Branched Chain Lipid Metabolism As a Determinant of the N-Acyl Variation of Streptomyces Natural Products,ACS Chemical Biology

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Branched Chain Lipid Metabolism As a Determinant of the N-Acyl Variation of Streptomyces Natural Products
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-01-07 , DOI: 10.1021/acschembio.0c00799
Neil P J Price ₁ , Michael A Jackson ₁ , Trina M Hartman ₁ , Gisela Brändén ₂ , Margareta Ek ₃ , Aaron A Koch ₄ , Paul D Kennedy ₄

Affiliation

Branched-chain fatty acids (BCFA) are encountered in Gram-positive bacteria, but less so in other organisms. The bacterial BCFA in membranes are typically saturated, with both odd- and even-numbered carbon chain lengths, and with methyl branches at either the ω-1 (iso) or ω-2 (anteiso) positions. The acylation with BCFA also contributes to the structural diversity of microbial natural products and potentially modulates biological activity. For the tunicamycin (TUN) family of natural products, the toxicity toward eukaryotes is highly dependent upon N-acylation with trans-2,3-unsaturated BCFA. The loss of the 2,3-unsaturation gives modified TUN with reduced eukaryotic toxicity but crucially with retention of the synergistic enhancement of the β-lactam group of antibiotics. Here, we infer from genomics, mass spectrometry, and deuterium labeling that the trans-2,3-unsaturated TUN variants and the saturated cellular lipids found in TUN-producing Streptomyces are derived from the same pool of BCFA metabolites. Moreover, non-natural primers of BCFA metabolism are selectively incorporated into the cellular lipids of TUN-producing Streptomyces and concomitantly produce structurally novel neo-branched TUN N-acyl variants.

中文翻译：

支链脂质代谢作为链霉菌天然产物N-酰基变异的决定因素

革兰氏阳性细菌中会遇到支链脂肪酸（BCFA），而在其他生物中则较少。膜中的细菌BCFA通常是饱和的，具有奇数和偶数碳链长度，并且在ω-1（iso）或ω-2（anteiso）位置具有甲基分支。与BCFA的酰化作用还有助于微生物天然产物的结构多样性，并可能调节生物活性。对于天然产物衣霉素（TUN）系列，其对真核生物的毒性高度依赖于反式的N-酰化作用。-2,3-不饱和BCFA。2,3-不饱和度的丧失使修饰的TUN具有降低的真核毒性，但至关重要的是保留了β-内酰胺类抗生素的协同增效作用。在这里，我们从基因组学，质谱和氘标记推断出，在产生TUN的链霉菌中发现的反式-2,3-不饱和TUN变体和饱和细胞脂质均来自相同的BCFA代谢物库。此外，将BCFA代谢的非天然引物选择性地掺入产生TUN的链霉菌的细胞脂质中，并同时产生结构上新颖的新分支的TUN N-酰基变体。

更新日期：2021-01-15

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