Recent Structural Insights into Cytochrome P450 Function

Abstract

Cytochrome P450 (P450) enzymes are important in the metabolism of drugs, steroids, fat-soluble vitamins, carcinogens, pesticides, and many other types of chemicals. Their catalytic activities are important issues in areas such as drug-drug interactions and endocrine function. During the past 30 years, structures of P450s have been very helpful in understanding function, particularly the mammalian P450 structures available in the past 15 years. We review recent activity in this area, focusing on the past two years (2014–2015). Structural work with microbial P450s includes studies related to the biosynthesis of natural products and the use of parasitic and fungal P450 structures as targets for drug discovery. Studies on mammalian P450s include the utilization of information about ‘drug-metabolizing’ P450s to improve drug development and also to understand the molecular bases of endocrine dysfunction.

A Histone Code Reader and a Transcriptional Activator Interact to Regulate Genes for Salt Tolerance

“…The cytochrome P450 superfamily consists of large numbers of monooxygenase enzymes, which catalyze oxidation/reduction reactions of enormous organic chemicals (Munro et al, 2013;Rendic and Guengerich, 2015). They are also involved in drug metabolism, endocrine activity, and steroid and hormone biosynthesis, as well as other processes (Girvan and Munro, 2016;Guengerich et al, 2016). In plants, CYP genes take part in the biosynthesis or catabolism of several phytohormones, such as cytokinins, ABAs, gibberellins, and brassinosteroids (Saito et al, 2004;Takei et al, 2004;Zhu et al, 2006;Sakamoto et al, 2012;Yoshida, 2012).…”

Structural characterization of CYP260A1 from Sorangium cellulosum to investigate the 1α‐hydroxylation of a mineralocorticoid

“…Among them, the investigation of steroid hydroxylating P450s is of great interest, because of the pharmaceutical values of the steroidal derivatives. Although 14 human P450s (CYP1B1, CYP7A1, CYP7B1, CYP8B1, CYP11A1, CYPB1, CYP11B2, CYP17A1, CYP19A1, CYP21A2, CYP27A1, CYP39A1, CYP46A1, and CYP51A1) are able to perform physiologically relevant steroid hydroxylation , the membrane integrated feature and the low expression level of these P450s hindered their application as biocatalysts. In this regard, bacterial P450s could be the best alternatives.…”

Picturing the Membrane‐assisted Choreography of Cytochrome P450 with Lipid Nanodiscs

“…Only very recently such ambiguity has been finally recognized, and protein-membrane and protein-protein dynamics in the P450's metabolon have been approached at both ensemble and single-molecule level using mimetics closely resembling the ER membrane. [39] On the other hand, full-length structural studies of P450 have been overwhelming for many decades; the structure of the yeast CYP51 in detergents by Monk et al [40] is the only full-length P450 X-ray structure to date, albeit the lack of a lipid bilayer in the sample. [38] Removal of the transmembrane domain of cytochrome P450 results in a solubilized form of the enzyme that -although only marginally active -has been found to be suitable for crystallization studies.…”