Structural Study of Metal Binding and Coordination in Ancient Metallo-β-Lactamase PNGM-1 Variants

Park, Yoon Sik; Kim, Tae Yeong; Park, Hyunjae; Lee, Jung Hun; Nguyen, Diem Quynh; Hong, Myoung-Ki; Lee, Sangeun; Kang, Lin Woo

doi:10.3390/ijms21144926

Cited by 5 publications

(7 citation statements)

References 24 publications

(27 reference statements)

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“…While it is described as a B3 MBL, conferring resistance to β-lactam antibiotics and possessesing 15–18% sequence identity with that lactamase subclass, its catalytic efficiency toward these substrates is limited ( k cat / K M = 10 2 –10 3 M –1 s –1 for penicillins, cephalosporins, and carbapenems) . Additionally, phylogenetic analysis shows the protein to be more closely related to tRNase Z enzymes, and both its active-site structure and in vitro RNase degradation assays display characteristics compatible with this protein class. , As such, although its physiological function has not been characterized, the fact that PNGM-1 displays dual β-lactamase and tRNase Z activities may provide clues regarding the potential origin of B3 MBLs. Similarly, MBL-fold proteins from humans have been shown to possess residual β-lactamase activity …”

Section: Mbls B1 B2 B3: Folding Evolution Superfamily Active Sites An...mentioning

confidence: 99%

“…596 Additionally, phylogenetic analysis shows the protein to be more closely related to tRNase Z enzymes, and both its active-site structure and in vitro RNase degradation assays display characteristics compatible with this protein class. 597,598 As such, although its physiological function has not been characterized, the fact that PNGM-1 displays dual β-lactamase and tRNase Z activities may provide clues regarding the potential origin of B3 MBLs. Similarly, MBL-fold proteins from humans have been shown to possess residual β-lactamase activity.…”

Section: Mbl Superfamilymentioning

confidence: 99%

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Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

2021

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Antimicrobial resistance is one of the major problems in current practical medicine. The spread of genes coding for resistance determinants among bacteria challenges the use of approved antibiotics, narrowing the options for treatment. Resistance to carbapenems, last resort antibiotics, is a major concern. Metallo-β-lactamases (MBLs) hydrolyze carbapenems, penicillins, and cephalosporins, becoming central to this problem. These enzymes diverge with respect to serine-β-lactamases by exhibiting a different fold, active site, and catalytic features. Elucidating their catalytic mechanism has been a big challenge in the field that has limited the development of useful inhibitors. This review covers exhaustively the details of the active-site chemistries, the diversity of MBL alleles, the catalytic mechanism against different substrates, and how this information has helped developing inhibitors. We also discuss here different aspects critical to understand the success of MBLs in conferring resistance: the molecular determinants of their dissemination, their cell physiology, from the biogenesis to the processing involved in the transit to the periplasm, and the uptake of the Zn(II) ions upon metal starvation conditions, such as those encountered during an infection. In this regard, the chemical, biochemical and microbiological aspects provide an integrative view of the current knowledge of MBLs.

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Section: Mbls B1 B2 B3: Folding Evolution Superfamily Active Sites An...mentioning

confidence: 99%

Section: Mbl Superfamilymentioning

confidence: 99%

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

2021

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“…Phylogenetics suggests that there were two convergent evolutionary events, with one resulting in the B1 and B2 subclasses and the other resulting in the B3 subclass. Both events involve changes in the metal binding motif which could shift metal geometries , Park et al, 2020b, as well as changes to the overall shape of the active site that affect substrate specificity (Chen et al, 2020, Sun et al, 2018.…”

Section: Convergent Evolution Within the Mbl Superfamilymentioning

confidence: 99%

Evolution of β-lactamases and enzyme promiscuity

Fröhlich

Chen

Gholipour

et al. 2021

Protein Engineering, Design and Selection

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β-Lactamases represent one of the most prevalent resistance mechanisms against β-lactam antibiotics. Beyond their clinical importance, they have also become key models in enzymology and evolutionary biochemistry. A global understanding of their evolution and sequence and functional diversity can therefore aid a wide set of different disciplines. Interestingly, β-lactamases have evolved multiple times from distinct evolutionary origins, with ancestries that reach back billions of years. It is therefore no surprise that these enzymes exhibit diverse structural features and enzymatic mechanisms. In this review, we provide a bird’s eye view on the evolution of β-lactamases within the two enzyme superfamilies—i.e. the penicillin-binding protein-like and metallo-β-lactamase superfamily—through phylogenetics. We further discuss potential evolutionary origins of each β-lactamase class by highlighting signs of evolutionary connections in protein functions between β-lactamases and other enzymes, especially cases of enzyme promiscuity.

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“…The most common mechanism of β-lactam resistance among MDR bacteria is the production of β-lactamases, which hydrolyze β-lactams into inactive forms ( Paterson et al, 2020 ; Bahr et al, 2021 ). The evolution and catalytic mechanisms of various β-lactamases have been studied ( Hall and Barlow, 2004 ; Sidjabat et al, 2018 ; Lee et al, 2019 ; Park et al, 2020 ; Pedroso et al, 2020 ). β-lactamases can be divided into serine β-lactamases and metallo- β-lactamases (MBLs).…”

Section: Introductionmentioning

confidence: 99%

“…There are currently no effective and clinically available inhibitors against MBLs ( Fisher et al, 2005 ). MBLs are further classified into the B1, B2, and B3 subclasses depending on their sequence, structure, and zinc ion site(s) and have diverse substrate profile or specificity for β-lactams ( Crowder et al, 2006 ; Palacios et al, 2019 ; Behzadi et al, 2020 ; Park et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Structural Insights for Core Scaffold and Substrate Specificity of B1, B2, and B3 Metallo-β-Lactamases

et al. 2022

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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.

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Structural Study of Metal Binding and Coordination in Ancient Metallo-β-Lactamase PNGM-1 Variants

Cited by 5 publications

References 24 publications

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

Evolution of β-lactamases and enzyme promiscuity

Structural Insights for Core Scaffold and Substrate Specificity of B1, B2, and B3 Metallo-β-Lactamases

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