Contributors: Myongji University; Niigata University of Pharmacy and Applied Life Sciences; Konkuk University [Seoul]; Marine Biotechnology Research Center; Korea Institute of Ocean Science and Technology (KIOST); This work was supported by research grants from the Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT; grants NRF-2017M3A9E4078014 and NRF-2017R1A2B4002315 to S.H.L., NRF-2017M3A9E4078017 to L.-W.K., and NRF-2019R1C1C1008615 to J.H.L.); the Korea Centers for Disease Control and Prevention (grant 2017ER540402 to S.H.L.); and the Takeda Science Foundation to M.T.; We thank our colleagues, both past and present, at the National Leading Research Laboratory of Drug Resistance Proteomics, Myongji University, for sharing their insights into the concepts presented here; S.G. Kang and B.C. Jeong for early support of this work; and J.H. Kim and S.K. Malik for helpful discussions. J.H.L., J.H.J., and J.-H.L. identified and prepared a novel MBL gene and protein. J.H.L., M.T., M.N., K.S.P., and M.S. performed a genetic and functional analysis. J.H.J., T.Y.K., and A.M.K. conducted the mutant analysis. L.-W.K., M.-K.H., and Y.S.P. carried out the crystal structure studies and data analysis. S.H.L. and M.N. analyzed the evolutionary origin.
نبذة مختصرة : International audience; Resistance to β-lactams is one of the most serious problems associated with Gram-negative infections. β-Lactamases are able to hydrolyze β-lactams such as cephalosporins and/or carbapenems. Evolutionary origin of metallo-β-lactamases (MBLs), conferring critical antibiotic resistance threats, remains unknown. We discovered PNGM-1, the novel subclass B3 MBL, in deep-sea sediments that predate the antibiotic era. Here, our phylogenetic analysis suggests that PNGM-1 yields insights into the evolutionary origin of subclass B3 MBLs. We reveal the structural similarities between tRNase Zs and PNGM-1, and demonstrate that PNGM-1 has both MBL and tRNase Z activities, suggesting that PNGM-1 is thought to have evolved from a tRNase Z. We also show kinetic and structural comparisons between PNGM-1 and other proteins including subclass B3 MBLs and tRNase Zs. These comparisons revealed that the B3 MBL activity of PNGM-1 is a promiscuous activity and subclass B3 MBLs are thought to have evolved through PNGM-1 activity.
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