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af510

Gene
af510
Protein
Multifunctional cytochrome P450 monooxygenase af510
Organism
Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100)
Length
536 amino acids
Function
Multifunctional cytochrome P450 monooxygenase; part of the gene cluster that mediates the biosynthesis of fumagillin, a meroterpenoid that has numerous biological activities including irreversible inhibition of human type 2 methionine aminopeptidase (METAP2) (PubMed:23488861, PubMed:24568283). The pathway begins with the conversion of farnesyl pyrophosphate (FPP) to beta-trans-bergamotene by the membrane-bound beta-trans-bergamotene synthase af520 (PubMed:23488861). The initial oxidation of beta-trans-bergamotene by the multifunctional cytochrome P450 monooxygenase af510 involves C-H hydroxylation at the bridgehead C5 position to yield 5R-hydroxyl-beta-trans-bergamotene (PubMed:24568283). Subsequently, a four electron oxidation initiated at C-9 coupled to cleavage of the cyclobutane C5-C8 bond of the bicyclo[3.1.1] core yields the epoxyketone intermediate 5-keto-cordycol (PubMed:24568283). An additional epoxidation reaction also catalyzed by af510 then furnishes the characteristic bisepoxide ketone 5-keto-demethoxyfumagillol (PubMed:24568283). 5-keto-demethoxyfumagillol is then subjected to successive C-6 hydroxylation and O-methylation by the dioxygenase af480 and O-methyltransferase af390-400, respectively, to yield 5-keto-fumagillol, which is then stereoselectively reduced by the keto-reductase af490 to 5R-hydroxy-seco-sesquiterpene (PubMed:24568283). The next step is the polyketide transferase af380-catalyzed transfer of a dodecapentaenoyl group synthesized by the polyketide synthase af370 onto 5R-hydroxy-seco-sesquiterpene which leads to the production of prefumagillin (PubMed:24568283). Finally, oxidative cleavage by the monooxygenase af470 converts prefumagillin to fumagillin (PubMed:24568283).
Similarity
Belongs to the cytochrome P450 family.
Mass
60.965 kDa
Sequence
MAYELSTLQLSCVAFVAFMAVLVFRTRTRNLKQNVPPGPRPLPIIGNFFDLPPKGQPEYLHWFKHKDAYGPVSSINVMGTTLVIFHDKDAAHAVMGKKAQKTSARPQLNFAQLCGFENFLITHQYNDKYRLHRKMVHQEIGTKGLSAGFRPIQEQESIRFILQTFNRPDDILQHLKTLAAAIVLKITYGYSIERKGQDPLVELIEHAMENLSQAFVPLAWAVDSVPAIKYLPDWFPGMSYRKTARKWRAINEAAAELPYDFVKRQMAHKAHQPSYVSNLLEKHMIKSEDNKINVSAADEEAIKWTAVSLYAAGSDSTVAIIHSVICGLVMFPEVVTRAQEEIDRVVGSDRLPNFDDRTNLPYVDGIIKEAWRWNPVGPMGLTHKSEEDLVCGEYLIPKGSYLLPSLWWFLNDPKEYPEPRVFKPERYMEPFNHPDPSEIAFGYGRRSCAGRYFADASVYITVVQLLAVFNVRKARDDQGNEIPVTLQAIPGMVNRPAPFQFKVEPRSQHHIDLLRRIESEQIPEVSHASLLKPSTV