Amino acid (acyl carrier protein) ligase-associated biosynthetic gene clusters reveal unexplored biosynthetic potential.

This study aimed to evaluate the postulated cellular function of a novel family of amino acid (acyl carrier protein) ligases (AALs) in natural product biosynthesis. Here, we analyzed the manually curated, putative, aal-associated natural product biosynthetic gene clusters (NP BGCs) using two computational platforms for NP prediction, antiSMASH-BiG-SCAPE-CORASON and DeepBGC. The detected BGCs included a diversity of type I polyketide/nonribosomal peptide (PKS/NRPS) hybrid BGCs, exemplified by the guadinomine BGC, which suggested a dedicated function of AALs in the biosynthesis of rare (2S)-aminomalonyl-ACP extension units. Besides modular PKS/NRPSs and NRPSs, AAL-associated BGCs were predicted to assemble arylpolyenes, ladderane lipids, phosphonates, aminoglycosides, β-lactones, and thioamides of both nonribosomal and ribosomal origins. Additionally, we revealed a frequent association of AALs with putative, seldom observed transglutaminase-like and BtrH-like transferases of the cysteine protease superfamily, which may form larger families of ACP-dependent amide bond catalysts used in NP synthesis. Our results disclosed an exceptional chemical novelty and biosynthetic potential of the AAL-associated BGCs in NP biosynthesis. The presented in silico evidence supports the initial hypothesis and provides an important foundation for future experimental studies aimed at discovering novel pharmaceutically relevant active compounds.