Hojati Zohreh, Milne Claire, Harvey Barbara, Gordon Lyndsey, Borg Matthew, Flett Fiona, Wilkinson Barrie, Sidebottom Philip J, Rudd Brian A M, Hayes Martin A, Smith Colin P, Micklefield Jason
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), Sackville Street, PO Box 88, Manchester M60 1QD, UK.
Chem Biol. 2002 Nov;9(11):1175-87. doi: 10.1016/s1074-5521(02)00252-1.
The calcium-dependent antibiotic (CDA), from Streptomyces coelicolor, is an acidic lipopeptide comprising an N-terminal 2,3-epoxyhexanoyl fatty acid side chain and several nonproteinogenic amino acid residues. S. coelicolor grown on solid media was shown to produce several previously uncharacterized peptides with C-terminal Z-dehydrotryptophan residues. The CDA biosynthetic gene cluster contains open reading frames encoding nonribosomal peptide synthetases, fatty acid synthases, and enzymes involved in precursor supply and tailoring of the nascent peptide. On the basis of protein sequence similarity and chemical reasoning, the biosynthesis of CDA is rationalized. Deletion of SCO3229 (hmaS), a putative 4-hydroxymandelic acid synthase-encoding gene, abolishes CDA production. The exogenous supply of 4-hydroxymandelate, 4-hydroxyphenylglyoxylate, or 4-hydroxyphenylglycine re-establishes CDA production by the DeltahmaS mutant. Feeding analogs of these precursors to the mutant resulted in the directed biosynthesis of novel lipopeptides with modified arylglycine residues.
来自天蓝色链霉菌的钙依赖性抗生素（CDA）是一种酸性脂肽，由N端的2,3-环氧己酰脂肪酸侧链和几个非蛋白质ogenic氨基酸残基组成。在固体培养基上生长的天蓝色链霉菌被证明能产生几种以前未被表征的带有C端Z-脱氢色氨酸残基的肽。CDA生物合成基因簇包含编码非核糖体肽合成酶、脂肪酸合成酶以及参与新生肽前体供应和修饰的酶的开放阅读框。基于蛋白质序列相似性和化学推理，对CDA的生物合成进行了合理化分析。删除假定的编码4-羟基扁桃酸合酶的基因SCO3229（hmaS）会消除CDA的产生。向DeltahmaS突变体外源供应4-羟基扁桃酸、4-羟基苯乙二醛或4-羟基苯甘氨酸可重新建立CDA的产生。向突变体投喂这些前体的类似物导致了带有修饰芳基甘氨酸残基的新型脂肽的定向生物合成。
