A0A067Z9B6 · FMAD_ASPFU
- ProteinO-methyltransferase af390-400
- Geneaf390-400
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids400 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score4/5
Function
function
O-methyltransferase; 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 O-methyltransferase af390-400 acts as a 5-dehydro-6-demethoxy-6-hydroxyfumagillol O-methyltransferase that methyltes the hydroxylated position C-6 of 5-dehydro-6-demethoxy-6-hydroxyfumagillol to yield 5-keto-fumagillol (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 O-methyltransferase af390-400 acts as a 5-dehydro-6-demethoxy-6-hydroxyfumagillol O-methyltransferase that methyltes the hydroxylated position C-6 of 5-dehydro-6-demethoxy-6-hydroxyfumagillol to yield 5-keto-fumagillol (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
- 5-dehydro-6-demethoxy-6-hydroxyfumagillol + S-adenosyl-L-methionine = 5-dehydrofumagillol + H+ + S-adenosyl-L-homocysteineThis 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.
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 145-158 | substrate | ||||
Sequence: TDHVAPCAMHWPDF | ||||||
Binding site | 239-240 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: GG | ||||||
Binding site | 265 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 286-287 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: DL | ||||||
Active site | 309 | Proton acceptor | ||||
Sequence: H |
GO annotations
Aspect | Term | |
---|---|---|
Molecular Function | O-methyltransferase activity | |
Biological Process | methylation | |
Biological Process | secondary metabolite biosynthetic process | |
Biological Process | terpenoid biosynthetic process |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameO-methyltransferase af390-400
- 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 accessionA0A067Z9B6
- Secondary accessions
Proteomes
Phenotypes & Variants
Disruption phenotype
Completely abolishes the production of fumagillin (PubMed:24082142).
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000437041 | 1-400 | O-methyltransferase af390-400 | |||
Sequence: MADIAEQLIEKLQTLETSIFEGQDATRQKLALAARKLFHTLETKEEKTMRLAIEEPVMFSVLQALIDTGLFEGWAAAGGGERDVTELAKLSKRDVEPELLRHQLRLMAANHIILETANDRYAPTPYALAIGDKSTKVAPALRIRTDHVAPCAMHWPDFLAKTNYRKPRDDKASCYIDTFPEKKSFFERCSANPVHQESFSSFMDVWAKGKRPWPEFYDTQALLDGADLSNGSPFVVDVGGHHGIDLMRVAEKHPDLPAGSLVLEDLPDVVGAVHLTTDKIRTVAHDLFEEGVEQPIKGARAYFMHAVLHDWSDETSVKILRQIAAVMKPGYSKVLINDIVIPSTGASCYQAAMDCLVLQASANERTEAVWSKVIKDAGLKLVKYYPDGRGYESVIEAELP |
Expression
Interaction
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 185-205 | Substrate binding | ||||
Sequence: FFERCSANPVHQESFSSFMDV |
Sequence similarities
Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-independent O-methyltransferase family. COMT subfamily.
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length400
- Mass (Da)44,502
- Last updated2014-10-01 v1
- Checksum9D48606969CC6D63
Sequence caution
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
KJ187001 EMBL· GenBank· DDBJ | AHL19974.1 EMBL· GenBank· DDBJ | mRNA | ||
AAHF01000014 EMBL· GenBank· DDBJ | EAL85127.1 EMBL· GenBank· DDBJ | Genomic DNA | Sequence problems. | |
AAHF01000014 EMBL· GenBank· DDBJ | EAL85126.1 EMBL· GenBank· DDBJ | Genomic DNA | Sequence problems. |