Cholesterol side-chain cleavage enzyme: Wikis

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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 XM_976231
RefSeq (protein) NP_000772 XP_981325
Location (UCSC) Chr 15:
72.42 - 72.45 Mb
Chr 9:
57.81 - 57.83 Mb
PubMed search [1] [2]

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 The gene name is CYP11A1.[1] The term "desmolase" is becoming outdated and the enzyme is now commonly referred to as P450scc, where "scc" refers to side chain cleavage.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 family of enzymes. It catalyzes the first step in all steroid hormone production -- the conversion of cholesterol to pregnenolone, the first steroid formed (See illustrations below).

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

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 primarily regulated by two pituitary hormones: LH and ACTH. Hormonal and developmental regulation of CYP11A1 gene expression is primarily controlled by trans-acting factors including steroid factor 1 (SF-1), transcription factor AP-2 alpha (AP2), and many others [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 may in extremely rare cases, corroborated by now only in a single report,[4] result in a steroid hormone deficiency, causing the rare and potentially fatal condition, lipoid congenital adrenal hyperplasia.

More often but still rarely, the mutation may cause one of the subforms of congenital adrenal insufficiency.

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. PMID 3948785.  
  3. ^ 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.  
  4. ^ Tajima T, Fujieda K, Kouda N, Nakae J, Miller WL (August 2001). "Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency". J. Clin. Endocrinol. Metab. 86 (8): 3820–5. PMID 11502818. http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=11502818.  

Further reading

  • Helmberg A (1993). "Twin genes and endocrine disease: CYP21 and CYP11B genes.". Acta Endocrinol. 129 (2): 97–108. PMID 8372604.  
  • Papadopoulos V, Amri H, Boujrad N, et al. (1997). "Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis.". Steroids 62 (1): 21–8. doi:10.1016/S0039-128X(96)00154-7. PMID 9029710.  
  • Stocco DM (2000). "Intramitochondrial cholesterol transfer.". Biochim. Biophys. Acta 1486 (1): 184–97. PMID 10856721.  
  • Kristensen VN, Kure EH, Erikstein B, et al. (2001). "Genetic susceptibility and environmental estrogen-like compounds.". Mutat. Res. 482 (1-2): 77–82. PMID 11535251.  
  • Strauss JF (2004). "Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome.". Ann. N. Y. Acad. Sci. 997: 42–8. doi:10.1196/annals.1290.005. PMID 14644808.  
  • 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.  
  • Wada A, Waterman MR (1992). "Identification by site-directed mutagenesis of two lysine residues in cholesterol side chain cleavage cytochrome P450 that are essential for adrenodoxin binding.". J. Biol. Chem. 267 (32): 22877–82. PMID 1429635.  
  • Hu MC, Guo IC, Lin JH, Chung BC (1991). "Regulated expression of cytochrome P-450scc (cholesterol-side-chain cleavage enzyme) in cultured cell lines detected by antibody against bacterially expressed human protein.". Biochem. J. 274 ( Pt 3): 813–7. PMID 1849407.  
  • Sparkes RS, Klisak I, Miller WL (1991). "Regional mapping of genes encoding human steroidogenic enzymes: P450scc to 15q23-q24, adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17 to 10q24-q25.". DNA Cell Biol. 10 (5): 359–65. PMID 1863359.  
  • Coghlan VM, Vickery LE (1991). "Site-specific mutations in human ferredoxin that affect binding to ferredoxin reductase and cytochrome P450scc.". J. Biol. Chem. 266 (28): 18606–12. PMID 1917982.  
  • Matteson KJ, Chung BC, Urdea MS, Miller WL (1986). "Study of cholesterol side-chain cleavage (20,22 desmolase) deficiency causing congenital lipoid adrenal hyperplasia using bovine-sequence P450scc oligodeoxyribonucleotide probes.". Endocrinology 118 (4): 1296–305. PMID 2419119.  
  • Chung BC, Matteson KJ, Voutilainen R, et al. (1987). "Human cholesterol side-chain cleavage enzyme, P450scc: cDNA cloning, assignment of the gene to chromosome 15, and expression in the placenta.". Proc. Natl. Acad. Sci. U.S.A. 83 (23): 8962–6. doi:10.1073/pnas.83.23.8962. PMID 3024157.  
  • Morohashi K, Sogawa K, Omura T, Fujii-Kuriyama Y (1987). "Gene structure of human cytochrome P-450(SCC), cholesterol desmolase.". J. Biochem. 101 (4): 879–87. PMID 3038854.  
  • Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.  
  • Gharani N, Waterworth DM, Batty S, et al. (1997). "Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism.". Hum. Mol. Genet. 6 (3): 397–402. doi:10.1093/hmg/6.3.397. PMID 9147642.  
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.  
  • Hukkanen J, Mäntylä M, Kangas L, et al. (1998). "Expression of cytochrome P450 genes encoding enzymes active in the metabolism of tamoxifen in human uterine endometrium.". Pharmacol. Toxicol. 82 (2): 93–7. PMID 9498238.  
  • Zhou Z, Shackleton CH, Pahwa S, et al. (1998). "Prominent sex steroid metabolism in human lymphocytes.". Mol. Cell. Endocrinol. 138 (1-2): 61–9. doi:10.1016/S0303-7207(98)00052-5. PMID 9685215.  

Steroid hormone synthesis

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

Additional images

External links

See also

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