Q4WAZ2 · FMAE_ASPFU
- ProteinMonooxygenase af470
- Geneaf470
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids275 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score3/5
Function
function
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 monooxygenase af470 catalyzes the oxidative cleavage of prefumagillin to yield the final compound of the pathway, fumagillin (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 monooxygenase af470 catalyzes the oxidative cleavage of prefumagillin to yield the final compound of the pathway, fumagillin (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
- NADPH + 2 O2 + prefumagillin = acetaldehyde + fumagillin + H2O + NADP+This reaction proceeds in the forward direction.
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.
GO annotations
Aspect | Term | |
---|---|---|
Molecular Function | monooxygenase activity | |
Biological Process | fumagillin biosynthetic process | |
Biological Process | terpenoid biosynthetic process |
Keywords
- Molecular function
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameMonooxygenase af470
- 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 accessionQ4WAZ2
Proteomes
Organism-specific databases
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000437045 | 1-275 | Monooxygenase af470 | |||
Sequence: MDQSMKPLLSPTERPRRHLTASVISFFLPNQFRLSTILCIGALLQTILCAVLPLRYAAVPCVTVLLISVLTTIQECFQPNTNSFMADVIRGRTTAQIPGKDGTHGREPGKGSVVVFHLGIQYNHPLGVFAPHMREISNRFLAMQQDILRRKDELGLLAVQNWRGSERDSGNTTLIKYFFKDVESIHKFAHEPLHKETWTYYNQHHPGHVGIFHETFITKDGGYESMYVNCHPILLGRGEVKVNNRKDGTEEWVGTLVSADTPGLKSFKARLGRDD |
Interaction
Protein-protein interaction databases
Structure
Sequence
- Sequence statusComplete
- Length275
- Mass (Da)31,023
- Last updated2005-07-05 v1
- Checksum27BEE09D00383001
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AAHF01000014 EMBL· GenBank· DDBJ | EAL85120.1 EMBL· GenBank· DDBJ | Genomic DNA |