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CYP51A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3JUS, 3JUV, 3LD6, 4UHI, 4UHL
Identifiers
Aliases	CYP51A1, CP51, CYP51, CYPL1, LDM, P450-14DM, P450L1, cytochrome P450 family 51 subfamily A member 1
External IDs	OMIM: 601637; MGI: 106040; HomoloGene: 55488; GeneCards: CYP51A1; OMA:CYP51A1 - orthologs
Gene location (Human) Chr. Chromosome 7 (human) Band 7q21.2 Start 92,084,987 bp End 92,134,803 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5 A1|5 2.3 cM Start 4,131,145 bp End 4,154,746 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ventricular zone islet of Langerhans ganglionic eminence corpus callosum C1 segment right testis duodenum left testis liver superior frontal gyrus Top expressed in tail of embryo genital tubercle proximal tubule right kidney skin of external ear superior cervical ganglion human kidney neural tube ventricular zone sciatic nerve More reference expression data BioGPS n/a
Gene ontology Molecular function iron ion binding metal ion binding monooxygenase activity heme binding oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen oxidoreductase activity sterol 14-demethylase activity Cellular component integral component of membrane organelle membrane endoplasmic reticulum membrane membrane intracellular membrane-bounded organelle plasma membrane endoplasmic reticulum Biological process steroid metabolic process sterol biosynthetic process lipid metabolism cholesterol metabolic process cholesterol biosynthetic process via 24,25-dihydrolanosterol sterol metabolic process cholesterol biosynthetic process steroid biosynthetic process demethylation regulation of cholesterol biosynthetic process negative regulation of protein catabolic process negative regulation of protein secretion negative regulation of amyloid-beta clearance Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1595 13121 Ensembl ENSG00000001630 ENSMUSG00000001467 UniProt Q16850 Q8K0C4 RefSeq (mRNA) NM_001146152 NM_000786 NM_020010 RefSeq (protein) NP_000777 NP_001139624 NP_064394 Location (UCSC) Chr 7: 92.08 – 92.13 Mb Chr 5: 4.13 – 4.15 Mb PubMed search
Wikidata
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Lanosterol 14α-demethylase (CYP51A1) is the animal version of a cytochrome P450 enzyme that is involved in the conversion of lanosterol to 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol. The cytochrome P450 isoenzymes are a conserved group of proteins that serve as key players in the metabolism of organic substances and the biosynthesis of important steroids, lipids, and vitamins in eukaryotes. As a member of this family, lanosterol 14α-demethylase is responsible for an essential step in the biosynthesis of sterols. In particular, this protein catalyzes the removal of the C-14α-methyl group from lanosterol. This demethylation step is regarded as the initial checkpoint in the transformation of lanosterol to other sterols that are widely used within the cell.

Evolution

The structural and functional properties of the cytochrome P450 superfamily have been subject to extensive diversification over the course of evolution. Recent estimates indicate that there are currently 10 classes and 267 families of CYP proteins. It is believed that 14α-demethylase or CYP51 diverged early in the cytochrome's evolutionary history and has preserved its function ever since; namely, the removal of the 14α-methyl group from sterol substrates.

Although CYP51's mode of action has been well conserved, the protein's sequence varies considerably between biological kingdoms. CYP51 sequence comparisons between kingdoms reveal only a 22-30% similarity in amino acid composition.

Structure

Although the structure of 14α-demethylase may vary substantially from one organism to the next, sequence alignment analysis reveals that there are six regions in the protein that are highly conserved in eukaryotes. These include residues in the B' helix, B'/C loop, C helix, I helix, K/β1-4 loop, and β-strand 1-4 that are responsible for forming the surface of the substrate binding cavity. Homology modeling reveals that substrates migrate from the surface of the protein to the enzyme's buried active site through a channel that is formed in part by the A' alpha helix and the β4 loop. Finally, the active site contains a heme prosthetic group in which the iron is tethered to the sulfur atom on a conserved cysteine residue. This group also binds diatomic oxygen at the sixth coordination site, which is eventually incorporated onto the substrate.

Mechanism

The enzyme-catalyzed demethylation of lanosterol is believed to occur in three steps, each of which requires one molecule of diatomic oxygen and one molecule of NADPH (or some other reducing equivalent). During the first two steps, the 14α-methyl group undergoes typical cytochrome monooxygenation in which one oxygen atom is incorporated by the substrate and the other is reduced to water, resulting in the sterol's conversion to a carboxyalcohol and then a carboxyaldehyde. The aldehyde then departs as formic acid and a double bond is simultaneously introduced to yield the demethylated product.

See also

• Steroidogenic enzyme
• Azole antifungals

References

1. ^ GRCh38: Ensembl release 89: ENSG00000001630 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000001467 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Metabocard for 4,4-Dimethylcholesta-8,14,24-trienol (HMDB01023)". Human Metabolome Database. February 2014.
6. ^ Lepesheva GI, Waterman MR (March 2007). "Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms". Biochimica et Biophysica Acta (BBA) - General Subjects. 1770 (3): 467–77. doi:10.1016/j.bbagen.2006.07.018. PMC 2324071. PMID 16963187.
7. ^ Becher R, Wirsel SG (August 2012). "Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens". Applied Microbiology and Biotechnology. 95 (4): 825–40. doi:10.1007/s00253-012-4195-9. PMID 22684327. S2CID 17688962.
8. Hannemann F, Bichet A, Ewen KM, Bernhardt R (March 2007). "Cytochrome P450 systems--biological variations of electron transport chains". Biochimica et Biophysica Acta (BBA) - General Subjects. 1770 (3): 330–44. doi:10.1016/j.bbagen.2006.07.017. PMID 16978787.
9. Lepesheva GI, Waterman MR (February 2004). "CYP51--the omnipotent P450". Molecular and Cellular Endocrinology. 215 (1–2): 165–70. doi:10.1016/j.mce.2003.11.016. PMID 15026190. S2CID 22489096.
10. ^ Lepesheva GI, Waterman MR (January 2011). "Structural basis for conservation in the CYP51 family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1814 (1): 88–93. doi:10.1016/j.bbapap.2010.06.006. PMC 2962772. PMID 20547249.
11. Hargrove TY, Wawrzak Z, Liu J, Nes WD, Waterman MR, Lepesheva GI (July 2011). "Substrate preferences and catalytic parameters determined by structural characteristics of sterol 14alpha-demethylase (CYP51) from Leishmania infantum". The Journal of Biological Chemistry. 286 (30): 26838–48. doi:10.1074/jbc.M111.237099. PMC 3143644. PMID 21632531.
12. Podust LM, von Kries JP, Eddine AN, Kim Y, Yermalitskaya LV, Kuehne R, et al. (November 2007). "Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by X-ray crystallography". Antimicrobial Agents and Chemotherapy. 51 (11): 3915–23. doi:10.1128/AAC.00311-07. PMC 2151439. PMID 17846131.
13. Vanden Bossche H, Koymans L (1998). "Cytochromes P450 in fungi". Mycoses. 41 (Suppl 1): 32–8. doi:10.1111/j.1439-0507.1998.tb00581.x. PMID 9717384. S2CID 83821510.

Further reading

• Bak S, Kahn RA, Olsen CE, Halkier BA (February 1997). "Cloning and expression in Escherichia coli of the obtusifoliol 14 alpha-demethylase of Sorghum bicolor (L.) Moench, a cytochrome P450 orthologous to the sterol 14 alpha-demethylases (CYP51) from fungi and mammals". The Plant Journal. 11 (2): 191–201. doi:10.1046/j.1365-313X.1997.11020191.x. PMID 9076987.
• Aoyama Y, Yoshida Y (August 1991). "Different substrate specificities of lanosterol 14a-demethylase (P-45014DM) of Saccharomyces cerevisiae and rat liver for 24-methylene-24,25-dihydrolanosterol and 24,25-dihydrolanosterol". Biochemical and Biophysical Research Communications. 178 (3): 1064–71. doi:10.1016/0006-291X(91)91000-3. PMID 1872829.
• Aoyama Y, Yoshida Y (March 1992). "The 4 beta-methyl group of substrate does not affect the activity of lanosterol 14 alpha-demethylase (P-450(14)DM) of yeast: difference between the substrate recognition by yeast and plant sterol 14 alpha-demethylases". Biochemical and Biophysical Research Communications. 183 (3): 1266–72. doi:10.1016/S0006-291X(05)80327-4. PMID 1567403.
• Alexander K, Akhtar M, Boar RB, McGhie JF, Barton DH (1972). "The removal of the 32-carbon atom as formic acid in cholesterol biosynthesis". Journal of the Chemical Society, Chemical Communications (7): 383. doi:10.1039/C39720000383.

External links

• cytochrome+P-450+CYP51 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

• Biology

• Genes on human chromosome 7
• EC 1.14.14
• Cytochrome P450
• NADPH-dependent enzymes
• Enzymes of known structure