Protein family review
This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.
Authors:
Correspondence:
Danièle Werck-Reichhart
Email:
daniele.werck@ibmp-ulp.u-strasbg.fr
Read the full article
Subscribers to GenomeBiology may view the full version of this review article online at http://genomebiology.com/2000/1/6/reviews/3003
Published:
8 December 2000
Cytochromes P450: a success story
Summary
Cytochrome P450 proteins, named for the absorption band at 450 nm of their carbon-monoxide-bound form, are one of the largest superfamilies of enzyme proteins. The P450 genes (also called CYP) are found in the genomes of virtually all organisms, but their number has exploded in plants. Their amino-acid sequences are extremely diverse, with levels of identity as low as 16% in some cases, but their structural fold has remained the same throughout evolution. P450s are heme-thiolate proteins; their most conserved structural features are related to heme binding and common catalytic properties, the major feature being a completely conserved cysteine serving as fifth (axial) ligand to the heme iron. Canonical P450s use electrons from NAD(P)H to catalyze activation of molecular oxygen, leading to regiospecific and stereospecific oxidative attack of a plethora of substrates. The reactions carried out by P450s, though often hydroxylation, can be extremely diverse and sometimes surprising. They contribute to vital processes such as carbon source assimilation, biosynthesis of hormones and of structural components of living organisms, and also carcinogenesis and degradation of xenobiotics. In plants, chemical defense seems to be a major reason for P450 diversification. In prokaryotes, P450s are soluble proteins. In eukaryotes, they are usually bound to the endoplasmic reticulum or inner mitochondrial membranes. The electron carrier proteins used for conveying reducing equivalents from NAD(P)H differ with subcellular localization. P450 enzymes catalyze many reactions that are important in drug metabolism or that have practical applications in industry; their economic impact is therefore considerable.
Frontiers
Issues most studied
Medical, pharmacological and toxicological studies of P450 enzymes and genes for the prediction of drug metabolism and the prevention of adverse drug reactions remain a key field of investigation. For instance, there are many allelic variants of the human CYP2D6 gene, which encodes a liver enzyme that metabolizes a quarter of all known drugs. The CYP2D6 genotype will determine a person's response to important drugs, such as antipsychotics and antidepressants. Another very active field is the tailoring of P450 enzymes for specific functions, via site-directed mutagenesis or in vitro directed evolution. The development of new approaches to improve solubility and implement crystallization of membrane-bound enzymes probably opens a new era for the understanding of P450 mechanisms and substrate specificity, as well as engineering of such catalytic properties.
Major unresolved questions
A major unresolved issue in the field is the physiological function of many of the newly discovered P450 enzymes. Whereas this question can be practically addressed in microorganisms or other organisms amenable to homologous recombination, this is not the case in most eukaryotes such as humans, where the endogenous substrate(s) of many enzymes that have been extensively studied for xenobiotic metabolism are still unknown. Also, the molecular basis and impact of receptor-mediated transcriptional activation of many P450 genes remains a challenging area of research. An interesting point to clarify is the subcellular localization of some P450 enzymes, some of which might have more than one localization. Many P450-catalyzed reactions in plants generate compounds that might be toxic if released in the cytoplasm. There is increasing evidence of the channeling of such compounds inside multi-enzyme complexes. How do P450s interact with such complexes, and do they serve to anchor them on membranes? From a mechanistic point of view, simple hydroxylation reactions are now rather well understood. More complex reactions, for example multi-step reactions or those involving no overt oxygen insertion, are still a very open field of investigation.
© BioMedCentral Ltd. Protein family reviews appear as regular features in GenomeBiology. A complete list of protein family reviews is available online at http://genomebiology.com/proteinfamilyreviews/
Primary structures of P450 proteins
Secondary and tertiary structures of P450 proteins