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词条 Cholesterol side-chain cleavage enzyme
释义

  1. Nomenclature

  2. Tissue and intracellular localization

  3. Mechanism of action

  4. Regulation

  5. Pathology

  6. See also

  7. References

  8. Further reading

  9. Steroid hormone synthesis

  10. Additional images

  11. External links

{{Infobox_gene}}Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an acronym for side-chain cleavage. P450scc is a mitochondrial enzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reaction in the process of steroidogenesis in all mammalian tissues that specialize in the production of various steroid hormones.[1]{{wide image|P450scc reaction.svg|910px|cholesterol + 3 NADPH + 3 H+ + 3 O2 ⇄ pregnenolone + 4-methylpentanal + 3 NADP+ + 3 H2O}}

P450scc is a member of the cytochrome P450 superfamily of enzymes (family 11, subfamily A, polypeptide 1). The gene name is CYP11A1.[2]

Nomenclature

{{Infobox enzyme|align=left
| Name = cholesterol monooxygenase (side-chain-cleaving)
| EC_number = 1.14.15.6
| CAS_number = 37292-81-2
| IUBMB_EC_number = 1/14/15/6
| GO_code = 0008386
| image =
| width =
| caption =
}}

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

{{col-begin|width=auto}}{{col-break|gap=1em}}
  • 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
  • steroid 20-22-lyase.
{{col-end}}{{clear left}}

Tissue and intracellular localization

The highest level of the cholesterol side-chain cleavage system is found in the adrenal cortex and the corpus luteum.[1] The system is also expressed at high levels in steroidogenic theca cells in the ovary, and Leydig cells in the testis.[1] During pregnancy, the placenta also expresses significant levels of this enzyme system.[3] P450scc is also present at much lower levels in several other tissue types, including the brain.[4] In the adrenal cortex, the concentration of adrenodoxin is similar to that of P450scc, but adrenodoxin reductase is expressed at lower levels.[5]

Immunofluorescence studies using specific antibodies against P450scc system enzymes have demonstrated that proteins are located exclusively within the mitochondria.[6][7] P450scc is associated with the inner mitochondrial membrane, facing the interior (matrix).[8][9] Adrenodoxin and adrenodoxin reductase are soluble peripheral membrane proteins located inside the mitochondrial matrix that appear to associate with each other primarily through electrostatic interactions.[10]

Mechanism of action

P450scc catalyzes the conversion of cholesterol to pregnenolone in three monooxygenase reactions. These 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 aldehyde.

Each monooxygenase step requires 2 electrons (reducing equivalents). The initial source of the electrons is NADPH.[11] The electrons are transferred from NADPH to P450scc via two electron transfer proteins: adrenodoxin reductase[12] and adrenodoxin.[13][14] All three proteins together constitute the cholesterol side-chain cleavage complex.

The involvement of three proteins in cholesterol side-chain cleavage reaction raises the question of whether the

three proteins function as a ternary complex as reductase:adrenodoxin:P450. Both spectroscopic studies of adrenodoxin binding to P450scc and kinetic studies in the presence of varying concentrations of adrenodoxin reductase demonstrated that the reductase competes with P450scc for binding to adrenodoxin. These results demonstrated that the formation of a functional ternary complex is not possible.[13] From these studies, it was concluded that the binding sites of adrenodoxin to its reductase and to P450 are overlapping and, as a consequence, adrenodoxin functions as a mobile electron shuttle between reductase and P450.[13] These conclusions have been confirmed by structural analysis of adrenodoxin and P450 complex.[15]

The process of electron transfer from NADPH to P450scc is not tightly coupled; that is, during electron transfer from adrenodoxin reductase via adrenodoxin to P450scc, a certain portion of the electrons leak outside of the chain and react with O2, generating superoxide radicals.[16] Steroidogenic cells include a diverse array of antioxidant systems to cope with the radicals generated by the steroidogenic enzymes.[17]

Regulation

In each steroidogenic cell, the expression of the P450scc system proteins is regulated by the trophic hormonal system specific for the cell type.[1] In adrenal cortex cells from zona fasciculata, the expression of the mRNAs encoding all three P450scc proteins is induced by corticotropin (ACTH).[7][18] The trophic hormones 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.[18][19] The production of this enzyme is inhibited notably by the nuclear receptor DAX-1.[18]

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 mediated primarily 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.

Corticotropin (ACTH) is a hormone that is released from the anterior pituitary in response to stress situations. A study of the steroidogenic capacity of the adrenal cortex in infants with acute respiratory disease demonstrated that indeed during disease state there is a specific increase in the steroidogenic capacity for the synthesis of the glucocorticoid cortisol but not for the mineralocorticoid aldosterone or androgen DHEAS that are secreted from other zones of the adrenal cortex.[20]

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.[21][22][23]

See also

  • Steroidogenic enzyme
  • Cytochrome P450 oxidase

References

1. ^1 2 3 {{cite journal | author = Hanukoglu I | title = Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 43 | issue = 8 | pages = 779–804 | date = December 1992 | pmid = 22217824 | doi = 10.1016/0960-0760(92)90307-5 }}
2. ^{{cite web | title = Entrez Gene: CYP11A1 cytochrome P450, family 11, subfamily A, polypeptide 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1583| accessdate = }}
3. ^{{cite journal | vauthors = Strauss JF, Martinez F, Kiriakidou M | title = Placental steroid hormone synthesis: unique features and unanswered questions | journal = Biology of Reproduction | volume = 54 | issue = 2 | pages = 303–11 | date = February 1996 | pmid = 8788180 | doi = 10.1095/biolreprod54.2.303 }}
4. ^{{cite journal | vauthors = Stoffel-Wagner B | title = Neurosteroid metabolism in the human brain | journal = European Journal of Endocrinology / European Federation of Endocrine Societies | volume = 145 | issue = 6 | pages = 669–79 | date = December 2001 | pmid = 11720889 | doi = 10.1530/eje.0.1450669 }}
5. ^{{cite journal | vauthors = Hanukoglu I, Hanukoglu Z | title = Stoichiometry of mitochondrial cytochromes P-450, adrenodoxin and adrenodoxin reductase in adrenal cortex and corpus luteum. Implications for membrane organization and gene regulation | journal = European Journal of Biochemistry | volume = 157 | issue = 1 | pages = 27–31 | date = May 1986 | pmid = 3011431 | doi = 10.1111/j.1432-1033.1986.tb09633.x }}
6. ^{{cite journal | vauthors = Hanukoglu I, Suh BS, Himmelhoch S, Amsterdam A | title = Induction and mitochondrial localization of cytochrome P450scc system enzymes in normal and transformed ovarian granulosa cells | journal = The Journal of Cell Biology | volume = 111 | issue = 4 | pages = 1373–81 | date = October 1990 | pmid = 2170421 | pmc = 2116250 | doi = 10.1083/jcb.111.4.1373 }}
7. ^1 {{cite journal | vauthors = Hanukoglu I, Feuchtwanger R, Hanukoglu A | title = Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells | journal = The Journal of Biological Chemistry | volume = 265 | issue = 33 | pages = 20602–8 | date = November 1990 | pmid = 2173715 | doi = | url = http://www.jbc.org/content/265/33/20602.full.pdf }}
8. ^Topological studies of cytochromes P-450scc and P-45011 beta in bovine adrenocortical inner mitochondrial membranes. Effects of controlled tryptic digestion. J. Biol. Chem. 1979 254: 10443-8.
9. ^{{cite journal | vauthors = Farkash Y, Timberg R, Orly J | title = 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 | journal = Endocrinology | volume = 118 | issue = 4 | pages = 1353–65 | date = April 1986 | pmid = 3948785 | doi = 10.1210/endo-118-4-1353 }}
10. ^{{cite journal | vauthors = Hanukoglu I, Privalle CT, Jefcoate CR | title = Mechanisms of ionic activation of adrenal mitochondrial cytochromes P-450scc and P-45011 beta | journal = The Journal of Biological Chemistry | volume = 256 | issue = 9 | pages = 4329–35 | date = May 1981 | pmid = 6783659 | doi = }}
11. ^{{cite journal | vauthors = Hanukoglu I, Rapoport R | title = Routes and regulation of NADPH production in steroidogenic mitochondria | journal = Endocrine Research | volume = 21 | issue = 1–2 | pages = 231–41 | year = 1995 | pmid = 7588385 | doi = 10.3109/07435809509030439 }}
12. ^{{cite journal | vauthors = Hanukoglu I, Gutfinger T, Haniu M, Shively JE | title = Isolation of a cDNA for adrenodoxin reductase (ferredoxin-NADP+ reductase). Implications for mitochondrial cytochrome P-450 systems. | journal = European Journal of Biochemistry | volume = 169 | issue = 3 | pages = 449–455 |date=Dec 1987 | doi = 10.1111/j.1432-1033.1987.tb13632.x | pmid = 3691502 }}
13. ^1 2 {{cite journal | vauthors = Hanukoglu I, Jefcoate CR | title = Mitochondrial cytochrome P-450scc. Mechanism of electron transport by adrenodoxin | journal = The Journal of Biological Chemistry | volume = 255 | issue = 7 | pages = 3057–61 | date = April 1980 | pmid = 6766943 | doi = }}
14. ^{{cite journal | vauthors = Hanukoglu I, Spitsberg V, Bumpus JA, Dus KM, Jefcoate CR | title = Adrenal mitochondrial cytochrome P-450scc. Cholesterol and adrenodoxin interactions at equilibrium and during turnover | journal = The Journal of Biological Chemistry | volume = 256 | issue = 9 | pages = 4321–8 | date = May 1981 | pmid = 7217084 | doi = }}
15. ^{{cite journal | vauthors = Strushkevich N, MacKenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW | title = Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 25 | pages = 10139–43 | date = June 2011 | pmid = 21636783 | doi = 10.1073/pnas.1019441108 | pmc=3121847}}
16. ^{{cite journal | vauthors = Hanukoglu I, Rapoport R, Weiner L, Sklan D | title = Electron leakage from the mitochondrial NADPH-adrenodoxin reductase-adrenodoxin-P450scc (cholesterol side chain cleavage) system | journal = Archives of Biochemistry and Biophysics | volume = 305 | issue = 2 | pages = 489–98 | date = September 1993 | pmid = 8396893 | doi = 10.1006/abbi.1993.1452 }}
17. ^{{cite journal | vauthors = Hanukoglu I | title = Antioxidant protective mechanisms against reactive oxygen species (ROS) generated by mitochondrial P450 systems in steroidogenic cells | journal = Drug Metabolism Reviews | volume = 38 | issue = 1–2 | pages = 171–96 | year = 2006 | pmid = 16684656 | doi = 10.1080/03602530600570040 |url=https://zenodo.org/record/890701}}
18. ^1 2 {{cite journal | vauthors = Lavoie HA, King SR | title = Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B | journal = Experimental Biology and Medicine | volume = 234 | issue = 8 | pages = 880–907 | date = August 2009 | pmid = 19491374 | doi = 10.3181/0903-MR-97 }}
19. ^{{cite journal | vauthors = Guo IC, Shih MC, Lan HC, Hsu NC, Hu MC, Chung BC | title = Transcriptional regulation of human CYP11A1 in gonads and adrenals | journal = Journal of Biomedical Science | volume = 14 | issue = 4 | pages = 509–15 | date = July 2007 | pmid = 17594537 | doi = 10.1007/s11373-007-9177-z }}
20. ^{{cite journal | vauthors = Hanukoglu A, Fried D, Nakash I, Hanukoglu I | title = Selective increases in adrenal steroidogenic capacity during acute respiratory disease in infants | journal = European Journal of Endocrinology / European Federation of Endocrine Societies | volume = 133 | issue = 5 | pages = 552–6 | date = November 1995 | pmid = 7581984 | doi = 10.1530/eje.0.1330552 }}
21. ^{{cite journal | vauthors = Bhangoo A, Anhalt H, Ten S, King SR | title = Phenotypic variations in lipoid congenital adrenal hyperplasia | journal = Pediatric Endocrinology Reviews | volume = 3 | issue = 3 | pages = 258–71 | date = March 2006 | pmid = 16639391 | doi = }}
22. ^{{cite journal | vauthors = al Kandari H, Katsumata N, Alexander S, Rasoul MA | title = 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 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 8 | pages = 2821–6 | date = August 2006 | pmid = 16705068 | doi = 10.1210/jc.2005-2230 }}
23. ^{{cite journal | vauthors = Kim CJ, Lin L, Huang N, Quigley CA, AvRuskin TW, Achermann JC, Miller WL | title = Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 93 | issue = 3 | pages = 696–702 | date = March 2008 | pmid = 18182448 | pmc = 2266942 | doi = 10.1210/jc.2007-2330 }}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Helmberg A | title = Twin genes and endocrine disease: CYP21 and CYP11B genes | journal = Acta Endocrinologica | volume = 129 | issue = 2 | pages = 97–108 | date = August 1993 | pmid = 8372604 | doi = 10.1530/acta.0.1290097 }}
  • {{cite journal | vauthors = Papadopoulos V, Amri H, Boujrad N, Cascio C, Culty M, Garnier M, Hardwick M, Li H, Vidic B, Brown AS, Reversa JL, Bernassau JM, Drieu K | title = Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis | journal = Steroids | volume = 62 | issue = 1 | pages = 21–8 | date = January 1997 | pmid = 9029710 | doi = 10.1016/S0039-128X(96)00154-7 }}
  • {{cite journal | vauthors = Stocco DM | title = Intramitochondrial cholesterol transfer | journal = Biochimica et Biophysica Acta | volume = 1486 | issue = 1 | pages = 184–97 | date = June 2000 | pmid = 10856721 | doi = 10.1016/S1388-1981(00)00056-1 }}
  • {{cite journal | vauthors = Kristensen VN, Kure EH, Erikstein B, Harada N, Børresen-Dale A | title = Genetic susceptibility and environmental estrogen-like compounds | journal = Mutation Research | volume = 482 | issue = 1–2 | pages = 77–82 | date = October 2001 | pmid = 11535251 | doi = 10.1016/S0027-5107(01)00212-3 }}
  • {{cite journal | vauthors = Strauss JF | title = Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome | journal = Annals of the New York Academy of Sciences | volume = 997 | issue = 1 | pages = 42–8 | date = November 2003 | pmid = 14644808 | doi = 10.1196/annals.1290.005 }}
  • {{cite journal | vauthors = Wada A, Waterman MR | title = Identification by site-directed mutagenesis of two lysine residues in cholesterol side chain cleavage cytochrome P450 that are essential for adrenodoxin binding | journal = The Journal of Biological Chemistry | volume = 267 | issue = 32 | pages = 22877–82 | date = November 1992 | pmid = 1429635 | doi = }}
  • {{cite journal | vauthors = Hu MC, Guo IC, Lin JH, Chung BC | title = Regulated expression of cytochrome P-450scc (cholesterol-side-chain cleavage enzyme) in cultured cell lines detected by antibody against bacterially expressed human protein | journal = The Biochemical Journal | volume = 274 | issue = Pt 3 | pages = 813–7 | date = March 1991 | pmid = 1849407 | pmc = 1149983 | doi = 10.1042/bj2740813}}
  • {{cite journal | vauthors = Sparkes RS, Klisak I, Miller WL | title = 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 | journal = DNA and Cell Biology | volume = 10 | issue = 5 | pages = 359–65 | date = June 1991 | pmid = 1863359 | doi = 10.1089/dna.1991.10.359 }}
  • {{cite journal | vauthors = Coghlan VM, Vickery LE | title = Site-specific mutations in human ferredoxin that affect binding to ferredoxin reductase and cytochrome P450scc | journal = The Journal of Biological Chemistry | volume = 266 | issue = 28 | pages = 18606–12 | date = October 1991 | pmid = 1917982 | doi = }}
  • {{cite journal | vauthors = Matteson KJ, Chung BC, Urdea MS, Miller WL | title = Study of cholesterol side-chain cleavage (20,22 desmolase) deficiency causing congenital lipoid adrenal hyperplasia using bovine-sequence P450scc oligodeoxyribonucleotide probes | journal = Endocrinology | volume = 118 | issue = 4 | pages = 1296–305 | date = April 1986 | pmid = 2419119 | doi = 10.1210/endo-118-4-1296 }}
  • {{cite journal | vauthors = Chung BC, Matteson KJ, Voutilainen R, Mohandas TK, Miller WL | title = Human cholesterol side-chain cleavage enzyme, P450scc: cDNA cloning, assignment of the gene to chromosome 15, and expression in the placenta | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 23 | pages = 8962–6 | date = December 1986 | pmid = 3024157 | pmc = 387054 | doi = 10.1073/pnas.83.23.8962 }}
  • {{cite journal | vauthors = Morohashi K, Sogawa K, Omura T, Fujii-Kuriyama Y | title = Gene structure of human cytochrome P-450(SCC), cholesterol desmolase | journal = Journal of Biochemistry | volume = 101 | issue = 4 | pages = 879–87 | date = April 1987 | pmid = 3038854 | doi = }}
  • {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
  • {{cite journal | vauthors = Gharani N, Waterworth DM, Batty S, White D, Gilling-Smith C, Conway GS, McCarthy M, Franks S, Williamson R | title = Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism | journal = Human Molecular Genetics | volume = 6 | issue = 3 | pages = 397–402 | date = March 1997 | pmid = 9147642 | doi = 10.1093/hmg/6.3.397 }}
  • {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
  • {{cite journal | vauthors = Hukkanen J, Mäntylä M, Kangas L, Wirta P, Hakkola J, Paakki P, Evisalmi S, Pelkonen O, Raunio H | title = Expression of cytochrome P450 genes encoding enzymes active in the metabolism of tamoxifen in human uterine endometrium | journal = Pharmacology & Toxicology | volume = 82 | issue = 2 | pages = 93–7 | date = February 1998 | pmid = 9498238 | doi = 10.1111/j.1600-0773.1998.tb01404.x }}
  • {{cite journal | vauthors = Zhou Z, Shackleton CH, Pahwa S, White PC, Speiser PW | title = Prominent sex steroid metabolism in human lymphocytes | journal = Molecular and Cellular Endocrinology | volume = 138 | issue = 1–2 | pages = 61–9 | date = March 1998 | pmid = 9685215 | doi = 10.1016/S0303-7207(98)00052-5 }}
{{refend}}

Steroid hormone synthesis

Additional images

External links

  • {{MeshName|Cytochrome+P450scc}}
{{Steroid hydroxylases}}{{Cytochrome P450}}{{Multienzyme complexes}}{{Mitochondrial enzymes}}{{CH-NH oxidoreductases}}{{Enzymes}}{{Portal bar|Molecular and Cellular Biology|border=no}}

2 : Cytochrome P450|EC 1.14.15
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