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.[5] 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.[6] 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.[6] This demethylation step is regarded as the initial checkpoint in the transformation of lanosterol to other sterols that are widely used within the cell.[6]
CYP51A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Cytochrome P450, Family 51, Subfamily A, Polypeptide 1 | |||||||
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Identifiers | |||||||
Symbol | CYP51A1 | ||||||
Alt. symbols | CYP51, P45014DM | ||||||
NCBI gene | 1595 | ||||||
HGNC | 2649 | ||||||
OMIM | 601637 | ||||||
RefSeq | NM_000786 | ||||||
UniProt | Q16850 | ||||||
Other data | |||||||
EC number | 1.14.14.154 | ||||||
Locus | Chr. 7 q21.2-21.3 | ||||||
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The structural and functional properties of the cytochrome P450 superfamily have been subject to extensive diversification over the course of evolution.[7] Recent estimates indicate that there are currently 10 classes and 267 families of CYP proteins.[8] 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.[7]
Although CYP51's mode of action has been well conserved, the protein's sequence varies considerably between biological kingdoms.[9] CYP51 sequence comparisons between kingdoms reveal only a 22-30% similarity in amino acid composition.[10]
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.[10] 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.[7] 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.[11][12] Finally, the active site contains a heme prosthetic group in which the iron is tethered to the sulfur atom on a conserved cysteine residue.[10] This group also binds diatomic oxygen at the sixth coordination site, which is eventually incorporated onto the substrate.[10]
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).[13] 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.[10] The aldehyde then departs as formic acid and a double bond is simultaneously introduced to yield the demethylated product.[10]