Sterol 14α-demethylase, an abundant and essential mixed-function oxidase

doi:10.1016/j.bbrc.2005.08.118

Biochemical and Biophysical Research Communications

Volume 338, Issue 1, 9 December 2005, Pages 418-422

https://doi.org/10.1016/j.bbrc.2005.08.118 Get rights and content

Abstract

Sterol 14α-demethylase (CYP51) is the most widely distributed of all members of the cytochrome P450 gene superfamily and the only CYP family found in both prokaryotes and eukaryotes. It is well known as a drug target for microbial pathogenic infections. Studies of CYP51 gene regulation have been carried out primarily in animals because its regulation is similar to those of other genes involved in the cholesterol biosynthetic pathway. The function of CYP51 has been studied widely throughout biology including in animals, plants, yeast/fungi, protozoa, and bacteria. The structure has been determined by X-ray crystallography for the soluble prokaryotic form of CYP51 from Mycobacterium tuberculosis. Together these studies provide the most detailed understanding of any single cytochrome P450 and this minireview summarizes this information.

Section snippets

CYP51 gene regulation

Regulation of CYP51 transcription has been studied extensively in animals. Being cholesterologenic, CYP51 is a housekeeping gene expressed in virtually all animal cells because they all synthesize cholesterol [3]. The human genome contains three CYP51-related genes, one each on chromosomes 3, 7, and 13 [4]. The gene on chromosome 7 is the functional one while those on chromosomes 3 and 13 are processed pseudogenes which arise from reverse transcription of mRNA in germ cells and illegitimate

CYP51 activity

Fig. 1 illustrates the general CYP51 activity and Fig. 2 shows the four endogenous substrates known for this enzyme. It is seen that these molecules are very closely related with subtle differences in the sterol side chain and the presence of one or two methyl groups at C4. Currently, there are 64 complete CYP51 sequences known in biology and a majority of these will demethylate all 4 substrates although different CYP51s demonstrate different patterns of substrate preference among these four.

CYP51 structure

After Tom Poulos reported the high resolution X-ray structure of P450_cam[20] many investigators in the P450 field began to think about structural analysis of their favorite P450. The initial P450 structures were of soluble enzymes from bacteria and the first structure of a membrane P450 did not appear until 2003 [21]. Therefore for many years,structural information on CYP51 was not available. It was not known that there were soluble forms of CYP51 until the genomic structure of M. tuberculosis

Conclusion

Sterol 14α-demethylase is not the only P450-dependent activity to be present in all biological kingdoms. For example, P450-dependent fatty acid hydroxylation is also found in all phyla. However, the difference between sterol 14α-demethylation and other P450-dependent reactions across phyla is that CYP51 genes are recognizable according to their primary amino acid sequence. Generally speaking, P450s showing about 40% amino acid sequence identity are classified as members of the same gene family

Acknowledgments

The authors greatly appreciate the scientific contributions and insights of their many collaborators and colleagues, and support for research in this laboratory by NIH Grants DK28350, GM37942, and GM67871.

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In addition, studies have shown that regulation of the composition of gut microbiota can contribute to disease treatment [13–15]. Sterol 14α-demethylase (P45014DM, CYP51) is a key biosynthetic enzyme [16] belonging to the cytochrome P450 family of enzymes, which catalyze the 14α-methyl hydroxylation of sterol precursors [17,18]. More than 100 CYP51 sequences have been found in 82 species, some of which contain multiple cyp51 genes.
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ReviewSterol 14α-demethylase, an abundant and essential mixed-function oxidase

Abstract

Section snippets

CYP51 gene regulation

CYP51 activity

CYP51 structure

Conclusion

Acknowledgments

Biochem. Biophys. Res. Commun.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Genomics

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

Structure

Arch. Biochem. Biophys.

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg 11p, Cyp51p) to azole resistance in Cadida albicans

Microbiology

SREBPs, activators of the complete program of cholesterol and fatty acid synthesis in the liver

J. Clin. Invest.

Review
Sterol 14α-demethylase, an abundant and essential mixed-function oxidase