Journal
NATURE CHEMICAL BIOLOGY
Volume 14, Issue 7, Pages 730-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41589-018-0061-0
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Funding
- National Institute of General Medical Sciences Protein Structure Initiative [GM094585, GM098248]
- National Institutes of Health [GM109456, GM114353]
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- Institute of Applied Ecology, Chinese Academy of Sciences
- Chinese Scholarship Council [201504910034]
- Arnold O. Beckman Postdoctoral Fellowship
- Fellowship of Academia Sinica-The Scripps Research Institute Postdoctoral Talent Development Program
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U01GM098248, R01GM114353, U54GM094585, R01GM109456] Funding Source: NIH RePORTER
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Acyl-coenzyme A (CoA) ligases catalyze the activation of carboxylic acids via a two-step reaction of adenylation followed by thioesterification. Here, we report the discovery of a non-adenylating acyl-CoA ligase PtmA2 and the functional separation of an acyl-CoA ligase reaction. Both PtmA1 and PtmA2, two acyl-CoA ligases from the biosynthetic pathway of platensimycin and platencin, are necessary for the two steps of CoA activation. Gene inactivation of ptmA1 and ptmA2 resulted in the accumulation of free acid and adenylate intermediates, respectively. Enzymatic and structural characterization of PtmA2 confirmed its ability to only catalyze thioesterification. Structural characterization of PtmA2 revealed it binds both free acid and adenylate substrates and undergoes the established mechanism of domain alternation. Finally, site-directed mutagenesis restored both the adenylation and complete CoA activation reactions. This study challenges the currently accepted paradigm of adenylating enzymes and inspires future investigations on functionally separated acyl-CoA ligases and their ramifications in biology.
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