Q4WAZ6 · FMAG_ASPFU

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).

Catalytic activity

Cofactor

heme (UniProtKB | Rhea| CHEBI:30413 )

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.

TypeIDPosition(s)Description
Binding site448Fe (UniProtKB | ChEBI) of heme (UniProtKB | ChEBI); axial binding residue

GO annotations

AspectTerm
Cellular Componentmembrane
Molecular Functionheme binding
Molecular Functioniron ion binding
Molecular Functionmonooxygenase activity
Molecular Functionoxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
Biological Processfumagillin biosynthetic process
Biological Processsecondary metabolite biosynthetic process
Biological Processterpenoid biosynthetic process

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Multifunctional cytochrome P450 monooxygenase af510
  • EC number
  • Alternative names
    • 2,4,6-trichlorophenol monooxygenase
    • Fumagillin biosynthesis cluster P450 monooxygenase
      (Fma-P450
      )

Gene names

    • Name
      af510
    • Synonyms
      fmaG
    • ORF names
      AFUA_8G00510

Organism names

Accessions

  • Primary accession
    Q4WAZ6

Proteomes

Organism-specific databases

Subcellular Location

Membrane
; Single-pass membrane protein

Features

Showing features for transmembrane.

TypeIDPosition(s)Description
Transmembrane4-24Helical

Keywords

Phenotypes & Variants

Disruption phenotype

Completely abolishes the production of fumagillin but leads to the accumulation of the intermediate beta-trans-bergamotene (PubMed:24082142, PubMed:24568283).

PTM/Processing

Features

Showing features for chain, glycosylation.

TypeIDPosition(s)Description
ChainPRO_00004370441-536Multifunctional cytochrome P450 monooxygenase af510
Glycosylation210N-linked (GlcNAc...) asparagine
Glycosylation293N-linked (GlcNAc...) asparagine

Keywords

PTM databases

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

Structure

Family & Domains

Sequence similarities

Belongs to the cytochrome P450 family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    536
  • Mass (Da)
    60,965
  • Last updated
    2005-07-05 v1
  • Checksum
    8BB699E2A41E3E7E
MAYELSTLQLSCVAFVAFMAVLVFRTRTRNLKQNVPPGPRPLPIIGNFFDLPPKGQPEYLHWFKHKDAYGPVSSINVMGTTLVIFHDKDAAHAVMGKKAQKTSARPQLNFAQLCGFENFLITHQYNDKYRLHRKMVHQEIGTKGLSAGFRPIQEQESIRFILQTFNRPDDILQHLKTLAAAIVLKITYGYSIERKGQDPLVELIEHAMENLSQAFVPLAWAVDSVPAIKYLPDWFPGMSYRKTARKWRAINEAAAELPYDFVKRQMAHKAHQPSYVSNLLEKHMIKSEDNKINVSAADEEAIKWTAVSLYAAGSDSTVAIIHSVICGLVMFPEVVTRAQEEIDRVVGSDRLPNFDDRTNLPYVDGIIKEAWRWNPVGPMGLTHKSEEDLVCGEYLIPKGSYLLPSLWWFLNDPKEYPEPRVFKPERYMEPFNHPDPSEIAFGYGRRSCAGRYFADASVYITVVQLLAVFNVRKARDDQGNEIPVTLQAIPGMVNRPAPFQFKVEPRSQHHIDLLRRIESEQIPEVSHASLLKPSTV

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AAHF01000014
EMBL· GenBank· DDBJ
EAL85116.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice.
We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.
FeedbackHelp