Cholesterol side-chain cleavage enzyme


Cholesterol side-chain cleavage enzyme
Cytochrome P450, family 11, subfamily A, polypeptide 1
Identifiers
Symbols CYP11A1; CYP11A; P450SCC
External IDs OMIM118485 MGI88582 HomoloGene37347 GeneCards: CYP11A1 Gene
EC number 1.14.15.6
RNA expression pattern
PBB GE CYP11A1 204309 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1583 13070
Ensembl ENSG00000140459 ENSMUSG00000032323
UniProt P05108 Q6NV84
RefSeq (mRNA) NM_000781.2 NM_019779.3
RefSeq (protein) NP_000772.2 NP_062753.3
Location (UCSC) Chr 15:
74.63 – 74.66 Mb
Chr 9:
57.86 – 57.87 Mb
PubMed search [1] [2]
cholesterol monooxygenase (side-chain-cleaving)
Identifiers
EC number 1.14.15.6
CAS number 37292-81-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Cytochrome P450, family 11, subfamily A, polypeptide 1 (P45011a1), often referred to as P450scc (or 20,22-desmolase), is a mitochondrial enzyme associated with the conversion of cholesterol to pregnenolone. The gene name is CYP11A1.[1] The term "desmolase" is becoming outdated and the enzyme is now commonly referred to as P450scc, where "scc" refers to side-chain cleavage.

The protein is a member of the cytochrome P450 superfamily of enzymes. It catalyzes the first step in all steroid hormone production -- the conversion of cholesterol to pregnenolone, the first steroid formed:

cholesterol + reduced adrenal ferredoxin + O2 \rightleftharpoons pregnenolone + 4-methylpentanal + oxidized adrenal ferredoxin + H2O

The protein resides on the inner mitochondrial membrane, facing the interior (matrix).[2] The presence of this enzyme defines if a cell is steroidogenic. Consequently, P450scc is found in all steroid-producing cell types such as theca cells and luteal cells in the ovary, Leydig cells in the testis, and cell types in the adrenal cortex.

Contents

Nomenclature

The systematic name of this enzyme class is cholesterol,reduced-adrenal-ferredoxin:oxygen oxidoreductase (side-chain-cleaving). Other names in common use include:

  • C27-side-chain cleavage enzyme,
  • cholesterol 20-22-desmolase,
  • cholesterol C20-22 desmolase,
  • cholesterol desmolase,
  • cholesterol side-chain cleavage enzyme,
  • cholesterol side-chain-cleaving enzyme,
  • cytochrome P-450scc,
  • desmolase, steroid 20-22,
  • enzymes, cholesterol side-chain-cleaving,
  • steroid 20-22 desmolase, and
  • steroid 20-22-lyase.

Mechanism of action

P450scc catalyzes the conversion of cholesterol to pregnenolone in three monooxygenase reactions. They involve 2 hydroxylations of the cholesterol side-chain, which generate, first, 22R-hydroxycholesterol and then 20alpha,22R-dihydroxycholesterol. The final step cleaves the bond between carbons 20 and 22, resulting in the production of pregnenolone and isocaproic acid.

Each step requires 2 electrons (reducing equivalents). These are provided by 2 cofactors: adrenodoxin reductase and adrenodoxin, which shuttles electrons from the latter protein to P450scc. All three proteins together constitute the cholesterol side-chain cleavage complex.

The activity of P450scc is blocked by the drug aminoglutethimide.

Regulation

The expression of CYP11A1 in the adrenal and gonads is principally regulated by angiotensin II and two pituitary hormones, LH and ACTH [3]. They increase CYP11A1 gene expression through transcription factors such as steroidogenic factor 1 (SF-1), by the α isoform of activating protein 2 (AP-2) in the human, and many others [3][4]. The production of this enzyme is inhibited notably by the nuclear receptor DAX-1 [3].

P450scc is always active, however its activity is limited by the supply of cholesterol in the inner membrane. The supplying of cholesterol to this membrane (from the outer mitochondrial membrane) is thus considered the true rate-limiting step in steroid production. This step is primarily mediated by the steroidogenic acute regulatory protein (StAR or STARD1). Upon stimulation of a cell to make steroid, the amount of StAR available to transfer cholesterol to the inner membrane limits how fast the reaction can go (the acute phase). With prolonged (chronic) stimulation, it is thought that cholesterol supply becomes no longer an issue and that the capacity of the system to make steroid (i.e., level of P450scc in the mitochondria) is now more important.

Pathology

Mutations in the CYP11A1 gene result in a steroid hormone deficiency, causing a minority of cases of the rare and potentially fatal condition, lipoid congenital adrenal hyperplasia[5][6][7].

References

  1. ^ "Entrez Gene: CYP11A1 cytochrome P450, family 11, subfamily A, polypeptide 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1583. 
  2. ^ Farkash Y, Timberg R, Orly J (April 1986). "Preparation of antiserum to rat cytochrome P-450 cholesterol side chain cleavage, and its use for ultrastructural localization of the immunoreactive enzyme by protein A-gold technique". Endocrinology 118 (4): 1353–65. doi:10.1210/endo-118-4-1353. PMID 3948785. 
  3. ^ a b c Lavoie HA, King SR (2009). "Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B.". Exp. Biol. Med. (Maywood) 234 (8): 880–907. doi:10.3181/0903-MR-97. PMID 19491374. 
  4. ^ Guo IC, Shih MC, Lan HC, et al. (2007). "Transcriptional regulation of human CYP11A1 in gonads and adrenals.". J. Biomed. Sci. 14 (4): 509–15. doi:10.1007/s11373-007-9177-z. PMID 17594537. 
  5. ^ Bhangoo A, Anhalt H, Ten S, King SR (March 2006). "Phenotypic variations in lipoid congenital adrenal hyperplasia.". Pediatr. Endocrinol. Rev. 3 (3): 258–71. PMID 16639391. 
  6. ^ al Kandari H, Katsumata N, Alexander S, Rasoul MA (2006). "Homozygous mutation of P450 side-chain cleavage enzyme gene (CYP11A1) in 46,XY patient with adrenal insufficiency, complete sex reversal, and agenesis of corpus callosum.". J. Clin. Endocr. Metab. 91 (8): 2821–6. doi:10.1210/jc.2005-2230. PMID 16705068. 
  7. ^ Kim CJ, Lin L, Huang N, Quigley CA, AvRuskin TW, Achermann JC, Miller WL (March 2008). "Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side-chain cleavage enzyme, P450scc". J. Clin. Endocrinol. Metab. 93 (3): 696–702. doi:10.1210/jc.2007-2330. PMC 2266942. PMID 18182448. http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=18182448. 

Further reading

Steroid hormone synthesis

Steroidogenesis, showing cholesterol side-chain cleavage enzyme at top.
Steroid hormone synthesis

Additional images

External links

See also

  • Cytochrome P450 oxidase

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