A0A067Z9B6 · FMAD_ASPFU

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).

Catalytic activity

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).

Pathway

Secondary metabolite biosynthesis; terpenoid biosynthesis.

Features

Showing features for binding site, active site.

TypeIDPosition(s)Description
Binding site145-158substrate
Binding site239-240S-adenosyl-L-methionine (UniProtKB | ChEBI)
Binding site265S-adenosyl-L-methionine (UniProtKB | ChEBI)
Binding site286-287S-adenosyl-L-methionine (UniProtKB | ChEBI)
Active site309Proton acceptor

GO annotations

AspectTerm
Molecular FunctionO-methyltransferase activity
Biological Processmethylation
Biological Processsecondary metabolite biosynthetic process
Biological Processterpenoid biosynthetic process

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    O-methyltransferase af390-400
  • EC number
  • Alternative names
    • 5-dehydro-6-demethoxy-6-hydroxyfumagillol O-methyltransferase
    • Fumagillin biosynthesis methyltransferase
      (Fma-MT
      )

Gene names

    • Name
      af390-400
    • Synonyms
      fmaD
    • ORF names
      AFUA_8G00390/400

Organism names

Accessions

  • Primary accession
    A0A067Z9B6
  • Secondary accessions
    • Q4WAY5
    • Q4WAY6

Proteomes

Phenotypes & Variants

Disruption phenotype

Completely abolishes the production of fumagillin (PubMed:24082142).

PTM/Processing

Features

Showing features for chain.

TypeIDPosition(s)Description
ChainPRO_00004370411-400O-methyltransferase af390-400

Expression

Induction

Expression is controlled by the fumagillin biosynthesis cluster regulator fumR (PubMed:24082142).
Expression is also under the control of the developmental and secondary metabolism regulator veA (PubMed:24116213).
Expression is significantly up-regulated during infection (PubMed:30251593).

Interaction

Protein-protein interaction databases

Family & Domains

Features

Showing features for region.

TypeIDPosition(s)Description
Region185-205Substrate binding

Sequence similarities

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    400
  • Mass (Da)
    44,502
  • Last updated
    2014-10-01 v1
  • Checksum
    9D48606969CC6D63
MADIAEQLIEKLQTLETSIFEGQDATRQKLALAARKLFHTLETKEEKTMRLAIEEPVMFSVLQALIDTGLFEGWAAAGGGERDVTELAKLSKRDVEPELLRHQLRLMAANHIILETANDRYAPTPYALAIGDKSTKVAPALRIRTDHVAPCAMHWPDFLAKTNYRKPRDDKASCYIDTFPEKKSFFERCSANPVHQESFSSFMDVWAKGKRPWPEFYDTQALLDGADLSNGSPFVVDVGGHHGIDLMRVAEKHPDLPAGSLVLEDLPDVVGAVHLTTDKIRTVAHDLFEEGVEQPIKGARAYFMHAVLHDWSDETSVKILRQIAAVMKPGYSKVLINDIVIPSTGASCYQAAMDCLVLQASANERTEAVWSKVIKDAGLKLVKYYPDGRGYESVIEAELP

Sequence caution

The sequence EAL85126.1 differs from that shown. Reason: Erroneous gene model prediction The predicted genes AFUA_8G00390 and AFUA_8G00400 have been merged into 1 gene: AFUA_8G00390/400.
The sequence EAL85127.1 differs from that shown. Reason: Erroneous gene model prediction The predicted genes AFUA_8G00390 and AFUA_8G00400 have been merged into 1 gene: AFUA_8G00390/400.

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
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.

Genome annotation databases

Similar Proteins

Disclaimer

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