Lanosterol 14 alpha-demethylase

Lanosterol 14α-demethylase (CYP51A1) is a cytochrome P450 enzyme that is involved in the conversion of lanosterol to 4,4-dimethylcholesta-8(9),14,24-trien-3β-ol.[4] 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.[5] 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.[5] This demethylation step is regarded as the initial checkpoint in the transformation of lanosterol to other sterols that are widely used within the cell.[5]

CYP51A1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCYP51A1, CP51, CYP51, CYPL1, LDM, P450-14DM, P450L1, cytochrome P450 family 51 subfamily A member 1
External IDsOMIM: 601637 MGI: 106040 HomoloGene: 55488 GeneCards: CYP51A1
Gene location (Human)
Chr.Chromosome 7 (human)[1]
Band7q21.2Start92,112,153 bp[1]
End92,134,803 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

1595

13121

Ensembl

ENSG00000001630

n/a

UniProt

Q16850

Q8K0C4

RefSeq (mRNA)

NM_001146152
NM_000786

NM_020010

RefSeq (protein)

NP_000777
NP_001139624

NP_064394

Location (UCSC)Chr 7: 92.11 – 92.13 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse
Cytochrome P450, Family 51, Subfamily A, Polypeptide 1
Identifiers
SymbolCYP51A1
Alt. symbolsCYP51, P45014DM
NCBI gene1595
HGNC2649
OMIM601637
RefSeqNM_000786
UniProtQ16850
Other data
EC number1.14.14.154
LocusChr. 7 q21.2-21.3
Lanosterol

Evolution
Main article: CYP51

The structural and functional properties of the cytochrome P450 superfamily have been subject to extensive diversification over the course of evolution.[6] Recent estimates indicate that there are currently 10 classes and 267 families of CYP proteins.[7] 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.[6]

Although CYP51's mode of action has been well conserved, the protein's sequence varies considerably between biological kingdoms.[8] CYP51 sequence comparisons between kingdoms reveal only a 22-30% similarity in amino acid composition.[9]

Structure
Structure of lanosterol 14α-demethylase (CYP51), as identified by Podust et al.

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.[9] 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.[6] 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.[10][11] Finally, the active site contains a heme prosthetic group in which the iron is tethered to a thiolate ligand on a conserved cysteine residue.[9] This group also binds diatomic oxygen at the sixth coordination site, which is eventually incorporated onto the substrate.[9]

Mechanism
Three-step demethylation of lanosterol, mediated by lanosterol 14α-demethylase.

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).[12] 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.[9] The aldehyde then departs as formic acid and a double bond is simultaneously introduced to yield the demethylated product.[9]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000001630 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Metabocard for 4,4-Dimethylcholesta-8,14,24-trienol (HMDB01023)". Human Metabolome Database. February 2014.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.

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.
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