Dataset Information

Dual activity of PNGM-1 pinpoints the evolutionary origin of subclass B3 metallo-?-lactamases: a molecular and evolutionary study.

ABSTRACT: Resistance to ?-lactams is one of the most serious problems associated with Gram-negative infections. ?-Lactamases are able to hydrolyze ?-lactams such as cephalosporins and/or carbapenems. Evolutionary origin of metallo-?-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.

SUBMITTER: Lee JH

PROVIDER: S-EPMC6882493 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Dual activity of PNGM-1 pinpoints the evolutionary origin of subclass B3 metallo-β-lactamases: a molecular and evolutionary study.

Lee Jung Hun JH Takahashi Masayuki M Jeon Jeong Ho JH Kang Lin-Woo LW Seki Mineaki M Park Kwang Seung KS Hong Myoung-Ki MK Park Yoon Sik YS Kim Tae Yeong TY Karim Asad Mustafa AM Lee Jung-Hyun JH Nashimoto Masayuki M Lee Sang Hee SH

Emerging microbes & infections 20190101 1

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 yield ...[more]

PMID: 31749408

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Project description:Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems; however, no effective inhibitors are currently clinically available. MBLs are classified into three subclasses: B1, B2, and B3. Although the amino acid sequences of MBLs are varied, their overall scaffold is well conserved. In this study, we systematically studied the primary sequences and crystal structures of all subclasses of MBLs, especially the core scaffold, the zinc-coordinating residues in the active site, and the substrate-binding pocket. We presented the conserved structural features of MBLs in the same subclass and the characteristics of MBLs of each subclass. The catalytic zinc ions are bound with four loops from the two central β-sheets in the conserved αβ/βα sandwich fold of MBLs. The three external loops cover the zinc site(s) from the outside and simultaneously form a substrate-binding pocket. In the overall structure, B1 and B2 MBLs are more closely related to each other than they are to B3 MBLs. However, B1 and B3 MBLs have two zinc ions in the active site, while B2 MBLs have one. The substrate-binding pocket is different among all three subclasses, which is especially important for substrate specificity and drug resistance. Thus far, various classes of β-lactam antibiotics have been developed to have modified ring structures and substituted R groups. Currently available structures of β-lactam-bound MBLs show that the binding of β-lactams is well conserved according to the overall chemical structure in the substrate-binding pocket. Besides β-lactam substrates, B1 and cross-class MBL inhibitors also have distinguished differences in the chemical structure, which fit well to the substrate-binding pocket of MBLs within their inhibitory spectrum. The systematic structural comparison among B1, B2, and B3 MBLs provides in-depth insight into their substrate specificity, which will be useful for developing a clinical inhibitor targeting MBLs.

Dataset Information

Dual activity of PNGM-1 pinpoints the evolutionary origin of subclass B3 metallo-?-lactamases: a molecular and evolutionary study.

Publications

Dual activity of PNGM-1 pinpoints the evolutionary origin of subclass B3 metallo-<i>β</i>-lactamases: a molecular and evolutionary study.

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