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]

Quick Facts CYP51A1, Available structures ...

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)[1] Band 7q21.2 Start 92,084,987 bp[1] End 92,134,803 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 A1|5 2.3 cM Start 4,131,145 bp[2] End 4,154,746 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans ganglionic eminence corpus callosum duodenum liver superior frontal gyrus prefrontal cortex right adrenal gland right lobe of liver rectum Top expressed in proximal tubule superior cervical ganglion kidney neural tube sciatic nerve epithelium of stomach lip anterior horn of spinal cord supraoptic nucleus spermatid 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 [3] [4]
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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]

• Steroidogenic enzyme
• Azole antifungals