Q4WAZ4 · FMAH_ASPFU

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).

Caution

Was first identified as a pseudogene since it seemed to be altered polyketide synthase with only the dehydratase (DH) and ketoreductase (KR) domains remaining (PubMed:23488861).
Further study showed it encoded indeed for a functional keto-reductase involved in fumagillin biosynthesis (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.

GO annotations

AspectTerm
Molecular Functionfatty acid synthase activity
Molecular Functionoxidoreductase activity
Biological Processfatty acid biosynthetic process
Biological Processsecondary metabolite biosynthetic process
Biological Processterpenoid biosynthetic process

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Stereoselective keto-reductase af490
  • EC number
  • Alternative names
    • 5-dehydrofumagillol 5-reductase
    • Fumagillin biosynthesis cluster keto-reductase
      (Fma-KR
      )

Gene names

    • Name
      af490
    • ORF names
      AFUA_8G00490

Organism names

Accessions

  • Primary accession
    Q4WAZ4

Proteomes

Phenotypes & Variants

Disruption phenotype

Strongly decreases the production of fumagillin (PubMed:24568283).

PTM/Processing

Features

Showing features for chain.

TypeIDPosition(s)Description
ChainPRO_00004370421-1017Stereoselective keto-reductase af490

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).

Interaction

Protein-protein interaction databases

Structure

Family & Domains

Features

Showing features for region, domain.

TypeIDPosition(s)Description
Region6-138N-terminal hotdog fold
Domain6-311PKS/mFAS DH
Region8-306Dehydratase (DH)
Region153-311C-terminal hotdog fold
Region532-720Ketoreductase (KR)

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    1,017
  • Mass (Da)
    110,955
  • Last updated
    2005-07-05 v1
  • Checksum
    9A7514D7CD1A5CD4
MLGLPNELSGSQVPGATEYEPGWRRVFKVEDLPGLGDYHIDNQTAVPTSIVCVIALAAAMDISNGKQANSIELYDVTIGRPIHLGTSPVEIETMIAIEPGKDGADSIQAEFSLNKSAGHDENPVSVANGRLRMTFAGHELELLSSRQAKPCGLRPVSISPFYDSLREVGLGYSGPFRALTSAERRMDYACGVIAPTTGEASRTPALLHPAMLEACFQTLLLAFAAPRDGSLWTIFVPTQIGRLTIFPNSSVGINTPASVTIDTHLHEFTAGHKADLPMIKGDVSVYSSEAGQLRIRLEGLTMSPIAPSTEKQDKRLYLKRTWLPDILSGPVLERGKPVFCYELFGLSLAPKSILAATRLLSHRYAKLKILQVGTSSVHLVHSLCRELGSSMDSYTIACESDSSMEDMRRRLLSDALPIKYVVLDIGKSLTEGDEPAAGEPTDLGSFDLIILLKASADDSPILKRTRGLIKPGGFLLMTVAATEAIPWEARDMTRKAIHDTLQSVGFSGVDLLQRDPEGDSSFVILSQAVDHQIRFLRAPFDSTPPFPTRGTLLVIGGASHRAKRPIETIQNSLRRVWAGEIVLIRSLTDLQTRGLDHVEAVLSLTELDQSVLENLSRDTFDGLHRLLHQSKIVLWVTYSAGNLNPHQSGAIGLVRAVQAETPDKVLQLLDVDQIDGNDGLVAESFLRLIGGVKMKDGSSNSLWTVEPELSVQGGRLLIPRVLFDKKRNDRLNCLRRQLKATDSFEKQSALARPIDPCSLFSPNKTYVLAGLSGQMGQSITRWIVQSGGRHIVITSRNPDKDDLWTKELEQRGAHIEIMAADVTKKQEMINVRNQILSAMPPIGGVANGAMLQSNCFFSDLTYEALQDVLKPKVDGSLVLDEVFSSDDLDFFLLFSSISAVVGQPFQANYDAANNFMTGLVLQRRARNLPASVINLGPIIGLGFIQNIDSGGGSEAVIATLRSLDYMLVSERELHHILAEAILIGKSDETPEIITGLETVSDNPAPFWHKSLLFSHII

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AAHF01000014
EMBL· GenBank· DDBJ
EAL85118.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

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