{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"E1ACQ5","uniProtkbId":"NOTJ_ASPSM","entryAudit":{"firstPublicDate":"2019-12-11","lastAnnotationUpdateDate":"2024-05-29","lastSequenceUpdateDate":"2010-11-02","entryVersion":20,"sequenceVersion":1},"annotationScore":2.0,"organism":{"scientificName":"Aspergillus sp. (strain MF297-2)","taxonId":877550,"lineage":["Eukaryota","Fungi","Dikarya","Ascomycota","Pezizomycotina","Eurotiomycetes","Eurotiomycetidae","Eurotiales","Aspergillaceae","Aspergillus"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"20722388"}],"value":"Notoamide biosynthesis cluster protein J"}},"flag":"Precursor"},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"20722388"}],"value":"notJ"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"20722388"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"22188465"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"23213353"}],"value":"Part of the gene cluster that mediates the biosynthesis of notoamide, a fungal indole alkaloid that belongs to a family of natural products containing a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:20722388). The first step of notoamide biosynthesis involves coupling of L-proline and L-tryptophan by the bimodular NRPS notE, to produce cyclo-L-tryptophan-L-proline called brevianamide F (PubMed:20722388). The reverse prenyltransferase notF then acts as a deoxybrevianamide E synthase and converts brevianamide F to deoxybrevianamide E via reverse prenylation at C-2 of the indole ring leading to the bicyclo[2.2.2]diazaoctane core (PubMed:20722388). Deoxybrevianamide E is further hydroxylated at C-6 of the indole ring, likely catalyzed by the cytochrome P450 monooxygenase notG, to yield 6-hydroxy-deoxybrevianamide E (Probable). 6-hydroxy-deoxybrevianamide E is a specific substrate of the prenyltransferase notC for normal prenylation at C-7 to produce 6-hydroxy-7-prenyl-deoxybrevianamide, also called notoamide S (PubMed:20722388). As the proposed pivotal branching point in notoamide biosynthesis, notoamide S can be diverted to notoamide E through an oxidative pyran ring closure putatively catalyzed by either notH cytochrome P450 monooxygenase or the notD FAD-linked oxidoreductase (Probable). This step would be followed by an indole 2,3-epoxidation-initiated pinacol-like rearrangement catalyzed by the notB FAD-dependent monooxygenase leading to the formation of notoamide C and notoamide D (PubMed:22188465). On the other hand notoamide S is converted to notoamide T by notH (or notD), a bifunctional oxidase that also functions as the intramolecular Diels-Alderase responsible for generation of (+)-notoamide T (Probable). To generate antipodal (-)-notoaminide T, notH' (or notD') in Aspergillus versicolor is expected to catalyze a Diels-Alder reaction leading to the opposite stereochemistry (Probable). The remaining oxidoreductase notD (or notH) likely catalyzes the oxidative pyran ring formation to yield (+)-stephacidin A (Probable). The FAD-dependent monooxygenase notI is highly similar to notB and is predicted to catalyze a similar conversion from (+)-stephacidin A to (-)-notoamide B via the 2,3-epoxidation of (+)-stephacidin A followed by a pinacol-type rearrangement (Probable). Finally, it remains unclear which enzyme could be responsible for the final hydroxylation steps leading to notoamide A and sclerotiamide (Probable). The function of notJ in the notoamide biosynthesis has not been determined yet (Probable)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17304611"}],"value":"Notoamides have been shown to exhibit antitumoral activities (PubMed:17304611). Notoamides A-C show moderate cytotoxicity against HeLa and L1210 cells with IC(50) values in the range of 22-52 mg/ml, but the IC(50) value of notoamide D is greater than 100 mg/ml (PubMed:17304611). Moreover, notoamide C induces G2/M-cell cycle arrest at a concentration of 6.3 mg/ml (PubMed:17304611)"}],"commentType":"BIOTECHNOLOGY"}],"features":[{"type":"Signal","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":22,"modifier":"EXACT"}},"description":"","evidences":[{"evidenceCode":"ECO:0000255"}]},{"type":"Chain","location":{"start":{"value":23,"modifier":"EXACT"},"end":{"value":370,"modifier":"EXACT"}},"description":"Notoamide biosynthesis cluster protein J","evidences":[{"evidenceCode":"ECO:0000255"}],"featureId":"PRO_5003143467"},{"type":"Glycosylation","location":{"start":{"value":159,"modifier":"EXACT"},"end":{"value":159,"modifier":"EXACT"}},"description":"N-linked (GlcNAc...) asparagine","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00498"}],"featureId":""},{"type":"Glycosylation","location":{"start":{"value":167,"modifier":"EXACT"},"end":{"value":167,"modifier":"EXACT"}},"description":"N-linked (GlcNAc...) asparagine","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00498"}],"featureId":""},{"type":"Glycosylation","location":{"start":{"value":192,"modifier":"EXACT"},"end":{"value":192,"modifier":"EXACT"}},"description":"N-linked (GlcNAc...) asparagine","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00498"}],"featureId":""},{"type":"Glycosylation","location":{"start":{"value":235,"modifier":"EXACT"},"end":{"value":235,"modifier":"EXACT"}},"description":"N-linked (GlcNAc...) asparagine","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00498"}],"featureId":""},{"type":"Glycosylation","location":{"start":{"value":282,"modifier":"EXACT"},"end":{"value":282,"modifier":"EXACT"}},"description":"N-linked (GlcNAc...) asparagine","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00498"}],"featureId":""},{"type":"Glycosylation","location":{"start":{"value":340,"modifier":"EXACT"},"end":{"value":340,"modifier":"EXACT"}},"description":"N-linked (GlcNAc...) asparagine","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00498"}],"featureId":""},{"type":"Glycosylation","location":{"start":{"value":346,"modifier":"EXACT"},"end":{"value":346,"modifier":"EXACT"}},"description":"N-linked (GlcNAc...) asparagine","evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00498"}],"featureId":""}],"keywords":[{"id":"KW-0325","category":"PTM","name":"Glycoprotein"},{"id":"KW-0732","category":"Domain","name":"Signal"}],"references":[{"referenceNumber":1,"citation":{"id":"20722388","citationType":"journal article","authors":["Ding Y.","de Wet J.R.","Cavalcoli J.","Li S.","Greshock T.J.","Miller K.A.","Finefield J.M.","Sunderhaus J.D.","McAfoos T.J.","Tsukamoto S.","Williams R.M.","Sherman D.H."],"citationCrossReferences":[{"database":"PubMed","id":"20722388"},{"database":"DOI","id":"10.1021/ja1049302"}],"title":"Genome-based characterization of two prenylation steps in the assembly of the stephacidin and notoamide anticancer agents in a marine-derived Aspergillus sp.","publicationDate":"2010","journal":"J. Am. Chem. Soc.","firstPage":"12733","lastPage":"12740","volume":"132"},"referencePositions":["NUCLEOTIDE SEQUENCE [GENOMIC DNA]"],"referenceComments":[{"value":"MF297-2","type":"STRAIN"}]},{"referenceNumber":2,"citation":{"id":"17304611","citationType":"journal article","authors":["Kato H.","Yoshida T.","Tokue T.","Nojiri Y.","Hirota H.","Ohta T.","Williams R.M.","Tsukamoto S."],"citationCrossReferences":[{"database":"PubMed","id":"17304611"},{"database":"DOI","id":"10.1002/anie.200604381"}],"title":"Notoamides A-D: prenylated indole alkaloids isolated from a marine-derived fungus, Aspergillus sp.","publicationDate":"2007","journal":"Angew. Chem. Int. Ed.","firstPage":"2254","lastPage":"2256","volume":"46"},"referencePositions":["BIOTECHNOLOGY"]},{"referenceNumber":3,"citation":{"id":"22188465","citationType":"journal article","authors":["Li S.","Finefield J.M.","Sunderhaus J.D.","McAfoos T.J.","Williams R.M.","Sherman D.H."],"citationCrossReferences":[{"database":"PubMed","id":"22188465"},{"database":"DOI","id":"10.1021/ja2093212"}],"title":"Biochemical characterization of NotB as an FAD-dependent oxidase in the biosynthesis of notoamide indole alkaloids.","publicationDate":"2012","journal":"J. Am. Chem. Soc.","firstPage":"788","lastPage":"791","volume":"134"},"referencePositions":["FUNCTION"]},{"referenceNumber":4,"citation":{"id":"23213353","citationType":"journal article","authors":["Li S.","Anand K.","Tran H.","Yu F.","Finefield J.M.","Sunderhaus J.D.","McAfoos T.J.","Tsukamoto S.","Williams R.M.","Sherman D.H."],"citationCrossReferences":[{"database":"PubMed","id":"23213353"},{"database":"DOI","id":"10.1039/c2md20029e"}],"title":"Comparative analysis of the biosynthetic systems for fungal bicyclo[2.2.2]diazaoctane indole alkaloids: the (+)/(-)-notoamide, paraherquamide and malbrancheamide pathways.","publicationDate":"2012","journal":"Med. Chem. Commun.","firstPage":"987","lastPage":"996","volume":"3"},"referencePositions":["FUNCTION"]}],"uniProtKBCrossReferences":[{"database":"EMBL","id":"HM622670","properties":[{"key":"ProteinId","value":"ADM34143.1"},{"key":"Status","value":"-"},{"key":"MoleculeType","value":"Genomic_DNA"}]},{"database":"AlphaFoldDB","id":"E1ACQ5","properties":[{"key":"Description","value":"-"}]},{"database":"SMR","id":"E1ACQ5","properties":[{"key":"Description","value":"-"}]},{"database":"GlyCosmos","id":"E1ACQ5","properties":[{"key":"glycosylation","value":"7 sites, No reported glycans"}]},{"database":"InterPro","id":"IPR025442","properties":[{"key":"EntryName","value":"DUF4185"}]},{"database":"InterPro","id":"IPR023296","properties":[{"key":"EntryName","value":"Glyco_hydro_beta-prop_sf"}]},{"database":"Pfam","id":"PF13810","properties":[{"key":"EntryName","value":"DUF4185"},{"key":"MatchStatus","value":"1"}]},{"database":"SUPFAM","id":"SSF75005","properties":[{"key":"EntryName","value":"Arabinanase/levansucrase/invertase"},{"key":"MatchStatus","value":"1"}]}],"sequence":{"value":"MRIMSIMLHLLATILLSSAVSAQNANAASTRRLIGEDRESGRRWGVAATDLGIPYDQHNGEIGFLFGDTVSTKWVQEAKDLRSPVMLRSGIHPGEDGGIVFESAAGVDGDGLAPRLFYNGDRGDDGTGTGTWEFTVLPNDGISFPETGEHIISYLSIMNFTTPWTPNYSGLAYSTDGNTFTRLPTKWLNNDNNTDPFQMWTMQRDGDWVYVFTVRSAPQYGPLMLQRVPWDKMTNKTEYQGWGWNGEDWGWQRPCSPILDGYFGEPSVRRLHDGTWAMVYLNASTSTPHIVSRSAKDPTGPWSEEKVQVNQEGDGSLLYGGFIHPWSTSKGNQLYLMVSNWTSTSNLSQTTEAVADYEGTVSVSQFTGTL","length":370,"molWeight":41041,"crc64":"1F3BF35481DB7179","md5":"1693F3FF82BC804573471DCCA4DAA682"},"extraAttributes":{"countByCommentType":{"FUNCTION":1,"BIOTECHNOLOGY":1},"countByFeatureType":{"Signal":1,"Chain":1,"Glycosylation":7},"uniParcId":"UPI0001E43C50"}}