Cholesterol side-chain cleavage enzyme

The systematic name of this enzyme class is cholesterol, reduced-adrenal-ferredoxin:oxygen oxidoreductase (side-chain-cleaving). Other names 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 • steroid 20-22-lyase. == Tissue and intracellular localization ==

The highest level of the cholesterol side-chain cleavage system is found in the adrenal cortex and the corpus luteum. P450scc is also present at much lower levels in several other tissue types, including the brain. In the adrenal cortex, the concentration of adrenodoxin is similar to that of P450scc, but adrenodoxin reductase is expressed at lower levels. Immunofluorescence studies using specific antibodies against P450scc system enzymes have demonstrated that proteins are located exclusively within the mitochondria. P450scc is associated with the inner mitochondrial membrane, facing the interior (matrix). 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. == 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. The electrons are transferred from NADPH to P450scc via two electron transfer proteins: adrenodoxin reductase and adrenodoxin. 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. 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. Steroidogenic cells include a diverse array of antioxidant systems to cope with the radicals generated by the steroidogenic enzymes. == Regulation ==

In each steroidogenic cell, the expression of the P450scc system proteins is regulated by the trophic hormonal system specific for the cell type. 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. The production of this enzyme is inhibited notably by the nuclear receptor DAX-1. == 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. Deficiency of CYP11A1 can result in hyperpigmentation, hypoglycemia, and recurrent infections. ==Inhibitors==

Cholesterol side-chain cleavage enzyme inhibitors include aminoglutethimide, ketoconazole, and mitotane, among others. == Steroid hormone synthesis ==

, showing cholesterol side-chain cleavage enzyme at top. == Additional images ==

File:Cholesterol.svg|Cholesterol File:Pregnenolone.svg|Pregnenolone == See also ==