Functional Cross-talk between Fatty Acid Synthesis and Nonribosomal Peptide Synthesis in Quinoxaline Antibiotic-producing Streptomycetes
Gernot SchmoockFrank PfennigJulien JewiarzWilhelm SchlumbohmWerner LaubingerFlorian SchauweckerUllrich Keller
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Abstract:
Quinoxaline antibiotics are chromopeptide lactones embracing the two families of triostins and quinomycins, each having characteristic sulfur-containing cross-bridges. Interest in these compounds stems from their antineoplastic activities and their specific binding to DNA via bifunctional intercalation of the twin chromophores represented by quinoxaline-2-carboxylic acid (QA). Enzymatic analysis of triostin A-producing Streptomyces triostinicus and quinomycin A-producing Streptomyces echinatus revealed four nonribosomal peptide synthetase modules for the assembly of the quinoxalinoyl tetrapeptide backbone of the quinoxaline antibiotics. The modules were contained in three protein fractions, referred to as triostin synthetases (TrsII, III, and IV). TrsII is a 245-kDa bimodular nonribosomal peptide synthetase activating as thioesters for both serine and alanine, the first two amino acids of the quinoxalinoyl tetrapeptide chain. TrsIII, represented by a protein of 250 kDa, activates cysteine as a thioester. TrsIV, an unstable protein of apparent Mr about 280,000, was identified by its ability to activate and N-methylate valine, the last amino acid. QA, the chromophore, was shown to be recruited by a free-standing adenylation domain, TrsI, in conjunction with a QA-binding protein, AcpPSE. Cloning of the gene for the QA-binding protein revealed that it is the fatty acyl carrier protein, AcpPSE, of the fatty acid synthase of S. echinatus and S. triostinicus. Analysis of the acylation reaction of AcpPSE by TrsI along with other A-domains and the aroyl carrier protein AcmACP from actinomycin biosynthesis revealed a specific requirement for AcpPSE in the activation and also in the condensation of QA with serine in the initiation step of QA tetrapeptide assembly on TrsII. These data show for the first time a functional interaction between nonribosomal peptide synthesis and fatty acid synthesis.Keywords:
Nonribosomal peptide
Quinoxaline
Production of chrysogine has been reported from several fungal genera including Penicillium, Aspergillus, and Fusarium. Anthranilic acid and pyruvic acid, which are expected precursors of chrysogine, enhance production of this compound. A possible route for the biosynthesis using these substrates is via a nonribosomal peptide synthetase (NRPS). Through comparative analysis of the NRPSs from genome-sequenced producers of chrysogine we identified a candidate NRPS cluster comprising five additional genes named chry2–6. Deletion of the two-module NRPS (NRPS14 = chry1) abolished chrysogine production in Fusarium graminearum, indicating that the gene cluster is responsible for chrysogine biosynthesis. Overexpression of NRPS14 enhanced chrysogine production, suggesting that the NRPS is the bottleneck in the biosynthetic pathway.
Nonribosomal peptide
Gene cluster
Polyketide synthase
Anthranilic acid
Secondary metabolism
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The quinoxaline derivatives are beneficial compounds because of their various medicinal and industrial applications. They are well-known for application in organic light emitting devices, polymers and pharmaceutical agents. The quinoxaline-containing polymers are applicable in optical devices due to their thermal stability and low band gap. There are many reported procedures for the synthesis of bis- and polyquinoxalines and quinoxaline-containing macrocycles. The quinoxaline-based compounds as fascinating structures are important subjects of interest in either basic or applied sciences. This review summarizes the latest progresses related to the quinoxalines, quinoxaline-containing macrocycles, and bis- and poly quinoxalines, including the synthesis, functionalization and modification methods and applications of these compounds.
Quinoxaline
Surface Modification
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A cryptic tetronate biosynthetic pathway was identified in Kitasatospora niigatensis DSM 44781 via heterologous expression. Distinct from the currently known biosynthetic pathways, this system utilizes a partially functional nonribosomal peptide synthetase and a broadly selective polyketide synthase to direct the assembly and lactonization of the tetronate scaffold. By employing a permissive crotonyl-CoA reductase/carboxylase to provide different extender units, seven new tetronates (kitaniitetronins A–G) were obtained via precursor-directed biosynthesis.
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Polyketide synthase
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Nonribosomal peptide
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Abstract The reaction of 6‐chloro‐2‐hydrazinoquinoxaline 4‐oxide 1b with acetylacetone or benzoylacetone gave 6‐chloro‐2‐(3,5‐dimethylpyrazol‐i‐yl)quinoxaline 4‐oxide 5a or 6‐chloro‐2‐(3‐methyl‐5‐phenylpyrazol‐1‐yl)quinoxaline 4‐oxide 5b , respXectively. Compound 5a or 5b was converted into the pyrrolo[1,5‐ a ]quinoxaline 6a or 6b , triazolo[4,3‐ a ]quinoxaline 9a or 9b , and tetrazolo[1,5‐ a ]quinoxaline 10.
Quinoxaline
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The review article attempts to give recent advances on quinoxaline and its derivatives. Some pathways to the synthesis of quinoxaline, quinoxaline-2-one and quinoxaline-2,3-dione were reported using simple reactive quinoxaline synthon. In addition, the reactions, biological and technological applications of derivatives of quinoxaline and related compounds were reported.
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The possible metabolites of quinocetone in animals had been prepared with different selective reagent by three synthetic routes. It was their principal reaction that Na2S2O4 reduced quinoxaline-1,4-dioxide derivatives to quinoxaline derivatives, H(2)O(2 s)oxidized 2-carboxyl-quinoxaline derivatives to 2-carboxyl-quinoxaline-1-oxide ones and P(OCH3)(3) reduced 2-carboxyl- quinoxaline-1,4-dioxide derivatives to 3-carboxyl-quinoxaline-1-oxide ones. The title compounds ware confirmed with NMR, UV, FAB-MS, et al.
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