Biology:Lanosterol 14 alpha-demethylase

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
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

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.[1] 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.[2] 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.[2] This demethylation step is regarded as the initial checkpoint in the transformation of lanosterol to other sterols that are widely used within the cell.[2]

Evolution

The structural and functional properties of the cytochrome P450 superfamily have been subject to extensive diversification over the course of evolution.[3] Recent estimates indicate that there are currently 10 classes and 267 families of CYP proteins.[4] 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.[3]

Although CYP51's mode of action has been well conserved, the protein's sequence varies considerably between biological kingdoms.[5] CYP51 sequence comparisons between kingdoms reveal only a 22-30% similarity in amino acid composition.[6]

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.[6] 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.[3] 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.[7][8] Finally, the active site contains a heme prosthetic group in which the iron is tethered to the sulfur atom on a conserved cysteine residue.[6] This group also binds diatomic oxygen at the sixth coordination site, which is eventually incorporated onto the substrate.[6]

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).[9] 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.[6] The aldehyde then departs as formic acid and a double bond is simultaneously introduced to yield the demethylated product.[6]

See also

References

  1. ↑ "Metabocard for 4,4-Dimethylcholesta-8,14,24-trienol (HMDB01023)". Human Metabolome Database. February 2014. http://www.hmdb.ca/metabolites/HMDB01023. 
  2. ↑ 2.0 2.1 2.2 "Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms". Biochimica et Biophysica Acta (BBA) - General Subjects 1770 (3): 467–77. March 2007. doi:10.1016/j.bbagen.2006.07.018. PMID 16963187. 
  3. ↑ 3.0 3.1 3.2 "Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens". Applied Microbiology and Biotechnology 95 (4): 825–40. August 2012. doi:10.1007/s00253-012-4195-9. PMID 22684327. 
  4. ↑ "Cytochrome P450 systems--biological variations of electron transport chains". Biochimica et Biophysica Acta (BBA) - General Subjects 1770 (3): 330–44. March 2007. doi:10.1016/j.bbagen.2006.07.017. PMID 16978787. 
  5. ↑ "CYP51--the omnipotent P450". Molecular and Cellular Endocrinology 215 (1–2): 165–70. February 2004. doi:10.1016/j.mce.2003.11.016. PMID 15026190. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Structural basis for conservation in the CYP51 family". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1814 (1): 88–93. January 2011. doi:10.1016/j.bbapap.2010.06.006. PMID 20547249. 
  7. ↑ "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. July 2011. doi:10.1074/jbc.M111.237099. PMID 21632531. 
  8. ↑ "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. November 2007. doi:10.1128/AAC.00311-07. PMID 17846131. 
  9. ↑ "Cytochromes P450 in fungi". Mycoses 41 (Suppl 1): 32–8. 1998. doi:10.1111/j.1439-0507.1998.tb00581.x. PMID 9717384. 

Further reading

  • "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. February 1997. doi:10.1046/j.1365-313X.1997.11020191.x. PMID 9076987. 
  • "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. August 1991. doi:10.1016/0006-291X(91)91000-3. PMID 1872829. 
  • "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. March 1992. doi:10.1016/S0006-291X(05)80327-4. PMID 1567403. 
  • "The removal of the 32-carbon atom as formic acid in cholesterol biosynthesis". Journal of the Chemical Society, Chemical Communications (7): 383. 1972. doi:10.1039/C39720000383. 

External links



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