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Proteins. 2014 Mar;82(3):491-504. doi: 10.1002/prot.24415. Epub 2013 Oct 17.

Conservation analysis of class-specific positions in cytochrome P450 monooxygenases: functional and structural relevance.

Author information

1
Institute of Technical Biochemistry, University of Stuttgart, 70569, Stuttgart, Germany.

Abstract

Cytochrome P450 monooxygenases (CYPs) constitute a ubiquitous, highly divergent protein family. Nevertheless, all CYPs share a common fold and conserved catalytic machinery. Based on the electron donor system, 10 classes of CYPs have been described, but most CYPs are members of class I accepting electrons from ferredoxin which is being reduced by FAD-containing reductase, or class II accepting electrons from FAD- and FMN-containing CPR-type reductase. Because of the low sequence conservation inside the two classes, the conserved class-specific positions are expected to be involved in aspects of electron transfer that are specific to the two types of reductases. In this work we present results from a conservation analysis of 16,732 CYP sequences derived from an updated version of the Cytochrome P450 Engineering Database (CYPED), using two class-specific numbering schemes. While no position was conserved on the distal, substrate-binding surface of the CYPs, several class-specific residues were found on the proximal, reductase-interacting surface; two class I-specific residues that were negatively charged, and three class II-specific residues that were aromatic or charged. The class-specific conservation of glycine and proline residues in the cysteine pocket indicates that there are class-specific differences in the flexibility of this element. Four heme-interacting arginines were conserved differently in each class, and a class-specific substitution of a heme-interacting tyrosine by histidine was found, pointing to a link between heme stabilization and the reductase type.

KEYWORDS:

CYP; P450; conservation; database; heme interaction; reductase interaction site; sequence-structure-function relationship

PMID:
24105833
DOI:
10.1002/prot.24415
[Indexed for MEDLINE]

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