Origin, Diversity, and Multiple Roles of Enzymes with Metallo-β-Lactamase Fold from Different Organisms

Abstract

β-lactamase enzymes have generated significant interest due to their ability to confer resistance to the most commonly used family of antibiotics in human medicine. Among these enzymes, the class B β-lactamases are members of a superfamily of metallo-β-lactamase (MβL) fold proteins which are characterised by conserved motifs (i.e., HxHxDH) and are not only limited to bacteria. Indeed, as the result of several barriers, including low sequence similarity, default protein annotation, or untested enzymatic activity, MβL fold proteins have long been unexplored in other organisms. However, thanks to search approaches which are more sensitive compared to classical Blast analysis, such as the use of common ancestors to identify distant homologous sequences, we are now able to highlight their presence in different organisms including Bacteria, Archaea, Nanoarchaeota, Asgard, Humans, Giant viruses, and Candidate Phyla Radiation (CPR). These MβL fold proteins are multifunctional enzymes with diverse enzymatic or non-enzymatic activities of which, at least thirteen activities have been reported such as β-lactamase, ribonuclease, nuclease, glyoxalase, lactonase, phytase, ascorbic acid degradation, anti-cancer drug degradation, or membrane transport. In this review, we (i) discuss the existence of MβL fold enzymes in the different domains of life, (ii) present more suitable approaches to better investigating their homologous sequences in unsuspected sources, and (iii) report described MβL fold enzymes with demonstrated enzymatic or non-enzymatic activities.

Glial swip-10expression controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

“…The single recognizable structural domain of swip-10 , bearing the mutations found in our genetic screen, (18), offered us little insight as to the molecule’s function given the variety of molecules hydrolyzed by MBDs in eukaryotic proteins(46, 47). Thus, we were excited by work de-orphanizing MBLAC1, the closest mammalian SWIP-10 ortholog.…”

Combating antimicrobial resistance: the silent war

“…β-lactamases, for instance, can hydrolyze a wide range of β-lactam antibiotics containing ester and amide bonds, such as penicillin, cephalosporins, monobactams, and carbapenems ( Diene et al, 2023 ). To date, approximately 300 different β-lactamases have been identified.…”

Four chromosomally clustered class-C β-lactamases (blaAmpH1/2/3/4) control the cephalosporin hydrolysis inMycobacterium tuberculosisand similar genetic loci appeared as pseudogenes inMycobacterium leprae

“…Such PBPs have 25-30% homologies with other bacterial penicillin-binding proteins like E. coli. E. coli possesses three class-A PBPs (PBP1a=OSL52747, PBP1b=AJF05047 and PBP1c=AKM36075) and two class-B PBPs (PBP2/penicillin resistant protein=AAB40835 and PBP3/peptidoglycan-binding protein=CAA38861) and five Class-C E. coli PBPs (PBP4=CAA42070, PBP5=EDV83509, PBP6=EGI51157, PBP7=OAF94491 and AmpH=ANK05711) [44][45][46]. M. tuberculosis produces two class A PBPs (ponA1 and ponA2), two class B PBPs (PbpA and PbpB) and a lipoprotein sharing some motifs with the class B PBPs [41].…”