Q4WAZ6 · FMAG_ASPFU
- ProteinMultifunctional cytochrome P450 monooxygenase af510
- Geneaf510
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids536 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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).
Within the pathway, the multifunctional cytochrome P450 monooxygenase af510 acts as a 2,4,6-trichlorophenol monooxygenase that first performs the 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).
The pathway begins with the conversion of farnesyl pyrophosphate (FPP) to beta-trans-bergamotene by the membrane-bound beta-trans-bergamotene synthase af520. The multifunctional cytochrome P450 monooxygenase af510 then converts beta-trans-bergamotene into 5-keto-demethoxyfumagillol via several oxydation steps. 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. 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. Finally, oxidative cleavage by the monooxygenase af470 converts prefumagillin to fumagillin (Probable) (PubMed:24568283).
Within the pathway, the multifunctional cytochrome P450 monooxygenase af510 acts as a 2,4,6-trichlorophenol monooxygenase that first performs the 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).
The pathway begins with the conversion of farnesyl pyrophosphate (FPP) to beta-trans-bergamotene by the membrane-bound beta-trans-bergamotene synthase af520. The multifunctional cytochrome P450 monooxygenase af510 then converts beta-trans-bergamotene into 5-keto-demethoxyfumagillol via several oxydation steps. 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. 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. Finally, oxidative cleavage by the monooxygenase af470 converts prefumagillin to fumagillin (Probable) (PubMed:24568283).
Catalytic activity
- +-exo-beta-bergamotene + 3 O2 + 2 reduced [NADPH--hemoprotein reductase] = 5-dehydro-6-demethoxyfumagillol + 2 H+ + 3 H2O + 2 oxidized [NADPH--hemoprotein reductase]This reaction proceeds in the forward direction.
Cofactor
Biotechnology
Fumagillin and its derivatives have been intensely studied for their potential use in the treatment of amebiasis, microsporidiosis and rheumatoid arthritis (PubMed:12075057, PubMed:14913169, PubMed:18209961).
They have also interesting antiangiogenic properties by the irreversible inhibition of human type 2 methionine aminopeptidase (METAP2) (PubMed:9177176).
They have also interesting antiangiogenic properties by the irreversible inhibition of human type 2 methionine aminopeptidase (METAP2) (PubMed:9177176).
Pathway
Secondary metabolite biosynthesis; terpenoid biosynthesis.
Features
Showing features for binding site.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | membrane | |
Molecular Function | heme binding | |
Molecular Function | iron ion binding | |
Molecular Function | monooxygenase activity | |
Molecular Function | oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | |
Biological Process | fumagillin biosynthetic process | |
Biological Process | secondary metabolite biosynthetic process | |
Biological Process | terpenoid biosynthetic process |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameMultifunctional cytochrome P450 monooxygenase af510
- EC number
- Alternative names
Gene names
Organism names
- Strain
- Taxonomic lineageEukaryota > Fungi > Dikarya > Ascomycota > Pezizomycotina > Eurotiomycetes > Eurotiomycetidae > Eurotiales > Aspergillaceae > Aspergillus > Aspergillus subgen. Fumigati
Accessions
- Primary accessionQ4WAZ6
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Membrane ; Single-pass membrane protein
Features
Showing features for transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Transmembrane | 4-24 | Helical | ||||
Sequence: ELSTLQLSCVAFVAFMAVLVF |
Keywords
- Cellular component
PTM/Processing
Features
Showing features for chain, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000437044 | 1-536 | Multifunctional cytochrome P450 monooxygenase af510 | |||
Sequence: MAYELSTLQLSCVAFVAFMAVLVFRTRTRNLKQNVPPGPRPLPIIGNFFDLPPKGQPEYLHWFKHKDAYGPVSSINVMGTTLVIFHDKDAAHAVMGKKAQKTSARPQLNFAQLCGFENFLITHQYNDKYRLHRKMVHQEIGTKGLSAGFRPIQEQESIRFILQTFNRPDDILQHLKTLAAAIVLKITYGYSIERKGQDPLVELIEHAMENLSQAFVPLAWAVDSVPAIKYLPDWFPGMSYRKTARKWRAINEAAAELPYDFVKRQMAHKAHQPSYVSNLLEKHMIKSEDNKINVSAADEEAIKWTAVSLYAAGSDSTVAIIHSVICGLVMFPEVVTRAQEEIDRVVGSDRLPNFDDRTNLPYVDGIIKEAWRWNPVGPMGLTHKSEEDLVCGEYLIPKGSYLLPSLWWFLNDPKEYPEPRVFKPERYMEPFNHPDPSEIAFGYGRRSCAGRYFADASVYITVVQLLAVFNVRKARDDQGNEIPVTLQAIPGMVNRPAPFQFKVEPRSQHHIDLLRRIESEQIPEVSHASLLKPSTV | ||||||
Glycosylation | 210 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 293 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N |
Keywords
- PTM
PTM databases
Expression
Interaction
Protein-protein interaction databases
Structure
Sequence
- Sequence statusComplete
- Length536
- Mass (Da)60,965
- Last updated2005-07-05 v1
- Checksum8BB699E2A41E3E7E
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AAHF01000014 EMBL· GenBank· DDBJ | EAL85116.1 EMBL· GenBank· DDBJ | Genomic DNA |