Cholesterol side-chain cleavage enzyme

Source: Wikipedia, the free encyclopedia.
CYP11A1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000140459
ENSG00000288362

ENSMUSG00000032323

UniProt

P05108

Q9QZ82

RefSeq (mRNA)

NM_001099773
NM_000781

NM_019779
NM_001346787

RefSeq (protein)

NP_000772
NP_001093243

NP_001333716
NP_062753

Location (UCSC)Chr 15: 74.34 – 74.37 MbChr 9: 57.91 – 57.93 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an acronym for

steroid hormones.[5]

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) and is encoded by the CYP11A1 gene.[6]

Nomenclature

cholesterol monooxygenase (side-chain-cleaving)
Identifiers
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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

Tissue and intracellular localization

The highest level of the cholesterol side-chain cleavage system is found in the

adrenodoxin is similar to that of P450scc, but adrenodoxin reductase is expressed at lower levels.[9]

peripheral membrane proteins located inside the mitochondrial matrix that appear to associate with each other primarily through electrostatic interactions.[14]

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

adrenodoxin.[17][18]
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.[17] 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.[17] These conclusions have been confirmed by structural analysis of adrenodoxin and P450 complex.[19]

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.[20] Steroidogenic cells include a diverse array of antioxidant systems to cope with the radicals generated by the steroidogenic enzymes.[21]

Regulation

In each steroidogenic cell, the expression of the P450scc system proteins is regulated by the trophic hormonal system specific for the cell type.

corticotropin (ACTH).[11][22] 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.[22][23] The production of this enzyme is inhibited notably by the nuclear receptor DAX-1.[22]

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

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.[24]

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.[25][26][27] Deficiency of CYP11A1 can result in hyperpigmentation, hypoglycemia, and recurrent infections.[28]

Inhibitors

Cholesterol side-chain cleavage enzyme inhibitors include aminoglutethimide, ketoconazole, and mitotane, among others.[29][30][31]

See also

References

  1. ^ a b c ENSG00000288362 GRCh38: Ensembl release 89: ENSG00000140459, ENSG00000288362 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032323 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^
    S2CID 112729
    .
  6. ^ "Entrez Gene: CYP11A1 cytochrome P450, family 11, subfamily A, polypeptide 1".
  7. PMID 8788180
    .
  8. PMID 11720889
    .
  9. PMID 3011431
    .
  10. PMID 2170421
    .
  11. ^
    PMID 2173715
    .
  12. ^ 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.
  13. PMID 3948785
    .
  14. PMID 6783659
    .
  15. PMID 7588385
    .
  16. PMID 3691502
    .
  17. ^
    PMID 6766943
    .
  18. PMID 7217084
    .
  19. PMID 21636783
    .
  20. PMID 8396893
    .
  21. S2CID 10766948
    .
  22. ^
    S2CID 5350278
    .
  23. PMID 17594537
    .
  24. S2CID 44439040
    .
  25. PMID 16639391
    .
  26. PMID 16705068
    .
  27. PMID 18182448
    .
  28. PMID 31610036
    .
  29. ISBN 978-0-7817-1750-2
    .
  30. ISBN 978-1-4557-1126-0
    .
  31. ISBN 978-3-319-12108-6
    .

Further reading

Steroid hormone synthesis

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

Additional images

External links

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