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fmqA

Gene
fmqA
Protein
Nonribosomal peptide synthetase fmqA
Organism
Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100)
Length
3955 amino acids
Function
Nonribosomal peptide synthetase; part of the gene cluster that mediates the biosynthesis of the antitumor fumiquinazolines (PubMed:20225828, PubMed:20804163, PubMed:21899262, PubMed:24612080). The simplest member is fumiquinazoline F (FQF) with a 6-6-6 tricyclic core derived from anthranilic acid (Ant), tryptophan (Trp), and alanine (Ala) (PubMed:20225828). The trimodular NRPS fmqA is responsible for FQF formation (PubMed:20225828). Modules 1, 2 and 3 of fmqA are predicted to activate and load Ant, Trp and Ala, respectively, providing for the assembly of an Ant-Trp-Ala-S-enzyme intermediate that would undergo double cyclization for chain release and generation of the tricyclic 6-6-6 product fumiquinazoline F (PubMed:20225828). The presence of an E domain predicted for module 2 of fmqA is consistent with epimerization of L-Trp to D-Trp during assembly to generate the R-stereocenter at C14 of FQF (PubMed:20225828). The FAD-dependent monooxygenase fmqB and the monomodular NRPS fmqC then maturate FQF to FQA (PubMed:20804163). FmqB oxidizes the 2',3'-double bond of the indole side chain of FQF, and fmqC activates L-Ala as the adenylate, installs it as the pantetheinyl thioester on its carrier protein domain, and acylates the oxidized indole for subsequent intramolecular cyclization to create the 6-5-5-imidazolindolone of FQA (PubMed:20804163). The FAD-linked oxidoreductase fmqD introduces a third layer of scaffold complexity by converting FQA to the spirohemiaminal FQC, presumably by catalyzing the formation of a transient imine within the pyrazinone ring (PubMed:21899262). FQC subsequently converts nonenzymatically to the known cyclic aminal FQD (PubMed:21899262).
Similarity
Belongs to the NRP synthase family.
Mass
437.813 kDa
Sequence
MERLEAKNQTTKHGERMAPQRYSVLRDEKCLFPVRNDGKLLVDEWRVTELAISSGEKGLKLCRTTCPTAGADPRYLAAAAWALLLWRFAEVDTVQIGLQDIPPGANEDILEAGLKRGMKVLAASRRQVQLLNELWQGDTWSISDADPTCYSYFDTGIVICRGNSQDCLAKCRSPNQLRKANGEACNVLLVLELDLDSNWRKCFLAYKTTVLTDIQATHLKSSFEEVVELARAGRGIPLSEICLVSRRQLDQIGKWNERALVQPKFKAMHQVVHDRATDRRHHPAVIAADRALSYSELETLSLKVAYRLRGSGVQPGDLIPVCFCKSSWAIVAMLAINKLGAAFVPLDPSQPVNRLKSITRQLDATLAVTSPENQSLVEDLVTTTVVVSETTVSELVDVHNEIVLPACDPGAPAYCLFTSGSTGKPKGCVVDHAALASVATHSHALHLGPTSRVLQFASFTFGVSLIEVWCTLAAGGTVCLPSDSDRVSRLADAIRSMGVDWCILTPTVLATLEPEAVPNLRTILVAGEPLKKAQFSLWAERARLFQAYGFTEWAGICCVSPQIRSIGDVGIIGTPANARCWLVEPGNPNQLAPIGAVAELAVEGPSLAQGYLHDPEKTAATLIPPPRWRAQYGHADGKRIYTTGDLVYYDSNGMLRYVSRKDRQVKIRGQRIDLAEPEYHIAQACCTIRNVVLDAIVPADSNGDAILVAFVLPSRDESSSNGGHDSPLFAVPDDHFTSSVRQLTSFLEDKLPDYMVPRLFLQLKETPVTITGKIARQKLREAAEALRHDELVALAGLETRVLPPNTHKETLIHQLVVELLHLPPEMVGMNHNFFSLGGDSVSVMKLVSRAKRVGLSFTVKDVFRSPQLGDLARLTDVVNSGAAQHMPPFSLLDRGAQPGLLSMAAKICQVESSMIQDIYPCTPLQEGMMTLSAAKAGSYIARFVYRLEEHVDSPRFRRAWEMTVEATPILRTRIISASDGRLYQVVIQEKFRWDDDGQPSGECVQNGQDRHMLLGEPLTHAALVRDRNQDGSLSTVFVLTMHHSVCDRWSVGLIMDSVETAYTGQTLTTNSMGPFLQYIQQLQGGDAFWRSQFVGVKAEVFPSLPSPEYTPTPTETIDLSVELRDAVPGGHTIANAIRLAWALVISHYTSCSDVVFGVTISGRAVPVPDIERIIGPIIATVPLRVRLKESSTVLEALKAIQDQSMEMIPFEQLGLRQIRKLSPEAEEACNFQSQLVVQPAWGDENRSLFATCEAGAAAEGGFAAYALSMICQLVGSSQIDVRTEFDPKVIQAPIMQRIVHHFVYTLQYLLAHPDARVAEIPVVSPGEKQLLRQWNGIVPPASHQCVHEIIQQRQIERPTSTAVWAWDGQLTYAELGELSDRLAEYLATKGVQPEVIVPVCLEKSYWTTVAMLGISKAGGAFALLDPSQPEQRLQSICHQLNSAVILTSEKNRDLAGKLASHPIVLSLQSSRRWGHGPAKQAPATARPDHTLYVAFTSGSTGTPKGVVIEHRSFCTSALALNRITGVNSESRMLQFAGYSFDGSIMEMLSALMAGACVCVPSEFQRRNELVAAAAKFELTHAHLTPSVARHLLRGNPEFTKTLVSVGEPMTASDVADWASNGQCKVMNGYGPAECAVSTTIQAAVTSASDPKNIGFPVAGVCWVVHPENHDILLPPGAVGELLIEGPTLARGYLNEPDKTAAAFIPLPAWIKDIRPEQPHGRLYKSGDLVRYNADGSFQYIGRRDSQIKLRGQRIELDEVEKHVYQCWPGVIAVVAVEMVSFTPATQTLVAFVVVEEHVDTTGDILAAPTQEFTGQVAVAQARLREAIPAFMVPEIFIPLLVLPQSASGKTDRRRLRSIATACTREKLAAYGAVGTGTKREPTSVAEREMQAIWAQALNLPLAEIGMDDSFYQLGGDSITAMQVVAHARSKGLAVTMDSILRLKSISKIMSHESSLSPAIVHIDEEEDVWFALSPIQQMFFDRQPSGWDRFSQVFLLRVSQPVTASQLQMALHTLVSKHPMLRARFAKQHDGSWRQVITSKIQESYRCRSHRLNRRSSVDGVVSSGACSLSIQKGPLIAVDLMSREDGAQYLSIVIHHLVVDLVSWRIILADLEAMLRGENPMANHSTPFQTWCRLQAEYARQYLSPQHAFPTDLPDHYHQDPSVFWGLAGQPNLVRDSRRQVFTLDEHTTRQLLGAANAAFATRTDEVLHAVLLYSFLKVFPHRIAPLTFSEGHGREPWDSAIDLSQTVGWFTTMWPVVAELQQNHSFLEVVCRVKDARRAVPCNGWAYFVSRYLNPSGRQAFQQFHPVELVFNYAGEYQQFNQAGAFFIPDMPEYQGSLDAGEQIQRFGIFEVFASVVRGCLQFQFMYNRYMKHQLEIQKWIESCRQTLIEGCSTLIAAKPSRTLSDFPLLPLTYSTLRELLDVTLPTAGVSVENVEDIYPCSPSQRGMLIAQAKAAHNYNASVTWSIRSRIDSRPNVARLKAAWCEVVKRHAILRTVFVESPWPESYMDQVVLQNVSPEFVFCRGSDSLPQSISSPGQTRWSKGQCQHIMRVWERDNGDILCRLDLSHAIMDRTTLAIIQKDLSLAYDERLLPGRAPLYRDYISYIYQQDSESARQYWQGYLEGVEPCEFPTLNPVDPSITKEWGNLYRTLEDRRRLEEFCRTHSVTPWNVAGLAWAMVLRSFTRTDSVCFGYVKSGRDLPIDGIAGTAGPVFNPLPCRVHLTERLTVRETIGRLQEEYLQSLAHQSFPLSDIHRLAGVTSGVLFNTSVAVQTEVASEAEEAKRSLEFTTVAMEDGTEDDMVITLVPRGGELVLHLRHRSRTLTTDQASTVLATFEKALCSILANAEAPMTSIDVFSDHDKAILWSRNRRVPDAVESCVHELIQKHCVERPHSPAVNAWDGAFTYGQLDELSSRLAVYLAAQGVGPNVVVPLCFEKTRWTPIAMMGVMKAGGAFLLLDPSYPLQRLKDICADIDCRLVVSSTTHEAMSRELASTVVVVGEDRHHWQLENTSHTITMPKVRPADALYVVFTSGSTGKPKGVVIEHRSYCSGALDHIRSYNLTPQSRVLQFSSYAFDISIVEQLSVLIAGGCICVISESQRKNSLGEAATALQANHAMLIPSVARLVRHEDLSTITSLSLAGECMQETDVSYWAQHVRLMNGYGPAECSALSLVQPCVLPHSDPHDIGYPVGSVAWVVDPHDHHKLVPNGAVGELLIEGPIVGRGYINNAEKTAEVFIEPPTWLRTLRGHCTSRLYKTGDLVRANPSGSLSILGRKDRQVKLRGQRLELGEVEANVQHCFPGALDVVADLLPSSRGGKPQLVAMVFQNAERAARIAPESDSKLIAEPSVDFMQSATTAETRLRQTVPNFMVPSMFLPLAQIPRTHSDKVDRNSLLKAVAAMSSIELQAYKASVDAGHCSTRAPSTEEEKKLAEIWADVLKVPVEHIGADDNFLLSGGDSIDAMKAAAFCRAAGMALSVADIFAHPVLSDLAKVAVPKSLNGSSTSHQPFSLSPVDSPKDLHMSLMEQGLVPPGSALADLLPGTQAQQFFIERGTFHSYNFSIRGPLDRCRLQKTCTAILSRHSILRTKFLQYEGRLIQIVLDNLETPFTHYTTDGDLLEFCKSLWERDLAALDGLGRLPCKFTLVSRSEQEHVFTIQISHAQWDGVSIPRLFSDIAAIYNQIPLPSTTHFADYVYHRSSRDERPAFDFWKKYLRGSSMPVPFPATNCQDREHKTQWTFQGIKNPRLPAGITMASLVKAACGFHLCQLLSQNDVVFGHTVNGRNLALDNVEALLGCCLNFIPLRVMLQPSWTVLDLLAHVQEQYTRALPHEHLELRDIFRHSTPWPADTQLSFIVQHQNIELHHNIALDGLQVQYSKFAQFDPLTEVWIFSEPHPDRLEIQVCANTRVLSEDQARALCRRLCDLIEFFSASPDCPLSKVVDHMDRPGLLAEEKVLN