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Dual activity of PNGM-1, a metallo-β-lactamase and tRNase Z, pinpoints the evolutionary origin of subclass B3 metallo-β-lactamases
| Content Provider | bioRxiv |
|---|---|
| Author | Lee, Jung Hun Takahashi, Masayuki Jeon, Jeong Ho Kang, Lin-woo Seki, Mineaki Park, Kwang Seung Hong, Myoung-ki Park, Yoon Sik Kim, Tae Yeong Karim, Asad Mustafa Lee, Jung-hyun Nashimoto, Masayuki Lee, Sang Hee |
| Copyright Year | 2019 |
| Abstract | Abstract Antibiotic resistance is a steadily increasing global problem which could lead to a fundamental upheaval in clinical care with the potential to return us to the pre-antibiotic era1-4. The production of β-lactamases, a group of enzymes that confer antibiotic resistance in Gram-negative bacteria, is now one of the major barriers in treating Gram-negative infections5. β-Lactamases are classified according to their catalytic mechanisms into serine β-lactamases and metallo-β-lactamases6,7. There are functional and structural similarities between serine β-lactamases and penicillin-binding proteins, and so serine β-lactamases are thought to have evolved from a penicillin-binding protein7,8. Given the functional and structural differences between serine β-lactamases and metallo-β-lactamases, metallo-β-lactamases are thought to have evolved from a protein other than a penicillin-binding protein, but to date this ancestor remains unknown8-11. We discovered PNGM-1, the first subclass B3 metallo-β-lactamase, in deep-sea sediments that predate the antibiotic era12. Here we discover the dual activity of PNGM-1, pinpointing the evolutionary origin of subclass B3 metallo-β-lactamases. Phylogenetic analysis suggested that PNGM-1 could yield insights into the evolutionary origin of subclass B3 metallo-β-lactamases. We reveal the structural similarities between tRNase Zs and PNGM-1, which prompted us to investigate their evolutionary relationship and the possibility of them possessing dual enzymatic activities. We demonstrate that PNGM-1 has dual activity with both true metallo-β-lactamase and tRNase Z activity, 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 metallo-β-lactamases and tRNase Zs. These comparisons revealed that the B3 metallo-β-lactamase activity of PNGM-1 is a promiscuous activity and subclass B3 metallo-β-lactamases are thought to have evolved through PNGM-1 activity. Our work provides a foundation for the evolution of tRNase Z into subclass B3 metallo-β-lactamases through the dual activity of PNGM-1. |
| Related Links | https://www.biorxiv.org/content/biorxiv/early/2019/03/13/575373.full.pdf |
| DOI | 10.1101/575373 |
| Language | English |
| Publisher | Cold Spring Harbor Laboratory |
| Publisher Date | 2019-03-13 |
| Access Restriction | Open |
| Rights License | Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0 |
| Subject Keyword | Microbiology |
| Content Type | Text |
| Resource Type | Preprint |
| Subject | Microbiology |
