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Structures	Swiss-model
Domains	InterPro

Cytochrome P450, Family 51, Subfamily A, Polypeptide 1
Cytochrome P450, Family 51, Subfamily A, Polypeptide 1
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
Structures
Search for
Structures	Swiss-model
Domains	InterPro

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)
End	92,134,803 bp
Gene location (Mouse)
Chr.	Chromosome 5 (mouse)
End	4,154,746 bp
RNA expression pattern
	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
	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
	1595
	13121
	ENSG00000001630
	ENSMUSG00000001467
	Q16850
	Q8K0C4
	NM_001146152; NM_000786
	NM_020010
	NP_000777; NP_001139624
	NP_064394
	Wikidata
View/Edit Human	View/Edit Mouse

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]

Evolution

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]

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.^[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]

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).^[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]