies are categorized.

Rationalization of stereospecific binding of propranolol to cytochrome P450 2D6 by free energy calculations

Cytochrome P450 2D6 is a major drug-metabolising enzyme with a wide substrate range. A single-point mutation introduced in this enzyme induces stereoselective binding of R and S-propranolol whereas

Prediction of cytochrome P450 mediated metabolism.

Drug metabolism: Enigmatic enzyme

  • J. Owens
  • Chemistry, Biology
    Nature Reviews Drug Discovery
  • 2006
10.1038/nrd2183 Cytochrome P450 (CYP) 3A4 is the most studied, and yet probably the most challenging, drug-metabolizing enzyme for those involved in drug R&D. Now, a report in PNAS sheds further

Identification of CYP1A2 Ligands by Structure-Based and Ligand-Based Virtual Screening

The applied virtual screening methods are useful for considering CYP1A2 inhibition, either to identify inhibitors of CYP 1A2, e.g. for cancer therapy, or to identify undesirable inhibitory effects of the enzyme.

Cytochrome P450 Enzymes

Multiple Sequential Steps Involved in the Binding of Inhibitors to Cytochrome P450 3A4*

A three-step minimal model for inhibitor binding is proposed, developed with kinetic simulations, consistent with the previously reported model for the binding of substrates, although it is possible that even more steps are involved.

New findings in studies of cytochromes P450

The present state of the art concerning cytochromes P450, a numerous family of heme-containing enzymes belonging to the group of monooxygenases, and its role in mitochondrial dysfunction, cell apoptosis, and pathogenesis of some diseases is considered.

High-throughput enzymology and combinatorial mutagenesis for mining cytochrome P450 functions

The idea is to measure activities on a library of combinatorial variants of similar structure with a large collection of substrates presenting a similar chemical scaffold to relate functional features to structural determinants.
...

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