Branched Chain Lipid Metabolism As a Determinant of the <i>N</i>-Acyl Variation of <i>Streptomyces</i> Natural Products

Abstract

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 (<i>iso</i>) or ω-2 (<i>anteiso</i>) 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 <i>N</i>-acylation with <i>trans</i>-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 <i>trans</i>-2,3-unsaturated TUN variants and the saturated cellular lipids found in TUN-producing <i>Streptomyces</i> 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 <i>Streptomyces</i> and concomitantly produce structurally novel <i>neo</i>-branched TUN <i>N</i>-acyl variants.