A malleable catalyst dominates the metabolism of drugs

  title={A malleable catalyst dominates the metabolism of drugs},
  author={F. Peter Guengerich},
  journal={Proceedings of the National Academy of Sciences},
  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… 

Substrate binding to cytochromes P450

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.



Structures of cytochrome P450 3A4.

Structural basis for ligand promiscuity in cytochrome P450 3A4

Cytochrome P450 (CYP) 3A4 is the most promiscuous of the human CYP enzymes and contributes to the metabolism of ≈50% of marketed drugs. It is also the isoform most often involved in unwanted

Heterotropic cooperativity of cytochrome P450 3A4 and potential drug-drug interactions.

Effector-induced increases in CYP3A4 activity were observed during the 1'-hydroxylation of midazolam and 4'- and 10-hydroxYLation of warfarin in human hepatocyte systems, implying that CYP cooperativity has the potential to cause in vivo drug-drug interactions.

The Structure of Human Microsomal Cytochrome P450 3A4 Determined by X-ray Crystallography to 2.05-Å Resolution*

The structure of P450 3A4 should facilitate a better understanding of the substrate selectivity of the enzyme, and may diminish the efficiency of substrate oxidation, which may be improved by space restrictions imposed by the presence of a second substrate molecule.

Conformational Flexibility of Mammalian Cytochrome P450 2B4 in Binding Imidazole Inhibitors with Different Ring Chemistry and Side Chains

The thermodynamic signature obtained for structurally similar inhibitors suggests remarkable plasticity of CYP2B4.

Kinetics and Thermodynamics of Ligand Binding by Cytochrome P450 3A4*

A three-step substrate binding model is proposed, based on absorbance and fluorescence stopped-flow kinetic data and equilibrium binding data obtained with bromocriptine, and evaluated using kinetic modeling.

Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone

The structures revealed a surprisingly small active site, with little conformational change associated with the binding of either compound, and an unexpected peripheral binding site is identified, located above a phenylalanine cluster, which may be involved in the initial recognition of substrates or allosteric effectors.

Pyrene.pyrene complexes at the active site of cytochrome P450 3A4: evidence for a multiple substrate binding site.

Fluorescence properties of pyrene are exploited to exploit and provide the first spectroscopic evidence for substrate complexes within a single fluid active site, and the possibility that turnover rate, regioselectivities, and stereoselectivity of the reaction are determined by the substrate.


The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data for drug-drug interactions of drugs primarily cleared by glucuronidation.

Substrate-induced Conformational Changes in the Transmembrane Segments of Human P-glycoprotein

Results provide direct evidence that the packing of the TM segments in the drug-binding site is changed when P-gp binds to a particular substrate, explaining how P- gp can accommodate a broad range of compounds.