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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.
Highlights
The family of quinoxaline antibiotics embraces two structurally similar series of compounds, the triostins and quinomycins, produced by various Streptomyces strains [1]
In the case of the quinoxaline antibiotics, in vivo studies of quinomycin A formation in Streptomyces echinatus have shown that quinoxaline-2-carboxylic acid (QA) is derived from tryptophan and that the amino acids of the peptide rings stem from the free cellular pool [12]
Isolation and Identification of Triostin Synthetases (TRSs)— To isolate nonribosomal peptide synthetase (NRPS) activities involved in quinoxalinoyl peptide assembly, protein fractions from S. echinatus or S. triostinicus were tested for protein-thioester formation with the amino acids serine, alanine, cysteine, and valine
Summary
The family of quinoxaline antibiotics embraces two structurally similar series of compounds, the triostins and quinomycins, produced by various Streptomyces strains [1] They consist of octadepsipeptide rings to which are attached two quinoxaline-2-carboxylic acid (QA) residues in amide linkages (Fig. 1). The triostins and quinomycins differ in their cross-bridges, represented by either a disulfide or a thioacetal structure, respectively These are contributed from the thiol groups of the two cysteines present in the octadepsipeptide rings [2] (Fig. 1). Triostin synthetase I (TrsI), a 58-kDa protein present in triostin A-producing S. triostinicus and in echinomycin-producing S. echinatus, activates QA as the adenylate [14] It can activate a number of structural analogues of QA such as quinoline-2-carboxylic acid, thieno[3,2b]pyridine-5-carboxylic acid (TPA), and 3-hydroxyquinoline-2-carboxylic acid. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY825941
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