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首页> 外文期刊>Journal of bacteriology >Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics
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Cloning and Characterization of the Tetrocarcin A Gene Cluster from Micromonospora chalcea NRRL 11289 Reveals a Highly Conserved Strategy for Tetronate Biosynthesis in Spirotetronate Antibiotics

机译：从小单孢菌NRRL 11289的Tetrocarcin A基因簇的克隆和表征揭示了螺保守的抗生素中Tetronate生物合成的高度保守的策略。

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Tetrocarcin A (TCA), produced by Micromonospora chalcea NRRL 11289, is a spirotetronate antibiotic with potent antitumor activity and versatile modes of action. In this study, the biosynthetic gene cluster of TCA was cloned and localized to a 108-kb contiguous DNA region. In silico sequence analysis revealed 36 putative genes that constitute this cluster (including 11 for unusual sugar biosynthesis, 13 for aglycone formation, and 4 for glycosylations) and allowed us to propose the biosynthetic pathway of TCA. The formation of d-tetronitrose, l-amicetose, and l-digitoxose may begin with d-glucose-1-phosphate, share early enzymatic steps, and branch into different pathways by competitive actions of specific enzymes. Tetronolide biosynthesis involves the incorporation of a 3-C unit with a polyketide intermediate to form the characteristic spirotetronate moiety and trans-decalin system. Further substitution of tetronolide with five deoxysugars (one being a deoxynitrosugar) was likely due to the activities of four glycosyltransferases. In vitro characterization of the first enzymatic step by utilization of 1,3-biphosphoglycerate as the substrate and in vivo cross-complementation of the bifunctional fused gene tcaD3 (with the functions of chlD3 and chlD4) to ΔchlD3 and ΔchlD4 in chlorothricin biosynthesis supported the highly conserved tetronate biosynthetic strategy in the spirotetronate family. Deletion of a large DNA fragment encoding polyketide synthases resulted in a non-TCA-producing strain, providing a clear background for the identification of novel analogs. These findings provide insights into spirotetronate biosynthesis and demonstrate that combinatorial-biosynthesis methods can be applied to the TCA biosynthetic machinery to generate structural diversity.
机译：NRRL 11289是由Microemspora chalcea NRRL 11289生产的Tetrocarcin A（TCA），是一种螺菌灵抗生素，具有强大的抗肿瘤活性和多种作用方式。在这项研究中，TCA的生物合成基因簇被克隆并定位到一个108 kb的连续DNA区域。在计算机序列分析中揭示了构成该簇的36个推定基因（包括11个用于异常糖生物合成，13个用于糖苷配基形成和4个用于糖基化），并允许我们提出TCA的生物合成途径。 d-四亚硝基酶，l-氨基葡萄糖和l-数字氧糖的形成可能始于d-葡萄糖-1-磷酸，共有早期的酶促步骤，并通过特定酶的竞争作用而分支为不同的途径。 Tetronolide的生物合成涉及将3-C单元与聚酮化合物中间体结合在一起以形成特征性的螺酮酸酯部分和 trans -十氢化萘系统。可能由于四种糖基转移酶的活性，用五种脱氧糖（一种是脱氧硝基糖）进一步取代了四氢内酯。以1,3-二磷酸甘油酸为底物并在体内交叉互补双功能融合基因 tcaD3 （具有 chlD3 的功能）的第一个酶促步骤的体外表征>和 chlD4 ）到叶绿素生物合成中的Δ chlD3 和Δ chlD4 ，支持了螺酮家族高度保守的四价生物合成策略。编码聚酮化合物合酶的大DNA片段的删除导致产生非TCA的菌株，为鉴定新的类似物提供了清晰的背景。这些发现为螺菌灵的生物合成提供了见识，并证明了组合生物合成方法可以应用于三氯乙酸TCA生物合成机制以产生结构多样性。

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