{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q4WAZ2","uniProtkbId":"FMAE_ASPFU","entryAudit":{"firstPublicDate":"2016-09-07","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2005-07-05","entryVersion":74,"sequenceVersion":1},"annotationScore":3.0,"organism":{"scientificName":"Aspergillus fumigatus (strain ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293)","commonName":"Neosartorya fumigata","taxonId":330879,"lineage":["Eukaryota","Fungi","Dikarya","Ascomycota","Pezizomycotina","Eurotiomycetes","Eurotiomycetidae","Eurotiales","Aspergillaceae","Aspergillus","Fumigati"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Monooxygenase af470"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24568283"}],"value":"1.13.1.-"}]},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"24568283"}],"value":"Fumagillin biosynthesis antibiotic biosynthesis monooxygenase superfamily monooxygenase"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"24568283"}],"value":"Fma-ABM"}]}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"23488861"}],"value":"af470"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"24082142"}],"value":"fmaE"}],"orfNames":[{"value":"AFUA_8G00470"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23488861"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24568283"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"24568283"}],"value":"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 monooxygenase af470 catalyzes the oxidative cleavage of prefumagillin to yield the final compound of the pathway, fumagillin (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)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"prefumagillin + NADPH + 2 O2 = fumagillin + acetaldehyde + NADP(+) + H2O","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:74627"},{"database":"ChEBI","id":"CHEBI:15343"},{"database":"ChEBI","id":"CHEBI:15377"},{"database":"ChEBI","id":"CHEBI:15379"},{"database":"ChEBI","id":"CHEBI:57783"},{"database":"ChEBI","id":"CHEBI:58349"},{"database":"ChEBI","id":"CHEBI:193520"},{"database":"ChEBI","id":"CHEBI:194019"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24568283"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:74628"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24568283"}]}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24568283"}],"value":"Secondary metabolite biosynthesis; terpenoid biosynthesis"}],"commentType":"PATHWAY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24082142"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24116213"}],"value":"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)"}],"commentType":"INDUCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24082142"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24568283"}],"value":"Completely abolishes the production of fumagillin but leads to the accumulation of the intermediate prefumagillin (PubMed:24082142, PubMed:24568283)"}],"commentType":"DISRUPTION PHENOTYPE"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12075057"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14913169"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"18209961"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9177176"}],"value":"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)"}],"commentType":"BIOTECHNOLOGY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":275,"modifier":"EXACT"}},"description":"Monooxygenase af470","featureId":"PRO_0000437045"}],"keywords":[{"id":"KW-0503","category":"Molecular function","name":"Monooxygenase"},{"id":"KW-0560","category":"Molecular function","name":"Oxidoreductase"},{"id":"KW-1185","category":"Technical term","name":"Reference proteome"}],"references":[{"referenceNumber":1,"citation":{"id":"16372009","citationType":"journal article","authors":["Nierman W.C.","Pain A.","Anderson M.J.","Wortman J.R.","Kim H.S.","Arroyo J.","Berriman M.","Abe K.","Archer D.B.","Bermejo C.","Bennett J.W.","Bowyer P.","Chen D.","Collins M.","Coulsen R.","Davies R.","Dyer P.S.","Farman M.L.","Fedorova N.","Fedorova N.D.","Feldblyum T.V.","Fischer R.","Fosker N.","Fraser A.","Garcia J.L.","Garcia M.J.","Goble A.","Goldman G.H.","Gomi K.","Griffith-Jones S.","Gwilliam R.","Haas B.J.","Haas H.","Harris D.E.","Horiuchi H.","Huang J.","Humphray S.","Jimenez J.","Keller N.","Khouri H.","Kitamoto K.","Kobayashi T.","Konzack S.","Kulkarni R.","Kumagai T.","Lafton A.","Latge J.-P.","Li W.","Lord A.","Lu C.","Majoros W.H.","May G.S.","Miller B.L.","Mohamoud Y.","Molina M.","Monod M.","Mouyna I.","Mulligan S.","Murphy L.D.","O'Neil S.","Paulsen I.","Penalva M.A.","Pertea M.","Price C.","Pritchard B.L.","Quail M.A.","Rabbinowitsch E.","Rawlins N.","Rajandream M.A.","Reichard U.","Renauld H.","Robson G.D.","Rodriguez de Cordoba S.","Rodriguez-Pena J.M.","Ronning C.M.","Rutter S.","Salzberg S.L.","Sanchez M.","Sanchez-Ferrero J.C.","Saunders D.","Seeger K.","Squares R.","Squares S.","Takeuchi M.","Tekaia F.","Turner G.","Vazquez de Aldana C.R.","Weidman J.","White O.","Woodward J.R.","Yu J.-H.","Fraser C.M.","Galagan J.E.","Asai K.","Machida M.","Hall N.","Barrell B.G.","Denning D.W."],"citationCrossReferences":[{"database":"PubMed","id":"16372009"},{"database":"DOI","id":"10.1038/nature04332"}],"title":"Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus.","publicationDate":"2005","journal":"Nature","firstPage":"1151","lastPage":"1156","volume":"438"},"referencePositions":["NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]"],"referenceComments":[{"value":"ATCC MYA-4609 / CBS 101355 / FGSC A1100 / Af293","type":"STRAIN"}]},{"referenceNumber":2,"citation":{"id":"14913169","citationType":"journal article","authors":["Killough J.H.","Magill G.B.","Smith R.C."],"citationCrossReferences":[{"database":"PubMed","id":"14913169"},{"database":"DOI","id":"10.1126/science.115.2977.71"}],"title":"The treatment of amebiasis with fumagillin.","publicationDate":"1952","journal":"Science","firstPage":"71","lastPage":"72","volume":"115"},"referencePositions":["BIOTECHNOLOGY"]},{"referenceNumber":3,"citation":{"id":"9177176","citationType":"journal article","authors":["Sin N.","Meng L.","Wang M.Q.","Wen J.J.","Bornmann W.G.","Crews C.M."],"citationCrossReferences":[{"database":"PubMed","id":"9177176"},{"database":"DOI","id":"10.1073/pnas.94.12.6099"}],"title":"The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2.","publicationDate":"1997","journal":"Proc. Natl. Acad. Sci. U.S.A.","firstPage":"6099","lastPage":"6103","volume":"94"},"referencePositions":["BIOTECHNOLOGY"]},{"referenceNumber":4,"citation":{"id":"12075057","citationType":"journal article","authoringGroup":["Agence Nationale de Recherches sur le SIDA 090 Study Group"],"authors":["Molina J.M.","Tourneur M.","Sarfati C.","Chevret S.","de Gouvello A.","Gobert J.G.","Balkan S.","Derouin F."],"citationCrossReferences":[{"database":"PubMed","id":"12075057"},{"database":"DOI","id":"10.1056/nejmoa012924"}],"title":"Fumagillin treatment of intestinal microsporidiosis.","publicationDate":"2002","journal":"N. Engl. J. Med.","firstPage":"1963","lastPage":"1969","volume":"346"},"referencePositions":["BIOTECHNOLOGY"]},{"referenceNumber":5,"citation":{"id":"18209961","citationType":"journal article","authors":["Lazarus D.D.","Doyle E.G.","Bernier S.G.","Rogers A.B.","Labenski M.T.","Wakefield J.D.","Karp R.M.","Clark E.J.","Lorusso J.","Hoyt J.G.","Thompson C.D.","Hannig G.","Westlin W.F."],"citationCrossReferences":[{"database":"PubMed","id":"18209961"},{"database":"DOI","id":"10.1007/s00011-007-7075-5"}],"title":"An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates the pathophysiological disease processes of rheumatoid arthritis.","publicationDate":"2008","journal":"Inflamm. Res.","firstPage":"18","lastPage":"27","volume":"57"},"referencePositions":["BIOTECHNOLOGY"]},{"referenceNumber":6,"citation":{"id":"23488861","citationType":"journal article","authors":["Lin H.C.","Chooi Y.H.","Dhingra S.","Xu W.","Calvo A.M.","Tang Y."],"citationCrossReferences":[{"database":"PubMed","id":"23488861"},{"database":"DOI","id":"10.1021/ja312503y"}],"title":"The fumagillin biosynthetic gene cluster in Aspergillus fumigatus encodes a cryptic terpene cyclase involved in the formation of beta-trans-bergamotene.","publicationDate":"2013","journal":"J. Am. Chem. Soc.","firstPage":"4616","lastPage":"4619","volume":"135"},"referencePositions":["FUNCTION"]},{"referenceNumber":7,"citation":{"id":"24116213","citationType":"journal article","authors":["Dhingra S.","Lind A.L.","Lin H.C.","Tang Y.","Rokas A.","Calvo A.M."],"citationCrossReferences":[{"database":"PubMed","id":"24116213"},{"database":"DOI","id":"10.1371/journal.pone.0077147"}],"title":"The fumagillin gene cluster, an example of hundreds of genes under veA control in Aspergillus fumigatus.","publicationDate":"2013","journal":"PLoS ONE","firstPage":"E77147","lastPage":"E77147","volume":"8"},"referencePositions":["INDUCTION"]},{"referenceNumber":8,"citation":{"id":"24082142","citationType":"journal article","authors":["Wiemann P.","Guo C.J.","Palmer J.M.","Sekonyela R.","Wang C.C.","Keller N.P."],"citationCrossReferences":[{"database":"PubMed","id":"24082142"},{"database":"DOI","id":"10.1073/pnas.1313258110"}],"title":"Prototype of an intertwined secondary-metabolite supercluster.","publicationDate":"2013","journal":"Proc. Natl. Acad. Sci. U.S.A.","firstPage":"17065","lastPage":"17070","volume":"110"},"referencePositions":["IDENTIFICATION","INDUCTION","DISRUPTION PHENOTYPE"]},{"referenceNumber":9,"citation":{"id":"24568283","citationType":"journal article","authors":["Lin H.C.","Tsunematsu Y.","Dhingra S.","Xu W.","Fukutomi M.","Chooi Y.H.","Cane D.E.","Calvo A.M.","Watanabe K.","Tang Y."],"citationCrossReferences":[{"database":"PubMed","id":"24568283"},{"database":"DOI","id":"10.1021/ja500881e"}],"title":"Generation of complexity in fungal terpene biosynthesis: discovery of a multifunctional cytochrome P450 in the fumagillin pathway.","publicationDate":"2014","journal":"J. Am. Chem. Soc.","firstPage":"4426","lastPage":"4436","volume":"136"},"referencePositions":["FUNCTION","DISRUPTION PHENOTYPE","CATALYTIC ACTIVITY"]}],"uniProtKBCrossReferences":[{"database":"EMBL","id":"AAHF01000014","properties":[{"key":"ProteinId","value":"EAL85120.1"},{"key":"Status","value":"-"},{"key":"MoleculeType","value":"Genomic_DNA"}]},{"database":"RefSeq","id":"XP_747158.1","properties":[{"key":"NucleotideSequenceId","value":"XM_742065.1"}]},{"database":"AlphaFoldDB","id":"Q4WAZ2","properties":[{"key":"Description","value":"-"}]},{"database":"STRING","id":"330879.Q4WAZ2","properties":[{"key":"Description","value":"-"}]},{"database":"EnsemblFungi","id":"Afu8g00470-T","properties":[{"key":"ProteinId","value":"Afu8g00470-T-p1"},{"key":"GeneId","value":"Afu8g00470"}]},{"database":"GeneID","id":"3504546","properties":[{"key":"Description","value":"-"}]},{"database":"KEGG","id":"afm:AFUA_8G00470","properties":[{"key":"Description","value":"-"}]},{"database":"VEuPathDB","id":"FungiDB:Afu8g00470","properties":[{"key":"Description","value":"-"}]},{"database":"eggNOG","id":"ENOG502SKYH","properties":[{"key":"ToxonomicScope","value":"Eukaryota"}]},{"database":"HOGENOM","id":"CLU_053354_1_0_1","properties":[{"key":"Description","value":"-"}]},{"database":"InParanoid","id":"Q4WAZ2","properties":[{"key":"Description","value":"-"}]},{"database":"OMA","id":"IHKFAHE","properties":[{"key":"Fingerprint","value":"-"}]},{"database":"OrthoDB","id":"3202396at2759","properties":[{"key":"Description","value":"-"}]},{"database":"BioCyc","id":"MetaCyc:MONOMER-124250","properties":[{"key":"Description","value":"-"}]},{"database":"UniPathway","id":"UPA00213","properties":[{"key":"RectionId","value":"-"}]},{"database":"Proteomes","id":"UP000002530","properties":[{"key":"Component","value":"Chromosome 8"}]},{"database":"GO","id":"GO:1902086","properties":[{"key":"GoTerm","value":"P:fumagillin biosynthetic process"},{"key":"GoEvidenceType","value":"IGC:AspGD"}],"evidences":[{"evidenceCode":"ECO:0000317","source":"PubMed","id":"23488861"}]},{"database":"GO","id":"GO:0016114","properties":[{"key":"GoTerm","value":"P:terpenoid biosynthetic process"},{"key":"GoEvidenceType","value":"IEA:UniProtKB-UniPathway"}]},{"database":"InterPro","id":"IPR025444","properties":[{"key":"EntryName","value":"Monooxy_af470"}]},{"database":"Pfam","id":"PF13826","properties":[{"key":"EntryName","value":"Monooxy_af470-like"},{"key":"MatchStatus","value":"1"}]}],"sequence":{"value":"MDQSMKPLLSPTERPRRHLTASVISFFLPNQFRLSTILCIGALLQTILCAVLPLRYAAVPCVTVLLISVLTTIQECFQPNTNSFMADVIRGRTTAQIPGKDGTHGREPGKGSVVVFHLGIQYNHPLGVFAPHMREISNRFLAMQQDILRRKDELGLLAVQNWRGSERDSGNTTLIKYFFKDVESIHKFAHEPLHKETWTYYNQHHPGHVGIFHETFITKDGGYESMYVNCHPILLGRGEVKVNNRKDGTEEWVGTLVSADTPGLKSFKARLGRDD","length":275,"molWeight":31023,"crc64":"27BEE09D00383001","md5":"1C29B4B45482E648102DCD3C49A409AF"},"extraAttributes":{"countByCommentType":{"FUNCTION":1,"CATALYTIC ACTIVITY":1,"PATHWAY":1,"INDUCTION":1,"DISRUPTION PHENOTYPE":1,"BIOTECHNOLOGY":1},"countByFeatureType":{"Chain":1},"uniParcId":"UPI000052047C"}}