What is it about?

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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Why is it important?

In addition to biochemical and cell-based results, the hydrolyzed form of β-lactam ring of doripenem shown in the active site structure of doripenem-bound H257A showed that PNGM-1 is a unique subclass B3 MBL. 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.

Perspectives

Based on our results, we suggest that subclass B3 MBLs arose through an evolutionary trajectory (tRNase Z → PNGM-1→ subclass B3 MBLs) and the origin of subclass B3 MBLs is a tRNase Z. The evolutionary processes process (dimer interfacial deformation to prevent dimerization of an ancestral protein such as a tRNase Z, dimer) provides a new strategy to develop novel enzymes (e.g., class B MBLs, monomer) as drug targets.

Professor Sang Hee Lee
Myongji University

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This page is a summary of: Dual activity of PNGM-1 pinpoints the evolutionary origin of subclass B3 metallo-β-lactamases: a molecular and evolutionary study, Emerging Microbes & Infections, January 2019, Taylor & Francis, DOI: 10.1080/22221751.2019.1692638.
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