RESUMO
The structures of five linear lipopeptides, thaxteramides A1, A2, B1, B2, and C isolated from the myxobacterium Jahnella thaxteri, were elucidated. They have a C-terminal common tetrapeptidic Tyr-Gly-ß-Ala-Tyr core but differ in the stereochemistry of the tyrosine units, methylations, the remaining amino acids, and the N-terminal polyketide. In silico analysis of the genome sequence complemented with feeding experiments revealed two distinct hybrid PKS/NRPS gene clusters. Three semisynthesized cyclic analogues were found to inhibit the growth of Gram-positive bacteria.
Assuntos
Lipopeptídeos/biossíntese , Myxococcales/metabolismo , Sequência de Aminoácidos , Simulação por Computador , Lipopeptídeos/químicaRESUMO
Natural product peptide-based proteasome inhibitors show great potential as anticancer drugs. Here we have cloned the biosynthetic gene cluster of a potent proteasome inhibitor-glidobactin from Burkholderia DSM7029-and successfully detected glidobactins/luminmycins in E. coli Nissle. We have also improved the yield of glidobactin A tenfold by promoter change in a heterologous host. In addition, two new biosynthetic intermediates were identified by comparative MS/MS fragmentation analysis. Identification of acyclic luminmycin E implies substrate specificity of the TE domain for cyclization. The establishment of a heterologous expression system for syrbactins provided the basis for the generation of new syrbactins as proteasome inhibitors by molecular engineering, but the TE domain's specificity cannot be ignored.
Assuntos
Produtos Biológicos/metabolismo , Burkholderia/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Família Multigênica/genética , Oligopeptídeos/biossíntese , Produtos Biológicos/química , Conformação Molecular , Oligopeptídeos/química , Oligopeptídeos/genética , Peptídeos Cíclicos/biossíntese , Peptídeos Cíclicos/química , Peptídeos Cíclicos/genética , EstereoisomerismoRESUMO
Myxalamids are potent inhibitors of the eukaryotic electron transport chain produced by different myxobacteria. Here, we describe the identification of the myxalamid biosynthesis gene cluster from Myxococcus xanthus. Additionally, new myxalamids (5-13) have been obtained by mutasynthesis from bkd mutants of M. xanthus and Stigmatella aurantiaca. Moreover, as these bkd mutants are still able to produce myxalamid B (2), the origin of the isobutyryl-CoA (IB-CoA) starter unit required for its biosynthesis has been determined. In a M. xanthus bkd mutant, IB-CoA originates from valine, but in S. aurantiaca this starter unit is derived from alpha-oxidation of iso-odd fatty acids, thereby connecting primary and secondary metabolism.
