P0DUR7 · QULF_PENCI
- ProteinFMN-dependent alpha-hydroxy acid dehydrogenase qulF
- GenequlF
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids402 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score3/5
Function
function
FMN-dependent alpha-hydroxy acid dehydrogenase; part of the gene cluster that mediates the biosynthesis of quinolactacin A2 (QUL A2), a fungal alkaloid that features a quinolone-gamma-lactam hybrid, which is a potential pharmacophore for the treatment of cancer and Alzheimer's disease (PubMed:32663343).
The quinolone-gamma-lactam hybrid scaffold is synthesized from the combination of L-isoleucine (L-Ile) and the nonproteinogenic amino acid L-kynurenine, followed by quinolone cyclization, oxidative decarboxylation, and lactam formation (PubMed:32663343).
Additionally, the N-methyl group is derived from methionine, which might be catalyzed by an S-adenosylmethionine (SAM)-dependent methyltransferase (PubMed:32663343).
Bioconversion of L-tryptophan to L-kynurenine could be catalyzed by the indoleamine-2,3-dioxygenase (IDO) qulI to produce an unstable product, N-formyl-L-kynurenine, followed by kynurenine formamidase catalyzed hydrolysis (PubMed:32663343).
QulM then acts as a methyltransferase that methylates L-kynurenine at the N-4 position (PubMed:32663343).
The FMN-dependent alpha-hydroxy acid dehydrogenase qulF than functions as an oxidative decarboxylase which converts N-methylkynurenine into 2-aminobenzoylacetamide via 2 tandem reactions, including dehydrogenation and decarboxylation (PubMed:32663343).
An amidase located outside of the qul gene cluster further produces the unstable beta-keto acid precursor N-methyl-2-aminobenzoylacetate, which could be spontaneously dehydrated to form N-methyl-4-hydroxy-2-quinolone (PubMed:32663343).
The NRPS qulB is able to incorporate N-methyl-2-aminobenzoylacetate and efficiently compete with the spontaneous reaction (PubMed:32663343).
By further extending the beta-keto acid with L-Ile, qulA performs a Dieckmann condensation to form the gamma-lactam ring and release a 4-ketopyrrolidinone intermediate from the assembly line (PubMed:32663343).
This intermediate could plausibly further undergo a spontaneous cyclization to yield the final quinolone-gamma-lactam hybrid structure (PubMed:32663343).
The quinolone-gamma-lactam hybrid scaffold is synthesized from the combination of L-isoleucine (L-Ile) and the nonproteinogenic amino acid L-kynurenine, followed by quinolone cyclization, oxidative decarboxylation, and lactam formation (PubMed:32663343).
Additionally, the N-methyl group is derived from methionine, which might be catalyzed by an S-adenosylmethionine (SAM)-dependent methyltransferase (PubMed:32663343).
Bioconversion of L-tryptophan to L-kynurenine could be catalyzed by the indoleamine-2,3-dioxygenase (IDO) qulI to produce an unstable product, N-formyl-L-kynurenine, followed by kynurenine formamidase catalyzed hydrolysis (PubMed:32663343).
QulM then acts as a methyltransferase that methylates L-kynurenine at the N-4 position (PubMed:32663343).
The FMN-dependent alpha-hydroxy acid dehydrogenase qulF than functions as an oxidative decarboxylase which converts N-methylkynurenine into 2-aminobenzoylacetamide via 2 tandem reactions, including dehydrogenation and decarboxylation (PubMed:32663343).
An amidase located outside of the qul gene cluster further produces the unstable beta-keto acid precursor N-methyl-2-aminobenzoylacetate, which could be spontaneously dehydrated to form N-methyl-4-hydroxy-2-quinolone (PubMed:32663343).
The NRPS qulB is able to incorporate N-methyl-2-aminobenzoylacetate and efficiently compete with the spontaneous reaction (PubMed:32663343).
By further extending the beta-keto acid with L-Ile, qulA performs a Dieckmann condensation to form the gamma-lactam ring and release a 4-ketopyrrolidinone intermediate from the assembly line (PubMed:32663343).
This intermediate could plausibly further undergo a spontaneous cyclization to yield the final quinolone-gamma-lactam hybrid structure (PubMed:32663343).
Cofactor
Features
Showing features for binding site, active site.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Binding site | 48 | a 2-oxocarboxylate (UniProtKB | ChEBI) | |||
Binding site | 130 | FMN (UniProtKB | ChEBI) | |||
Binding site | 152 | FMN (UniProtKB | ChEBI) | |||
Binding site | 154 | a 2-oxocarboxylate (UniProtKB | ChEBI) | |||
Binding site | 189 | a 2-oxocarboxylate (UniProtKB | ChEBI) | |||
Binding site | 265 | FMN (UniProtKB | ChEBI) | |||
Active site | 289 | Proton acceptor | |||
Binding site | 292 | a 2-oxocarboxylate (UniProtKB | ChEBI) | |||
Binding site | 320-324 | FMN (UniProtKB | ChEBI) | |||
Binding site | 343-344 | FMN (UniProtKB | ChEBI) | |||
GO annotations
Aspect | Term | |
---|---|---|
Molecular Function | FMN binding | |
Molecular Function | oxidoreductase activity |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameFMN-dependent alpha-hydroxy acid dehydrogenase qulF
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Fungi > Dikarya > Ascomycota > Pezizomycotina > Eurotiomycetes > Eurotiomycetidae > Eurotiales > Aspergillaceae > Penicillium
Accessions
- Primary accessionP0DUR7
Phenotypes & Variants
Disruption phenotype
Impairs the production of quinolactacin A2 and leads to the accumulatin of N-methylkynurenine.
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Mutagenesis | 289 | Blocks the formatin of 2-aminobenzoylacetamide. | |||
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Chain | PRO_0000453483 | 1-402 | FMN-dependent alpha-hydroxy acid dehydrogenase qulF | ||
Structure
Sequence
- Sequence statusComplete
- Length402
- Mass (Da)44,060
- Last updated2021-09-29 v1
- MD5 ChecksumEC5016C8196DA5C61312D8938CCA2CBE