Q4WAZ4 · FMAH_ASPFU
- ProteinStereoselective keto-reductase af490
- Geneaf490
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids1017 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score4/5
Function
function
Stereoselective keto-reductase; 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 keto-reductase af490 acts as a 5-dehydrofumagillol 5-reductase that stereoselectively reduces 5-keto-fumagillol to 5R-hydroxy-seco-sesquiterpene (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 keto-reductase af490 acts as a 5-dehydrofumagillol 5-reductase that stereoselectively reduces 5-keto-fumagillol to 5R-hydroxy-seco-sesquiterpene (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
- fumagillol + NADP+ = 5-dehydrofumagillol + H+ + NADPHThis 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 | fatty acid synthase activity | |
Molecular Function | oxidoreductase activity | |
Biological Process | fatty acid biosynthetic process | |
Biological Process | secondary metabolite biosynthetic process | |
Biological Process | terpenoid biosynthetic process |
Keywords
- Molecular function
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameStereoselective keto-reductase af490
- 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 accessionQ4WAZ4
Proteomes
Phenotypes & Variants
Disruption phenotype
Strongly decreases the production of fumagillin (PubMed:24568283).
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000437042 | 1-1017 | Stereoselective keto-reductase af490 | |||
Sequence: MLGLPNELSGSQVPGATEYEPGWRRVFKVEDLPGLGDYHIDNQTAVPTSIVCVIALAAAMDISNGKQANSIELYDVTIGRPIHLGTSPVEIETMIAIEPGKDGADSIQAEFSLNKSAGHDENPVSVANGRLRMTFAGHELELLSSRQAKPCGLRPVSISPFYDSLREVGLGYSGPFRALTSAERRMDYACGVIAPTTGEASRTPALLHPAMLEACFQTLLLAFAAPRDGSLWTIFVPTQIGRLTIFPNSSVGINTPASVTIDTHLHEFTAGHKADLPMIKGDVSVYSSEAGQLRIRLEGLTMSPIAPSTEKQDKRLYLKRTWLPDILSGPVLERGKPVFCYELFGLSLAPKSILAATRLLSHRYAKLKILQVGTSSVHLVHSLCRELGSSMDSYTIACESDSSMEDMRRRLLSDALPIKYVVLDIGKSLTEGDEPAAGEPTDLGSFDLIILLKASADDSPILKRTRGLIKPGGFLLMTVAATEAIPWEARDMTRKAIHDTLQSVGFSGVDLLQRDPEGDSSFVILSQAVDHQIRFLRAPFDSTPPFPTRGTLLVIGGASHRAKRPIETIQNSLRRVWAGEIVLIRSLTDLQTRGLDHVEAVLSLTELDQSVLENLSRDTFDGLHRLLHQSKIVLWVTYSAGNLNPHQSGAIGLVRAVQAETPDKVLQLLDVDQIDGNDGLVAESFLRLIGGVKMKDGSSNSLWTVEPELSVQGGRLLIPRVLFDKKRNDRLNCLRRQLKATDSFEKQSALARPIDPCSLFSPNKTYVLAGLSGQMGQSITRWIVQSGGRHIVITSRNPDKDDLWTKELEQRGAHIEIMAADVTKKQEMINVRNQILSAMPPIGGVANGAMLQSNCFFSDLTYEALQDVLKPKVDGSLVLDEVFSSDDLDFFLLFSSISAVVGQPFQANYDAANNFMTGLVLQRRARNLPASVINLGPIIGLGFIQNIDSGGGSEAVIATLRSLDYMLVSERELHHILAEAILIGKSDETPEIITGLETVSDNPAPFWHKSLLFSHII |
Interaction
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for region, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 6-138 | N-terminal hotdog fold | ||||
Sequence: NELSGSQVPGATEYEPGWRRVFKVEDLPGLGDYHIDNQTAVPTSIVCVIALAAAMDISNGKQANSIELYDVTIGRPIHLGTSPVEIETMIAIEPGKDGADSIQAEFSLNKSAGHDENPVSVANGRLRMTFAGH | ||||||
Domain | 6-311 | PKS/mFAS DH | ||||
Sequence: NELSGSQVPGATEYEPGWRRVFKVEDLPGLGDYHIDNQTAVPTSIVCVIALAAAMDISNGKQANSIELYDVTIGRPIHLGTSPVEIETMIAIEPGKDGADSIQAEFSLNKSAGHDENPVSVANGRLRMTFAGHELELLSSRQAKPCGLRPVSISPFYDSLREVGLGYSGPFRALTSAERRMDYACGVIAPTTGEASRTPALLHPAMLEACFQTLLLAFAAPRDGSLWTIFVPTQIGRLTIFPNSSVGINTPASVTIDTHLHEFTAGHKADLPMIKGDVSVYSSEAGQLRIRLEGLTMSPIAPSTEK | ||||||
Region | 8-306 | Dehydratase (DH) | ||||
Sequence: LSGSQVPGATEYEPGWRRVFKVEDLPGLGDYHIDNQTAVPTSIVCVIALAAAMDISNGKQANSIELYDVTIGRPIHLGTSPVEIETMIAIEPGKDGADSIQAEFSLNKSAGHDENPVSVANGRLRMTFAGHELELLSSRQAKPCGLRPVSISPFYDSLREVGLGYSGPFRALTSAERRMDYACGVIAPTTGEASRTPALLHPAMLEACFQTLLLAFAAPRDGSLWTIFVPTQIGRLTIFPNSSVGINTPASVTIDTHLHEFTAGHKADLPMIKGDVSVYSSEAGQLRIRLEGLTMSPIA | ||||||
Region | 153-311 | C-terminal hotdog fold | ||||
Sequence: LRPVSISPFYDSLREVGLGYSGPFRALTSAERRMDYACGVIAPTTGEASRTPALLHPAMLEACFQTLLLAFAAPRDGSLWTIFVPTQIGRLTIFPNSSVGINTPASVTIDTHLHEFTAGHKADLPMIKGDVSVYSSEAGQLRIRLEGLTMSPIAPSTEK | ||||||
Region | 532-720 | Ketoreductase (KR) | ||||
Sequence: QIRFLRAPFDSTPPFPTRGTLLVIGGASHRAKRPIETIQNSLRRVWAGEIVLIRSLTDLQTRGLDHVEAVLSLTELDQSVLENLSRDTFDGLHRLLHQSKIVLWVTYSAGNLNPHQSGAIGLVRAVQAETPDKVLQLLDVDQIDGNDGLVAESFLRLIGGVKMKDGSSNSLWTVEPELSVQGGRLLIPR |
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length1,017
- Mass (Da)110,955
- Last updated2005-07-05 v1
- Checksum9A7514D7CD1A5CD4
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AAHF01000014 EMBL· GenBank· DDBJ | EAL85118.1 EMBL· GenBank· DDBJ | Genomic DNA |