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Caprazamycins: Biosynthesis and structure activity relationship studies
International Journal of Medical Microbiology ( IF 4.5 ) Pub Date : 2019-05-24 , DOI: 10.1016/j.ijmm.2019.05.004
Franziska Wiker , Nils Hauck , Stephanie Grond , Bertolt Gust

Cell wall biosynthesis represents a valid target for antibacterial action but only a limited number of chemical structure classes selectively interact with specific enzymes or protein structures like transporters of the cell envelope. The integral membrane protein MraY translocase is essential for peptidoglycan biosynthesis catalysing the transfer of the peptidoglycan precursor phospho-MurNAc-pentapeptide to the lipid carrier undecaprenyl phosphate, thereby generating the cell wall intermediate lipid I. Not present in eukaryotic cells, MraY is a member of the superfamily of yet not well-understood integral membrane enzymes which involve proteins for bacterial lipopolysaccharide and teichoic acid or eukaryotic N-linked saccharides biosynthesis. Different natural nucleoside antibiotics as inhibitors of MraY translocase have been discovered comprising a glycosylated heterocyclic pyrimidin base among other potential lipid-, peptidic- or sugar moieties. Caprazamycins are liponucleoside antibiotics isolated from Streptomyces sp. MK730-62F2. They possess activity in vitro against Gram-positive bacteria, in particular against the genus Mycobacterium including M. intracellulare, M. avium and M. tuberculosis. Structural elucidation revealed the (+)-caprazol core skeleton as a unique moiety, the caprazamycins share with other MraY inhibitors such as the liposidomycins, A-90289 and the muraminomicins. They also share structural features such as uridyl-, aminoribosyl- and fatty acyl-moieties with other MraY translocase inhibitors like FR-900493 and the muraymycins. Intensive studies on their biosynthesis during the last decade identified not only common initial biosynthetic steps, but also revealed possible branching points towards individual biosynthesis of the respective compound. Structural diversity of caprazamycins was generated by feeding experiments, genetic engineering of the biosynthetic gene clusters and chemical synthesis for structure activity relationship studies with its target, MraY translocase.



中文翻译:

辣椒素:生物合成与结构活性关系的研究

细胞壁生物合成代表了抗菌作用的有效靶标,但是只有有限数量的化学结构类别与特定的酶或蛋白质结构(如细胞包膜的转运蛋白)选择性地相互作用。完整的膜蛋白MraY转位酶对于肽聚糖生物合成至关重要,该酶催化肽聚糖前体磷酸-MurNAc-五肽向脂质载体十一碳烯基磷酸酯的转移,从而生成细胞壁中间脂质I。MraY是真核细胞中的成员尚未完整理解的完整膜酶的超家族,其涉及细菌脂多糖和磷壁酸或真核生物N的蛋白质联糖的生物合成。已经发现了不同的天然核苷抗生素作为MraY转位酶的抑制剂,其中包括糖基化的杂环嘧啶碱基以及其他潜在的脂质,肽或糖部分。辣椒碱霉素是从链霉菌属(Streptomyces sp。)分离的脂核苷抗生素。MK730-62F2。它们在体外具有针对革兰氏阳性细菌的活性,特别是针对分枝杆菌属的细胞,包括胞内分枝杆菌鸟分枝杆菌结核分枝杆菌。结构解析表明,(+)-辣椒碱核心骨架是一个独特的部分,辣椒素与其他MraY抑制剂(如脂霉素,A-90289和muraminomicins)共享。它们还与其他MraY转移酶抑制剂(如FR-900493和穆雷霉素)具有结构特征,如尿苷基,氨基核糖基和脂肪酰基基团。在过去十年中,对其生物合成的深入研究不仅确定了常见的初始生物合成步骤,而且还揭示了各个化合物各自生物合成的可能分支点。吡raz霉素的结构多样性是通过进食实验,生物合成基因簇的遗传工程和化学合成产生的,用于与其靶标MraY Translocase进行结构活性关系研究。

更新日期:2019-05-24
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