Q4WLW5 · FMQA_ASPFU
- ProteinNonribosomal peptide synthetase fmqA
- GenefmqA
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids3955 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Nonribosomal peptide synthetase; part of the gene cluster that mediates the biosynthesis of the antitumor fumiquinazolines that confer a dual-usage capability to defend against phagocytes in the environment and animal hosts (PubMed:20225828, PubMed:20804163, PubMed:21899262, PubMed:24612080, PubMed:33705521).
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).
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).
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
18 μM | anthranilate | |||||
230 μM | ATP | |||||
17 μM | salicylic acid | |||||
29 μM | 2-chlorobenzoic acid | |||||
32 μM | 4-chlorobenzoic acid | |||||
74 μM | benzoic acid | |||||
416 μM | 3-aminobenzoic acidATP | |||||
1900 μM | 4-aminobenzoic acid |
Pathway
Alkaloid biosynthesis.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytoplasmic vesicle | |
Molecular Function | ligase activity | |
Molecular Function | phosphopantetheine binding | |
Biological Process | fumiquinazoline C biosynthetic process | |
Biological Process | nonribosomal peptide biosynthetic process | |
Biological Process | secondary metabolic process |
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameNonribosomal peptide synthetase fmqA
- EC number
- Alternative names
Gene names
Organism names
- Strain
- Taxonomic lineageEukaryota > Fungi > Dikarya > Ascomycota > Pezizomycotina > Eurotiomycetes > Eurotiomycetidae > Eurotiales > Aspergillaceae > Aspergillus > Aspergillus subgen. Fumigati
Accessions
- Primary accessionQ4WLW5
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Does not localize to endocytic vesicles, vacuoles nor mitochondria (PubMed:24612080).
Keywords
- Cellular component
PTM/Processing
Features
Showing features for chain, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000416553 | 1-3955 | Nonribosomal peptide synthetase fmqA | |||
Sequence: MERLEAKNQTTKHGERMAPQRYSVLRDEKCLFPVRNDGKLLVDEWRVTELAISSGEKGLKLCRTTCPTAGADPRYLAAAAWALLLWRFAEVDTVQIGLQDIPPGANEDILEAGLKRGMKVLAASRRQVQLLNELWQGDTWSISDADPTCYSYFDTGIVICRGNSQDCLAKCRSPNQLRKANGEACNVLLVLELDLDSNWRKCFLAYKTTVLTDIQATHLKSSFEEVVELARAGRGIPLSEICLVSRRQLDQIGKWNERALVQPKFKAMHQVVHDRATDRRHHPAVIAADRALSYSELETLSLKVAYRLRGSGVQPGDLIPVCFCKSSWAIVAMLAINKLGAAFVPLDPSQPVNRLKSITRQLDATLAVTSPENQSLVEDLVTTTVVVSETTVSELVDVHNEIVLPACDPGAPAYCLFTSGSTGKPKGCVVDHAALASVATHSHALHLGPTSRVLQFASFTFGVSLIEVWCTLAAGGTVCLPSDSDRVSRLADAIRSMGVDWCILTPTVLATLEPEAVPNLRTILVAGEPLKKAQFSLWAERARLFQAYGFTEWAGICCVSPQIRSIGDVGIIGTPANARCWLVEPGNPNQLAPIGAVAELAVEGPSLAQGYLHDPEKTAATLIPPPRWRAQYGHADGKRIYTTGDLVYYDSNGMLRYVSRKDRQVKIRGQRIDLAEPEYHIAQACCTIRNVVLDAIVPADSNGDAILVAFVLPSRDESSSNGGHDSPLFAVPDDHFTSSVRQLTSFLEDKLPDYMVPRLFLQLKETPVTITGKIARQKLREAAEALRHDELVALAGLETRVLPPNTHKETLIHQLVVELLHLPPEMVGMNHNFFSLGGDSVSVMKLVSRAKRVGLSFTVKDVFRSPQLGDLARLTDVVNSGAAQHMPPFSLLDRGAQPGLLSMAAKICQVESSMIQDIYPCTPLQEGMMTLSAAKAGSYIARFVYRLEEHVDSPRFRRAWEMTVEATPILRTRIISASDGRLYQVVIQEKFRWDDDGQPSGECVQNGQDRHMLLGEPLTHAALVRDRNQDGSLSTVFVLTMHHSVCDRWSVGLIMDSVETAYTGQTLTTNSMGPFLQYIQQLQGGDAFWRSQFVGVKAEVFPSLPSPEYTPTPTETIDLSVELRDAVPGGHTIANAIRLAWALVISHYTSCSDVVFGVTISGRAVPVPDIERIIGPIIATVPLRVRLKESSTVLEALKAIQDQSMEMIPFEQLGLRQIRKLSPEAEEACNFQSQLVVQPAWGDENRSLFATCEAGAAAEGGFAAYALSMICQLVGSSQIDVRTEFDPKVIQAPIMQRIVHHFVYTLQYLLAHPDARVAEIPVVSPGEKQLLRQWNGIVPPASHQCVHEIIQQRQIERPTSTAVWAWDGQLTYAELGELSDRLAEYLATKGVQPEVIVPVCLEKSYWTTVAMLGISKAGGAFALLDPSQPEQRLQSICHQLNSAVILTSEKNRDLAGKLASHPIVLSLQSSRRWGHGPAKQAPATARPDHTLYVAFTSGSTGTPKGVVIEHRSFCTSALALNRITGVNSESRMLQFAGYSFDGSIMEMLSALMAGACVCVPSEFQRRNELVAAAAKFELTHAHLTPSVARHLLRGNPEFTKTLVSVGEPMTASDVADWASNGQCKVMNGYGPAECAVSTTIQAAVTSASDPKNIGFPVAGVCWVVHPENHDILLPPGAVGELLIEGPTLARGYLNEPDKTAAAFIPLPAWIKDIRPEQPHGRLYKSGDLVRYNADGSFQYIGRRDSQIKLRGQRIELDEVEKHVYQCWPGVIAVVAVEMVSFTPATQTLVAFVVVEEHVDTTGDILAAPTQEFTGQVAVAQARLREAIPAFMVPEIFIPLLVLPQSASGKTDRRRLRSIATACTREKLAAYGAVGTGTKREPTSVAEREMQAIWAQALNLPLAEIGMDDSFYQLGGDSITAMQVVAHARSKGLAVTMDSILRLKSISKIMSHESSLSPAIVHIDEEEDVWFALSPIQQMFFDRQPSGWDRFSQVFLLRVSQPVTASQLQMALHTLVSKHPMLRARFAKQHDGSWRQVITSKIQESYRCRSHRLNRRSSVDGVVSSGACSLSIQKGPLIAVDLMSREDGAQYLSIVIHHLVVDLVSWRIILADLEAMLRGENPMANHSTPFQTWCRLQAEYARQYLSPQHAFPTDLPDHYHQDPSVFWGLAGQPNLVRDSRRQVFTLDEHTTRQLLGAANAAFATRTDEVLHAVLLYSFLKVFPHRIAPLTFSEGHGREPWDSAIDLSQTVGWFTTMWPVVAELQQNHSFLEVVCRVKDARRAVPCNGWAYFVSRYLNPSGRQAFQQFHPVELVFNYAGEYQQFNQAGAFFIPDMPEYQGSLDAGEQIQRFGIFEVFASVVRGCLQFQFMYNRYMKHQLEIQKWIESCRQTLIEGCSTLIAAKPSRTLSDFPLLPLTYSTLRELLDVTLPTAGVSVENVEDIYPCSPSQRGMLIAQAKAAHNYNASVTWSIRSRIDSRPNVARLKAAWCEVVKRHAILRTVFVESPWPESYMDQVVLQNVSPEFVFCRGSDSLPQSISSPGQTRWSKGQCQHIMRVWERDNGDILCRLDLSHAIMDRTTLAIIQKDLSLAYDERLLPGRAPLYRDYISYIYQQDSESARQYWQGYLEGVEPCEFPTLNPVDPSITKEWGNLYRTLEDRRRLEEFCRTHSVTPWNVAGLAWAMVLRSFTRTDSVCFGYVKSGRDLPIDGIAGTAGPVFNPLPCRVHLTERLTVRETIGRLQEEYLQSLAHQSFPLSDIHRLAGVTSGVLFNTSVAVQTEVASEAEEAKRSLEFTTVAMEDGTEDDMVITLVPRGGELVLHLRHRSRTLTTDQASTVLATFEKALCSILANAEAPMTSIDVFSDHDKAILWSRNRRVPDAVESCVHELIQKHCVERPHSPAVNAWDGAFTYGQLDELSSRLAVYLAAQGVGPNVVVPLCFEKTRWTPIAMMGVMKAGGAFLLLDPSYPLQRLKDICADIDCRLVVSSTTHEAMSRELASTVVVVGEDRHHWQLENTSHTITMPKVRPADALYVVFTSGSTGKPKGVVIEHRSYCSGALDHIRSYNLTPQSRVLQFSSYAFDISIVEQLSVLIAGGCICVISESQRKNSLGEAATALQANHAMLIPSVARLVRHEDLSTITSLSLAGECMQETDVSYWAQHVRLMNGYGPAECSALSLVQPCVLPHSDPHDIGYPVGSVAWVVDPHDHHKLVPNGAVGELLIEGPIVGRGYINNAEKTAEVFIEPPTWLRTLRGHCTSRLYKTGDLVRANPSGSLSILGRKDRQVKLRGQRLELGEVEANVQHCFPGALDVVADLLPSSRGGKPQLVAMVFQNAERAARIAPESDSKLIAEPSVDFMQSATTAETRLRQTVPNFMVPSMFLPLAQIPRTHSDKVDRNSLLKAVAAMSSIELQAYKASVDAGHCSTRAPSTEEEKKLAEIWADVLKVPVEHIGADDNFLLSGGDSIDAMKAAAFCRAAGMALSVADIFAHPVLSDLAKVAVPKSLNGSSTSHQPFSLSPVDSPKDLHMSLMEQGLVPPGSALADLLPGTQAQQFFIERGTFHSYNFSIRGPLDRCRLQKTCTAILSRHSILRTKFLQYEGRLIQIVLDNLETPFTHYTTDGDLLEFCKSLWERDLAALDGLGRLPCKFTLVSRSEQEHVFTIQISHAQWDGVSIPRLFSDIAAIYNQIPLPSTTHFADYVYHRSSRDERPAFDFWKKYLRGSSMPVPFPATNCQDREHKTQWTFQGIKNPRLPAGITMASLVKAACGFHLCQLLSQNDVVFGHTVNGRNLALDNVEALLGCCLNFIPLRVMLQPSWTVLDLLAHVQEQYTRALPHEHLELRDIFRHSTPWPADTQLSFIVQHQNIELHHNIALDGLQVQYSKFAQFDPLTEVWIFSEPHPDRLEIQVCANTRVLSEDQARALCRRLCDLIEFFSASPDCPLSKVVDHMDRPGLLAEEKVLN | ||||||
Modified residue | 840 | O-(pantetheine 4'-phosphoryl)serine | ||||
Sequence: S | ||||||
Modified residue | 1917 | O-(pantetheine 4'-phosphoryl)serine | ||||
Sequence: S | ||||||
Modified residue | 3459 | O-(pantetheine 4'-phosphoryl)serine | ||||
Sequence: S |
Keywords
- PTM
Expression
Induction
Expression is positively regulated by brlA, a conidiation-specific transcription factor involved in the early stage of asexual development and necessary for conidiophore formation (PubMed:24612080).
Expression is also induced by the cell wall integrity (CWI) signaling pathway that includes the mitogen-activated protein kinase mpkA and the transcription factor rlmA (PubMed:33705521).
Expression is negatively regulated by the transcription factor sebA (PubMed:33705521).
Expression is also induced by the cell wall integrity (CWI) signaling pathway that includes the mitogen-activated protein kinase mpkA and the transcription factor rlmA (PubMed:33705521).
Expression is negatively regulated by the transcription factor sebA (PubMed:33705521).
Interaction
Subunit
Interacts with the mitogen-activated protein kinase mpkA.
Protein-protein interaction databases
Family & Domains
Features
Showing features for region, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 293-691 | Adenylation 1 | ||||
Sequence: SYSELETLSLKVAYRLRGSGVQPGDLIPVCFCKSSWAIVAMLAINKLGAAFVPLDPSQPVNRLKSITRQLDATLAVTSPENQSLVEDLVTTTVVVSETTVSELVDVHNEIVLPACDPGAPAYCLFTSGSTGKPKGCVVDHAALASVATHSHALHLGPTSRVLQFASFTFGVSLIEVWCTLAAGGTVCLPSDSDRVSRLADAIRSMGVDWCILTPTVLATLEPEAVPNLRTILVAGEPLKKAQFSLWAERARLFQAYGFTEWAGICCVSPQIRSIGDVGIIGTPANARCWLVEPGNPNQLAPIGAVAELAVEGPSLAQGYLHDPEKTAATLIPPPRWRAQYGHADGKRIYTTGDLVYYDSNGMLRYVSRKDRQVKIRGQRIDLAEPEYHIAQACCTIRNV | ||||||
Domain | 806-879 | Carrier 1 | ||||
Sequence: THKETLIHQLVVELLHLPPEMVGMNHNFFSLGGDSVSVMKLVSRAKRVGLSFTVKDVFRSPQLGDLARLTDVVN | ||||||
Region | 916-1187 | Condensation 1 | ||||
Sequence: QDIYPCTPLQEGMMTLSAAKAGSYIARFVYRLEEHVDSPRFRRAWEMTVEATPILRTRIISASDGRLYQVVIQEKFRWDDDGQPSGECVQNGQDRHMLLGEPLTHAALVRDRNQDGSLSTVFVLTMHHSVCDRWSVGLIMDSVETAYTGQTLTTNSMGPFLQYIQQLQGGDAFWRSQFVGVKAEVFPSLPSPEYTPTPTETIDLSVELRDAVPGGHTIANAIRLAWALVISHYTSCSDVVFGVTISGRAVPVPDIERIIGPIIATVPLRVRL | ||||||
Region | 1371-1766 | Adenylation 2 | ||||
Sequence: TYAELGELSDRLAEYLATKGVQPEVIVPVCLEKSYWTTVAMLGISKAGGAFALLDPSQPEQRLQSICHQLNSAVILTSEKNRDLAGKLASHPIVLSLQSSRRWGHGPAKQAPATARPDHTLYVAFTSGSTGTPKGVVIEHRSFCTSALALNRITGVNSESRMLQFAGYSFDGSIMEMLSALMAGACVCVPSEFQRRNELVAAAAKFELTHAHLTPSVARHLLRGNPEFTKTLVSVGEPMTASDVADWASNGQCKVMNGYGPAECAVSTTIQAAVTSASDPKNIGFPVAGVCWVVHPENHDILLPPGAVGELLIEGPTLARGYLNEPDKTAAAFIPLPAWIKDIRPEQPHGRLYKSGDLVRYNADGSFQYIGRRDSQIKLRGQRIELDEVEKHVYQC | ||||||
Domain | 1880-1956 | Carrier 2 | ||||
Sequence: EPTSVAEREMQAIWAQALNLPLAEIGMDDSFYQLGGDSITAMQVVAHARSKGLAVTMDSILRLKSISKIMSHESSLS | ||||||
Region | 1970-2261 | Epimerase | ||||
Sequence: FALSPIQQMFFDRQPSGWDRFSQVFLLRVSQPVTASQLQMALHTLVSKHPMLRARFAKQHDGSWRQVITSKIQESYRCRSHRLNRRSSVDGVVSSGACSLSIQKGPLIAVDLMSREDGAQYLSIVIHHLVVDLVSWRIILADLEAMLRGENPMANHSTPFQTWCRLQAEYARQYLSPQHAFPTDLPDHYHQDPSVFWGLAGQPNLVRDSRRQVFTLDEHTTRQLLGAANAAFATRTDEVLHAVLLYSFLKVFPHRIAPLTFSEGHGREPWDSAIDLSQTVGWFTTMWPVVAE | ||||||
Region | 2438-2724 | Condensation 2 | ||||
Sequence: EDIYPCSPSQRGMLIAQAKAAHNYNASVTWSIRSRIDSRPNVARLKAAWCEVVKRHAILRTVFVESPWPESYMDQVVLQNVSPEFVFCRGSDSLPQSISSPGQTRWSKGQCQHIMRVWERDNGDILCRLDLSHAIMDRTTLAIIQKDLSLAYDERLLPGRAPLYRDYISYIYQQDSESARQYWQGYLEGVEPCEFPTLNPVDPSITKEWGNLYRTLEDRRRLEEFCRTHSVTPWNVAGLAWAMVLRSFTRTDSVCFGYVKSGRDLPIDGIAGTAGPVFNPLPCRVHL | ||||||
Region | 2906-3299 | Adenylation 3 | ||||
Sequence: TYGQLDELSSRLAVYLAAQGVGPNVVVPLCFEKTRWTPIAMMGVMKAGGAFLLLDPSYPLQRLKDICADIDCRLVVSSTTHEAMSRELASTVVVVGEDRHHWQLENTSHTITMPKVRPADALYVVFTSGSTGKPKGVVIEHRSYCSGALDHIRSYNLTPQSRVLQFSSYAFDISIVEQLSVLIAGGCICVISESQRKNSLGEAATALQANHAMLIPSVARLVRHEDLSTITSLSLAGECMQETDVSYWAQHVRLMNGYGPAECSALSLVQPCVLPHSDPHDIGYPVGSVAWVVDPHDHHKLVPNGAVGELLIEGPIVGRGYINNAEKTAEVFIEPPTWLRTLRGHCTSRLYKTGDLVRANPSGSLSILGRKDRQVKLRGQRLELGEVEANVQHC | ||||||
Domain | 3422-3498 | Carrier 3 | ||||
Sequence: APSTEEEKKLAEIWADVLKVPVEHIGADDNFLLSGGDSIDAMKAAAFCRAAGMALSVADIFAHPVLSDLAKVAVPKS | ||||||
Region | 3541-3805 | Condensation 3 | ||||
Sequence: PGTQAQQFFIERGTFHSYNFSIRGPLDRCRLQKTCTAILSRHSILRTKFLQYEGRLIQIVLDNLETPFTHYTTDGDLLEFCKSLWERDLAALDGLGRLPCKFTLVSRSEQEHVFTIQISHAQWDGVSIPRLFSDIAAIYNQIPLPSTTHFADYVYHRSSRDERPAFDFWKKYLRGSSMPVPFPATNCQDREHKTQWTFQGIKNPRLPAGITMASLVKAACGFHLCQLLSQNDVVFGHTVNGRNLALDNVEALLGCCLNFIPLRVM |
Domain
NRP synthetases are composed of discrete domains (adenylation (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation (C) domains) which when grouped together are referred to as a single module (PubMed:17464044).
Each module is responsible for the recognition (via the A domain) and incorporation of a single amino acid into the growing peptide product (PubMed:17464044).
Thus, an NRP synthetase is generally composed of one or more modules and can terminate in a thioesterase domain (TE) that releases the newly synthesized peptide from the enzyme (PubMed:17464044).
Occasionally, epimerase (E) domains (responsible for L- to D- amino acid conversion) are present within the NRP synthetase (PubMed:17464044).
NRPS12 has the following architecture: A-T-C-A-T-E-C-A-T-C (PubMed:17464044, PubMed:20225828).
Each module is responsible for the recognition (via the A domain) and incorporation of a single amino acid into the growing peptide product (PubMed:17464044).
Thus, an NRP synthetase is generally composed of one or more modules and can terminate in a thioesterase domain (TE) that releases the newly synthesized peptide from the enzyme (PubMed:17464044).
Occasionally, epimerase (E) domains (responsible for L- to D- amino acid conversion) are present within the NRP synthetase (PubMed:17464044).
NRPS12 has the following architecture: A-T-C-A-T-E-C-A-T-C (PubMed:17464044, PubMed:20225828).
Sequence similarities
Belongs to the NRP synthetase family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length3,955
- Mass (Da)437,813
- Last updated2005-07-05 v1
- ChecksumC66E17E07E1F5296
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AAHF01000006 EMBL· GenBank· DDBJ | EAL89049.1 EMBL· GenBank· DDBJ | Genomic DNA |