{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"B8NHD6","secondaryAccessions":["A0A7U2MMS8"],"uniProtkbId":"FLVA_ASPFN","entryAudit":{"firstPublicDate":"2022-02-23","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2026-06-10","entryVersion":68,"sequenceVersion":2},"annotationScore":4.0,"organism":{"scientificName":"Aspergillus flavus (strain ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357 / JCM 12722 / SRRC 167)","taxonId":332952,"lineage":["Eukaryota","Fungi","Dikarya","Ascomycota","Pezizomycotina","Eurotiomycetes","Eurotiomycetidae","Eurotiales","Aspergillaceae","Aspergillus","Circumdati"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"31885262"}],"value":"Bifunctional enzyme flvA"}},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"31885262"}],"value":"Flavunoidine biosynthesis cluster protein A"}}],"includes":[{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"31885262"}],"value":"Pyridoxal 5'-phosphate-dependent lyase"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"31885262"}],"value":"PLP-dependent lyase"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31885262"}],"value":"4.4.1.-"}]}},{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"31885262"}],"value":"Alpha-ketoglutarate-dependent oxygenase"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"31885262"}],"value":"Alpha-KG-dependent oxygenase"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31885262"}],"value":"1.14.11.-"}]}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"31885262"}],"value":"flvA"},"orfNames":[{"value":"AFLA_135410"},{"value":"F9C07_1460612"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31885262"}],"value":"Bifunctional enzyme; part of the gene cluster that mediates the biosynthesis of flavunoidine, an alkaloidal terpenoid with a tetracyclic cage-like core connected to dimethylcadaverine via a C-N bond and acylated with 5,5-dimethyl-L-pipecolate (PubMed:31885262). The tetracyclic core is synthesized by the terpene cyclase flvE and the cytochrome P450 monooxygenase flvD (PubMed:31885262). The terpene cyclase flvE catalyzes the cyclization of farnesyl pyrophosphate (FPP) to form (1R,4R,5S)-(+)-acoradiene and the cytochrome P450 monooxygenase flvD is then responsible for oxidative conversion of (1R,4R,5S)-(+)-acoradiene into the tetracyclic cage present in the final product flavunoidine (PubMed:31885262). In parallel, the N-methyltransferase flvH dimethylates L-lysine to give N,N-dimethyl-L-Lysin which is decarboxylated by flvG to afford dimethylcadaverine (PubMed:31885262). The terpene cyclase-like protein flvF is the enzyme that attaches the dimethylcadaverine precursor at the C-7 of the tetracyclic cage to yield pre-flavunoidine (PubMed:31885262). The cytochrome monooxygenase flvC hydroxylates the C-10 position of pre-flavunoidine whereas the NRPS flvI acylates the terpenoid core at the hydroxylated C-10 with dimethylpipecolate to yield final flavunoidine (PubMed:31885262). The bifunctional enzyme flvA and the dehydrogenase flvB are responsible for the synthesis of the dimethylpipecolate precursor (PubMed:31885262). The PLP-dependent lyase domain of flvA might use L-O-acetyl-homoserine and alpha-keto-isovalerate to form an intermediary ketone that can cyclize intramolecularly to yield an imine (PubMed:31885262). The imine can be reduced by flvB to yield the 6-carboxylated pipecolate (PubMed:31885262). The C-terminal alpha-KG-dependent oxygenase domain of flvA is then proposed to catalyze the decarboxylation to yield dimethylpipecolate (PubMed:31885262)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"O-acetyl-L-homoserine + 3-methyl-2-oxobutanoate = (6S)-6-amino-3,3-dimethyl-2-oxoheptanedioate + acetate + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:74631"},{"database":"ChEBI","id":"CHEBI:11851"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:30089"},{"database":"ChEBI","id":"CHEBI:57716"},{"database":"ChEBI","id":"CHEBI:193109"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31885262"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:74632"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31885262"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"(6S)-3,3-dimethylpiperidine-2,6-dicarboxylate + 2-oxoglutarate + AH2 + O2 + H(+) = (2S)-5,5-dimethylpiperidine-2-carboxylate + succinate + A + 2 CO2 + H2O","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:76587"},{"database":"ChEBI","id":"CHEBI:13193"},{"database":"ChEBI","id":"CHEBI:15377"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:15379"},{"database":"ChEBI","id":"CHEBI:16526"},{"database":"ChEBI","id":"CHEBI:16810"},{"database":"ChEBI","id":"CHEBI:17499"},{"database":"ChEBI","id":"CHEBI:30031"},{"database":"ChEBI","id":"CHEBI:194025"},{"database":"ChEBI","id":"CHEBI:194026"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31885262"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:76588"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31885262"}]}]},{"commentType":"COFACTOR","cofactors":[{"name":"pyridoxal 5'-phosphate","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P06721"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:597326"}},{"name":"Fe(2+)","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q96323"}],"cofactorCrossReference":{"database":"ChEBI","id":"CHEBI:29033"}}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31885262"}],"value":"Secondary metabolite biosynthesis; terpenoid biosynthesis"}],"commentType":"PATHWAY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"In the N-terminal section; belongs to the trans-sulfuration enzymes family"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"In the C-terminal section; belongs to the iron/ascorbate-dependent oxidoreductase family"}],"commentType":"SIMILARITY"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous initiation","sequence":"EED50778.1","note":"Truncated N-terminus.","evidences":[{"evidenceCode":"ECO:0000305"}]}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":849,"modifier":"EXACT"}},"description":"Bifunctional enzyme flvA","featureId":"PRO_0000454477"},{"type":"Region","location":{"start":{"value":82,"modifier":"EXACT"},"end":{"value":561,"modifier":"EXACT"}},"description":"Pyridoxal 5'-phosphate-dependent lyase","evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"31885262"}]},{"type":"Region","location":{"start":{"value":599,"modifier":"EXACT"},"end":{"value":849,"modifier":"EXACT"}},"description":"Alpha-ketoglutarate-dependent oxygenase","evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"31885262"}]},{"type":"Binding site","location":{"start":{"value":729,"modifier":"EXACT"},"end":{"value":729,"modifier":"EXACT"}},"description":"","featureCrossReferences":[{"database":"ChEBI","id":"CHEBI:24875"}],"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q96323"}],"ligand":{"name":"Fe cation","id":"ChEBI:CHEBI:24875","note":"catalytic"}},{"type":"Binding site","location":{"start":{"value":731,"modifier":"EXACT"},"end":{"value":731,"modifier":"EXACT"}},"description":"","featureCrossReferences":[{"database":"ChEBI","id":"CHEBI:24875"}],"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q96323"}],"ligand":{"name":"Fe cation","id":"ChEBI:CHEBI:24875","note":"catalytic"}},{"type":"Modified residue","location":{"start":{"value":357,"modifier":"EXACT"},"end":{"value":357,"modifier":"EXACT"}},"description":"N6-(pyridoxal phosphate)lysine","evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P06721"}]}],"keywords":[{"id":"KW-0223","category":"Molecular function","name":"Dioxygenase"},{"id":"KW-0379","category":"PTM","name":"Hydroxylation"},{"id":"KW-0408","category":"Ligand","name":"Iron"},{"id":"KW-0456","category":"Molecular function","name":"Lyase"},{"id":"KW-0479","category":"Ligand","name":"Metal-binding"},{"id":"KW-0511","category":"Molecular function","name":"Multifunctional enzyme"},{"id":"KW-0560","category":"Molecular function","name":"Oxidoreductase"},{"id":"KW-0663","category":"Ligand","name":"Pyridoxal phosphate"},{"id":"KW-1185","category":"Technical term","name":"Reference proteome"}],"references":[{"referenceNumber":1,"citation":{"id":"25883274","citationType":"journal article","authors":["Nierman W.C.","Yu J.","Fedorova-Abrams N.D.","Losada L.","Cleveland T.E.","Bhatnagar D.","Bennett J.W.","Dean R.","Payne G.A."],"citationCrossReferences":[{"database":"PubMed","id":"25883274"},{"database":"DOI","id":"10.1128/genomea.00168-15"}],"title":"Genome sequence of Aspergillus flavus NRRL 3357, a strain that causes aflatoxin contamination of food and feed.","publicationDate":"2015","journal":"Genome Announc.","firstPage":"E0016815","lastPage":"E0016815","volume":"3"},"referencePositions":["NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]"],"referenceComments":[{"value":"ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357 / JCM 12722 / SRRC 167","type":"STRAIN"}]},{"referenceNumber":2,"citation":{"id":"34849826","citationType":"journal article","authors":["Skerker J.M.","Pianalto K.M.","Mondo S.J.","Yang K.","Arkin A.P.","Keller N.P.","Grigoriev I.V.","Glass N.L."],"citationCrossReferences":[{"database":"PubMed","id":"34849826"},{"database":"DOI","id":"10.1093/g3journal/jkab213"}],"title":"Chromosome assembled and annotated genome sequence of Aspergillus flavus NRRL 3357.","publicationDate":"2021","journal":"G3 (Bethesda)","firstPage":"jkab213","lastPage":"jkab213","volume":"11"},"referencePositions":["NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]"],"referenceComments":[{"value":"ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357 / JCM 12722 / SRRC 167","type":"STRAIN"}]},{"referenceNumber":3,"citation":{"id":"31885262","citationType":"journal article","authors":["Yee D.A.","Kakule T.B.","Cheng W.","Chen M.","Chong C.T.Y.","Hai Y.","Hang L.F.","Hung Y.S.","Liu N.","Ohashi M.","Okorafor I.C.","Song Y.","Tang M.","Zhang Z.","Tang Y."],"citationCrossReferences":[{"database":"PubMed","id":"31885262"},{"database":"DOI","id":"10.1021/jacs.9b13046"}],"title":"Genome mining of alkaloidal terpenoids from a hybrid terpene and nonribosomal peptide biosynthetic pathway.","publicationDate":"2020","journal":"J. 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