Abstract
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.
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Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- AAL:
-
Amino acid (acyl carrier protein) ligase
- AAL collection:
-
AAL-associated collection of NP BGCs
- ACP:
-
Acyl carrier protein
- Acd:
-
Acyl-CoA dehydrogenase
- AGL:
-
ATP-grasp ligase
- AM-ACP:
-
Aminomalonyl-ACP
- APE:
-
Arylpolyene
- BGC:
-
Biosynthetic gene cluster
- DUF1839:
-
Domain of unknown function 1839
- GBK:
-
GenBank file
- GCF:
-
Gene cluster family
- KSα :
-
KSII of a type II PKS system
- KSβ :
-
Chain length factor
- KSII:
-
Type II ketosynthase
- KSIII:
-
Type III ketosynthase
- LAD:
-
Ladderane lipid
- MAT:
-
Malonyl-CoA (ACP) transacylase
- NP:
-
Natural product
- NRPS:
-
Nonribosomal peptide synthetase
- PKS:
-
Polyketide synthase
- PKS/NRPS:
-
Polyketide synthase/nonribosomal peptide synthetase
- RIPP:
-
Post-translationally modified peptide
- T1 PKS:
-
Type I polyketide synthase
- T2 PKS:
-
Type II polyketide synthase
- T3 PKS:
-
Type III polyketide synthase
- TG-like:
-
Transglutaminase-like
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Acknowledgements
This study was not supported by a research grant. The authors thank Juan-Pablo Gomez-Escribano for the insightful comments on the manuscript.
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VS conceived, designed, and supervised the study; VS manually curated the AAL collection; IG performed antiSMASH, BiG-SCAPE, and DeepBGC analyses; VS and IG analyzed data; VS wrote the manuscript; and VS and IG revised the manuscript.
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Communicated by Martine Collart.
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Simunović, V., Grubišić, I. Amino acid (acyl carrier protein) ligase-associated biosynthetic gene clusters reveal unexplored biosynthetic potential. Mol Genet Genomics 298, 49–65 (2023). https://doi.org/10.1007/s00438-022-01962-7
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DOI: https://doi.org/10.1007/s00438-022-01962-7