Sterol 14-Demethylase P450 (CYP51) Provides a Breakthrough for the Discussion on the Evolution of Cytochrome P450 Gene Superfamily

Yoshida, Yasuhiko; Aoyama, Yuri; Noshiro, Mitsuhide; Gotoh, Osamu

doi:10.1006/bbrc.2000.3030

Cited by 101 publications

(72 citation statements)

References 33 publications

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“…While conservation in the heme binding region is general amongst P450 families, high conservation within the SRSs (the sequences of highest variability in the drug metabolizing CYP2 family [44]) is a specific feature of CYP51 [45]. We believe that two of these regions, the most conserved and therefore the most thoroughly studied (SRS1 and SRS4) can be considered as a CYP51 signature (Figures 4, 5).…”

Section: Cyp51 Signature Structural Basis Of Conservation In the Cypmentioning

confidence: 99%

“…Supported by multiple sequence alignment analysis, the idea of the prokaryotic origin of sterol 14α-demethylase might indicate that it is evolutionarily the oldest P450 recognizable today [45,[53][54][55]. Even though an option of horizontal CYP51 gene transfer from plants to currently existing bacteria [31,56] (convolutionary process with loss of function) is not excluded, the CYP51 family remains an intriguing subject to study from two key evolutionary aspects: 1) evolution into different phyla with preserved metabolic role yet sometimes slightly different substrate preferences and 2) possible diversification into other P450 species with altered catalytic function.…”

Section: Cyp51 and P450 Evolutionmentioning

confidence: 99%

“…Insertion of sterols into cellular membranes may have paved the way toward the development of eukaryotic organisms [52]. The prokaryotic origin of the sterol biosynthetic pathway implies a common prokaryotic ancestor for all currently existing sterol 14α-demethylases, the only invariant P450 in every known sterol biosynthetic pathway, and in turn provides a very logical explanation for the presence of CYP51 orthologs in all evolutionarily younger biological kingdoms.Supported by multiple sequence alignment analysis, the idea of the prokaryotic origin of sterol 14α-demethylase might indicate that it is evolutionarily the oldest P450 recognizable today [45,[53][54][55]. Even though an option of horizontal CYP51 gene transfer from plants to currently existing bacteria [31,56] (convolutionary process with loss of function) is not excluded, the CYP51 family remains an intriguing subject to study from two key evolutionary aspects: 1) evolution into different phyla with preserved metabolic role yet sometimes slightly different substrate preferences and 2) possible diversification into other P450 species with altered catalytic function.…”

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Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms

Lepesheva

Waterman

2007

Biochimica et Biophysica Acta (BBA) - General Subjects

399

331

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SummaryThe CYP51 family is an intriguing subject for fundamental P450 structure/function studies and is also an important clinical drug target. This review updates information on the variety of the CYP51 family members, including their physiological roles, natural substrates and substrate preferences, and catalytic properties in vitro. We present experimental support for the notion that specific conserved regions in the P450 sequences represent a CYP51 signature. Two possible roles of CYP51 in P450 evolution are discussed and the major approaches for CYP51 inhibition are summarized.Keywords sterol 14α-demethylase (CYP51); sterol biosynthesis; substrate preferences; catalytic activity; inhibition Family overviewSterol 14α-demethylation as a general part of sterol biosynthetic pathways in eukaryotes [1] has been known and studied for more than 30 years [2][3][4][5][6][7]. The enzyme catalyzing this reaction was first purified from yeast in 1984 (Sacharomyces cerevisiea [8]), and following determination of its primary structure [9] the cytochrome P450 sterol 14α-demethylases were placed into the CYP51 family, a number reserved for fungal sequences [10]. In 1986 the orthologous mammalian P450 was purified from rat liver microsomes [11], in 1996 the first sterol 14α-demethylase was found in plants (Sorghum bicolor [12]), and in 2000 the orthologous nature of a CYP51-like gene [13] from Mycobacterium tuberculosis to eukaryotic CYP51s was confirmed [14].Currently the CYP51 family joins proteins found in 82 organisms from all biological kingdoms. In addition, several plants and fungi contain multiple CYP51 genes (e.g. rice (10), black oats (2), tobacco (2), Arabidopsis thaliana (2), Fuzarium graminearum (3) or Aspergillus species: A. fumigatus (2), A.nidulans (2), A. orizae (3)). As a result, the number of known CYP51 sequences exceeds 100. The reasons for the existence of homologous CYP51 genes in the same species or their precise functions remain unknown, though it was reported that only one of the two CYP51 genes from A. thaliana (CYP51A2) is functional, while the other is an expressed pseudogene [15]. Mammalian genomes contain only one CYP51 gene yet sometimes † Corresponding author: Michael R. Waterman, Tel.: 615-343-1373; Fax: 615-322-4349; E-mail: michael.waterman@vanderbilt.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The average amino acid sequence identity in the CYP51 family is about 30%, varying from relatively high between the proteins from evolutionary closely related species (e.g. 95% in mammals) to lower values within the highly diverse kingdoms of lower...

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Section: Cyp51 Signature Structural Basis Of Conservation In the Cypmentioning

confidence: 99%

Section: Cyp51 and P450 Evolutionmentioning

confidence: 99%

mentioning

confidence: 99%

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Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms

Lepesheva

Waterman

2007

Biochimica et Biophysica Acta (BBA) - General Subjects

399

331

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“…CYP51, called ERG11 in fungi, is a highly conserved cytochrome P450 enzyme required for the early steps of sterol metabolism in the animal, fungus, and plant kingdoms (16)(17)(18)(19). CYP51 enzymes have been identified in the genomes of M. tuberculosis and Mycobacterium smegmatis, and the inhibition of mycobacterial sterol biosynthesis may be therapeutically useful for patients with mycobacterial infections (20)(21)(22).…”

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confidence: 99%

Cloning and Characterization of CYP51 from Mycobacterium avium

Pietila

Vohra

Sanyal

et al. 2006

Am J Respir Cell Mol Biol

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Mycobacterium avium complex (MAC) causes chronic lung disease in immunocompetent people and disseminated infection in patients with AIDS. MAC is intrinsically resistant to many conventional antimycobacterial agents, it develops drug resistance rapidly to macrolide antibiotics, and patients with MAC infection experience frequent relapses or the inability to completely eradicate the infection with current treatment. Treatment regimens are prolonged and complicated by drug toxicity or intolerances. We sought to identify biochemical pathways in MAC that can serve as targets for novel antimycobacterial treatment. The cytochrome P450 enzyme, CYP51, catalyzes an essential early step in sterol metabolism, removing a methyl group from lanosterol in animals and fungi, or from obtusifoliol in plants. Azoles inhibit CYP51 function, leading to an accumulation of methylated sterol precursors. This perturbation of normal sterol metabolism compromises cell membrane integrity, resulting in growth inhibition or cell death. We have cloned and characterized a CYP51 from MAC that functions as a lanosterol 14␣-demethylase. We show the direct interactions of azoles with purified MAC-CYP51 by absorbance and electron paramagnetic resonance spectroscopy, and determine the minimum inhibitory concentrations (MICs) of econazole, ketoconazole, itraconazole, fluconazole, and voriconazole against MAC. Furthermore, we demonstrate that econazole has a MIC of 4 g/ml and a minimum bacteriocidal concentration of 4 g/ml, whereas ketoconazole has a MIC of 8 g/ml and a minimum bacteriocidal concentration of 16 g/ml. Itraconazole, voriconazole, and fluconazole did not inhibit MAC growth to any significant extent.

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“…Lanosterol 14a-demethylase (CYP51) is a cytochrome P450 enzyme of the sterol biosynthesis pathway belonging to the CYP51 gene family which is the most evolutionarily conserved member of the CYP superfamily and the only cytochrome P450 family present in all kingdoms of biology. 1,2) CYP51 protein catalyzes the oxidative removal of the 14a-methyl group (C32) of lanosterol and 24-methylene-24,25-dihydrolanosterol in yeast and fungi, lanosterol and 24,25-dihydrolanosterol in mammals, and obtusifoliol in plants.…”

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confidence: 99%

cDNA Cloning, Genomic Structure and Expression Analysis of the Bovine Lanosterol 14.ALPHA.-Demethylase (CYP51) in Gonads

Wang

Shen

Song

et al. 2006

Biological & Pharmaceutical Bulletin

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Sterol biosynthesis is an essential metabolic pathway in all eukaryotic organisms. Lanosterol 14a-demethylase (CYP51) is a cytochrome P450 enzyme of the sterol biosynthesis pathway belonging to the CYP51 gene family which is the most evolutionarily conserved member of the CYP superfamily and the only cytochrome P450 family present in all kingdoms of biology.1,2) CYP51 protein catalyzes the oxidative removal of the 14a-methyl group (C32) of lanosterol and 24-methylene-24,25-dihydrolanosterol in yeast and fungi, lanosterol and 24,25-dihydrolanosterol in mammals, and obtusifoliol in plants.In mammalian gonads, CYP51 enzyme is not only important to the synthesis of cholesterol, but also has a role in overproducing meiosis activating sterol (MAS), an intermediate of the postsqualene part of cholesterol biosynthesis, including follicular fluid meiosis activating sterol (FF-MAS) and testis meiosis activating sterol (T-MAS) accumulating mainly in ovaries and testis respectively. MAS was proved to have the ability to trigger resumption of oocytes meiosis, 3) which can promote not only the nuclear but also plasma maturation and preimplantation development of mouse oocytes and fertilized oocytes in vitro. 4,5) Our lab recently have proved MAS also can promote the formation of follicle in fetal mouse ovaries (Xie, unpublished, 2005). CYP51 protein is highly expressed in mammalian testis leydig cell and round, elongating spermatids.6,7) It resides in the endoplasmatic reticulum of most cells and also in acrosomal membranes of spermatids where transport through the Golgi apparatus is suggested.8) But the role of MAS in the spermatogenesis is not well known.The mammalian CYP51 cDNA and the gene have previously been characterized in mouse, 9) rat, 10) human, 11,12) and pig. 13) CYP51 mRNAs are widely expressed in those mammalian tissues with the highest level in haploid male germ cells spermatids. Two different types of CYP51 transcripts somatic transcripts and additional testis-specific transcripts are observed for differential polyadenylation site usage. CYP51 genes have several common characteristics: ten exons and nine introns, highly conserved exon/intron borders and proximal promoter structures.14) The promoter region is TATA-less and contains several highly conserved regulatory elements, such as GC-box, cAMP-responsive elements (CRE), sterol regulatory element (SRE), suggesting an evolutionary conserved mechanism of CYP51 transcriptional regulation in mammals. In somatic cells CYP51 expression is regulated by sterol regulatory element binding proteins (SREBPs), 14) while the germ-cell-specific cAMP/CREMtdependent upregulation of CYP51 expression might contribute to increase the production of MAS in testis. 14,15) Although T-MAS was first found and purified from bovine testis, the information of bovine CYP51 is little. In the present study, we characterized the bovine CYP51 gene and its expression and discussed the probable role of CYP51 and MAS in reproduction. MATERIALS AND METHODS RNA ExtractionBovine tissues were coll...

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Sterol 14-Demethylase P450 (CYP51) Provides a Breakthrough for the Discussion on the Evolution of Cytochrome P450 Gene Superfamily

Cited by 101 publications

References 33 publications

Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms

Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms

Cloning and Characterization of CYP51 from Mycobacterium avium

cDNA Cloning, Genomic Structure and Expression Analysis of the Bovine Lanosterol 14.ALPHA.-Demethylase (CYP51) in Gonads

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