Squalene monooxygenase

Squalene monooxygenase (also called squalene epoxidase) is a eukaryotic enzyme that uses NADPH and diatomic oxygen to oxidize squalene to 2,3-oxidosqualene (squalene epoxide). Squalene epoxidase catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway.[5] In humans, squalene epoxidase is encoded by the SQLE gene.[6] Several eukaryote genomes lack a squalene monooxygenase encoding gene, but instead encode an alternative squalene epoxidase that performs the same task.[7]

Squalene epoxidase
Chemical reaction catalyzed by squalene epoxidase.
Identifiers
EC no.1.14.13.132
CAS no.9029-62-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
SQLE
Identifiers
AliasesSQLE, entrez:6713, squalene epoxidase
External IDsOMIM: 602019; MGI: 109296; HomoloGene: 2355; GeneCards: SQLE; OMA:SQLE - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_003129

NM_009270

RefSeq (protein)

NP_003120

NP_033296

Location (UCSC)Chr 8: 125 – 125.02 MbChr 15: 59.19 – 59.2 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mechanism

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The canonical squalene monooxygenase is a flavoprotein monooxygenase. Flavoprotein monooxygenase form flavin hydroperoxides at the enzyme active site, which then transfer the terminal oxygen atom of the hydroperoxide to the substrate. Squalene monooxygenase differs from other flavin monooxygenases in that the oxygen is inserted into the substrate as an epoxide rather than as a hydroxyl group. This enzyme contains a loosely bound FAD flavin and obtains electrons from NADPH-cytochrome P450 reductase, rather than binding NADPH directly. The alternative squalene epoxidase belongs to the fatty acid hydroxylase superfamily and obtains electrons from cytochrome b5.[7]

Inhibitors

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Inhibitors of squalene epoxidase have found application mainly as antifungal drugs:[8]

Since squalene epoxidase is on the biosynthetic pathway leading to production of cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia.[10]

Localization

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In baker's yeast (Saccharomyces cerevisiae), squalene epoxidase is localized to both the endoplasmic reticulum and lipid droplets. Only the ER localized protein is active.

Additional products

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Squalene epoxidase also catalyzes the formation of diepoxysqualene (DOS). DOS is converted to 24(S),25-epoxylanosterol by lanosterol synthase.

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104549Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022351Ensembl, 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. ^ "Entrez Gene: SQLE squalene epoxidase".
  6. ^ Nagai M, Sakakibara J, Wakui K, Fukushima Y, Igarashi S, Tsuji S, Arakawa M, Ono T (Aug 1997). "Localization of the squalene epoxidase gene (SQLE) to human chromosome region 8q24.1". Genomics. 44 (1): 141–3. doi:10.1006/geno.1997.4825. PMID 9286711.
  7. ^ a b Pollier J, Vancaester E, Kuzhiumparambil U, Vickers CE, Vandepoele K, Goossens A, Fabris M (2019). "A widespread alternative squalene epoxidase participates in eukaryote steroid biosynthesis". Nature Microbiology. 4 (2): 226–233. doi:10.1038/s41564-018-0305-5. hdl:1854/LU-8587985. PMID 30478288. S2CID 53726187.
  8. ^ Favre B, Ryder NS (Feb 1996). "Characterization of squalene epoxidase activity from the dermatophyte Trichophyton rubrum and its inhibition by terbinafine and other antimycotic agents". Antimicrobial Agents and Chemotherapy. 40 (2): 443–7. doi:10.1128/AAC.40.2.443. PMC 163131. PMID 8834895.
  9. ^ Ryder NS (Feb 1992). "Terbinafine: mode of action and properties of the squalene epoxidase inhibition". The British Journal of Dermatology. 126 (Suppl 39): 2–7. doi:10.1111/j.1365-2133.1992.tb00001.x. PMID 1543672. S2CID 19780957.
  10. ^ Chugh A, Ray A, Gupta JB (Jan 2003). "Squalene epoxidase as hypocholesterolemic drug target revisited". Progress in Lipid Research. 42 (1): 37–50. doi:10.1016/S0163-7827(02)00029-2. PMID 12467639.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.