Metallo-β-Lactamase Fold Enzymes in Bacteria

Metallo-β-Lactamase Fold Enzymes in Bacteria: History

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Saïd Azza

Lucile Pinault

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.

metallo-β-lactamase (MβL) fold proteins
multifunctional enzymes
antibiotic-hydrolysing activity

1. Introduction

Initially discovered in bacteria due to their effectiveness against antibiotics with therapeutic interest in humans, β-lactamases are a group of enzymes capable of degrading several β-lactam antibiotics ^[1]^[2]. They are a typical example of the artificial naming of enzymes that have, in reality, multiple potential functions, and this nomenclature has prevented the exploration of their activities and their presence in other organisms or microorganisms. Furthermore, the nomenclature used to describe proteins of the same family may vary depending on the method adopted by researchers, thus enzymes belonging to the same family may be labelled as ribonucleases (RNases), nucleases (DNases), hydrolases, or β-lactamases, depending on the automatic protein annotation, which relies on the initial sequence hits obtained through Blast analysis. The study of the ancestry of β-lactamase motifs has shown that they exhibit some of the oldest enzymatic motifs in the world ^[3]. Once the antiquity of this type of enzyme has been recognised, the search for sequences which are unrelated to this group of β-lactamases becomes more difficult, due to their early divergence from the ancestral structure. As such, the use of more sensitive approaches (compared with classical Blast analysis) to search for distant homologous sequence, such as the reconstruction of a common ancestor sequence, as previously reported for class A β-lactamases ^[4]^[5] and using it as a query makes it possible to identify sequences that are too far away from contemporary sequences to be identified in a functional way.

2. Diversity of the Superfamily of Metallo-β-Lactamase (MβL) Fold Enzymes

Within the classification of bacterial β-lactamases, which consist of four classes: A, B, C, and D ^[6]^[7], MβL enzymes alone occupy class B which is subdivided into three subclasses (subclass B1/B2/B3) as the result of divergent evolution events. They differ from the other classes by their active site which requires bivalent metal ions (such as Zn²⁺, Fe^2+, Mg²⁺, or Ca²⁺) for their activity ^[6]^[8]^[9]^[10]. This catalytic site, characterised by a highly conserved motif (HxHxDH) and residues (H196 and H263), appears to be ancestrally shared by the superfamily of MβL fold proteins (with 34,000 proteins identified to date) with diverse biological functions including β-lactamases, nucleases, ribonucleases, lactonases, glyoxalases, hydrolases, phosphodiesterases, Aryl sulfatases, Alkylsulfatases, CMP-NeuAc hydroxylases, flavoproteins, and others which are distributed across the different domains of life including bacteria, archaea, and eukaryotes ^[11]^[12]^[13]. Moreover, as reported, the multifunctionality of these MβL fold enzymes and their affinities to different substrates are supported by the protein variable region of the enzymes (rather than the conserved motif (i.e., HxHxDH) and cofactor dependencies, which are responsible for the modulation of enzymatic activity, specificity, and oligomerisation proteins ^[9]^[14]. However, the protein similarity between enzymes of this MβL fold superfamily can be less than 20% ^[12]^[15] making it very unlikely that homologous sequences of contemporary bacterial MβLs in the other microorganisms such as Archaea, Giant viruses, Asgard, Nanoarchaeota, or Candidate Phyla Radiation (CPR) will be found. As reported in the “Darwinian Grandparenting” theory, we are genetically closer to our grandparents than to our cousins ^[16]; thus, the use of inferred common ancestor sequences as queries to identify homologous bacterial MβLs from not-yet investigated microorganisms represents one of the more pertinent approaches to identifying these enzymes in any domain of life. More sensitive approaches, including reconstruction of the common ancestor sequence ^[5]^[17], searching for Hidden Markov Models (HMM) profiles ^[17]^[18], Sequence Similarity Network analysis (SSN) ^[12]^[19], and 3D structure similarity analysis, have been used to look for homologous MβL enzymes in remote sources. As expected, these approaches appear significantly more flexible than classic Blast analysis in terms of identifying homologous MβL enzymes in unsuspected organisms and/or microorganisms.

3. MβL Fold Enzymes in Bacteria: Class B β-Lactamases

3.1. Distribution and Diversity of MβL Fold Enzymes in Bacteria

In bacteria, these MβL enzymes include more than 325 variants grouped into 63 MβL types and divided into three sub-groups: subgroup B1 (e.g., NDM-1, VIM-2, and IMP-1); sub-group B2 (e.g., CphA1, CphA7, and ImiS); sub-group B3 (e.g., GOB-13, LRA-1, and CAR-1) (Figure 1), based on their differences in amino acid sequences and their catalytic sites which interact with either one or two Zn²⁺ ions ^[20]^[21]^[22]. The metallo-β-lactamase enzyme was identified for the first time in 1966, in a non-pathogenic strain of Bacillus cereus with a cephalosporinase activity which was inhibited when pre-incubated with ethylene-diamine-tetra-acetic acid (EDTA) ^[23]. Nowadays, MβL enzymes can be identified in more than 50 different bacterial species including gram-negative bacteria such as Enterobacteriaceae spp. and non-fermentative bacteria (such as, Acinetobacter spp. and Pseudomonas spp.), Elizabethkingia spp., Stenotrophomonas spp., Neisseria spp., Aeromonas spp., Shewanella spp., Myroides spp., Pedobacter spp., Empedobacter spp., Bacteroides spp., Vibrio spp., Bradyrhizobium spp., Caulobacter spp., Eristalis spp., Sphingomonas spp., Massilia spp., Burkholderia spp., Pectobacterium spp., and Gemmatimona spp.) ^[20]^[21]^[22]. Interestingly, as shown in Figure 1, while all the bacterial B1 and B2 MβL enzymes group together separately to the other domains of life, the GOB type enzymes (sub-group B3), are strongly related with enzymes from archaea and archaea-related microorganisms (i.e., Asgard), suggestive of their origin from this domain of life, and a horizontal transfer has occurred from archaea to a single bacterial group, namely, the Flavobacteriacaea family, especially in Elizabethkingia species. All the bacterial MβLs presented in this phylogenetic tree have been reported with proof of hydrolase activity on β-lactams, especially on carbapenems, and are all described in gram-negative bacteria except one MβL type i.e., BcII MβL enzyme (with seven variants), reported in a single bacterial gram-positive species, Bacillus cereus ^[20]^[24]. However, based on the MβL signature, these proteins have also been identified in other Gram-positive bacteria such as Streptococcus pneumoniae, in which MβL fold proteins are recognised as choline-binding proteins, DNA uptake-related proteins (nucleases) and L-ascorbate 6-phosphate lactonase ^[25]^[26]^[27]. Interestingly, it has been reported that the enzymatic characterisation of the L-ascorbate 6-phosphate lactonase enzyme from S. pneumoniae ATCC 49136 shows a β-lactamase activity since the purified enzyme is able to hydrolyse both nitrocefin and ampicillin-based antibiotics ^[26].

Figure 1. Phylogenetic tree of MβL fold enzymes from the different domains of life, including Bacteria, Archaea, Asgard, Nanoarchaeota, Giant viruses, Candidate Phyla Radiation, and Humans.

3.2. Reported Activities of Bacterial MβL Enzymes Other Than β-Lactams Hydrolysis

Besides their hydrolytic activities on β-lactam antibiotics, some bacterial MβL enzymes have been reported with other enzymatic activities as a result of the striking similarity between their protein structures and other enzymes including ribonuclease, nuclease, and lactonase enzymes. Indeed, as reported recently, the classical bacterial MβL IMP-1 enzyme, which hydrolyses all β-lactams including carbapenems, exhibits significant protein structure similarity with tRNase Z, a tRNA 3′ processing endoribonuclease of the MβL superfamily from Thermotoga maritima. Its enzymatic characterisation demonstrates a significant RNA-hydrolysing activity on both cellular RNA and synthetic small unstructured RNAs ^[28]. Interestingly, while this study was being published, the researchers' research was beginning to reveal the ribonuclease and nuclease ability of the IMP-1 homologous enzyme i.e., class B NDM-1, described in almost all gram-negative bacteria, which significantly hydrolyses in vitro bacterial RNA and single-strand DNA substrates (Supplementary Figure S1). Moreover, while both bacterial MβL enzymes mentioned above can interact with RNA and/or DNA, others such as the ThnS enzyme can exhibit additional activities, such as the hydrolysis of ascorbic acid, as a result of its similarity with UlaG enzymes ^[29]. Indeed, as the researchers reported recently, while the thnS gene, part of the thienamycin (now chemically modified into imipenem in human medicine) biosynthesis gene cluster from Streptomyces cattleya, is annotated as putative β-lactamase with no reported proof of this activity. The researchers demonstrated its specific hydrolase activity and UlaG high affinity with imipenem in comparison with the other β-lactams (e.g., penicillin G and cefotaxime). As a result of the phylogenetic tree and conserved motif analyses, the ThnS enzyme appears to be a member of the superfamily of MβL fold enzymes, showing additional activities of ribonuclease, nuclease, and hydrolysis of ascorbic acid ^[29].

Recently, an MβL fold enzyme (BLEG-1) has been reported in the Bacillus lehensis G1 strain, exhibiting significant sequence similarity and activity with the B3 subclass of bacterial MβLs, despite its evolutionary divergence from them ^[30]^[31] (Table 1). Upon analysing the phylogenetic tree and comparing the protein structures, it was discovered that the enzyme possessed an active site that was remarkably similar to those found in both the L1 B3 MβL from Stenotrophomonas maltophilia and the glyoxalase II enzymes (YcbL and GloB) from Salmonella enterica. Interestingly, the enzymatic characterisation of the purified BLEG-1 protein demonstrates its dual β-lactams hydrolysis (e.g., ampicillin hydrolysis) and glyoxalase activities ^[30]. The authors identify an insertion of two amino acids into the active-site loop at the N-terminal region of the BLEG-1 protein and suggested an evolution of the BLEG-1 enzyme from glyoxalase II to the adopted MβL fold activity through this insertion of amino acids ^[30].

Table 1. β-lactamase fold enzymes with reported enzymatic activity from the different domains of life.

Kingdom	Acc. Number	Species	Gene Name	Size (aa)	Default Annotation	Reported Activities	References
Bacteria	AGM20433	Enterobacter cloacae	IMP-1	247	Imipenem hydrolysing β-lactamase	β-lactamase; Ribonuclease	^[28]
	AEW99090	Streptomyces cattleya	ThnS	330	Putative β-lactamase	Imipenemase; Ascorbic acid degradation; Nuclease; Ribonuclease	^[29]
	HQ328085	Klebsiella pneumoniae	NDM-1	270	New Delhi metallo-β-lactamase	β-lactamase; Ribonuclease	In this study
	NA	Streptococcus pneumoniae	-	363	L-ascorbate 6-phosphate lactonase	β-lactamase	^[26]
	P39300.2	Escherichia coli	UlaG	354	L-ascorbate-6-phosphate lactonase	β-lactamase; Ribonuclease	^[27]
	WP_010974862	Agrobacterium tumefaciens	AiiB	276	Zn-dependent hydrolases	Quorum-quenching lactonase	^[32]
	PDB: 7EV5_A	Bacillus lehensis	BLEG-1	210	β-lactamase domain containing protein	β-lactamase; Glyoxalase II	^[30]
	NA	Soil metagenome	MβLp01	312	Metallo-β-lactamase fold protein	β-lactamase; Phytase	^[33]
	NA	Soil metagenome	MβLP02	355	Metallo-β-lactamase fold protein	β-lactamase; Phytase	^[33]
	PDB: 7BZ4_B	Deep-seep sediments metagenome	PNGM-1	372	Metallo-β-lactamase	β-lactamase; Ribonuclease	^[34]
	WP_063100708	Escherichia coli	YjcS	661	Uncharacterised protein	Alkyl sulfatase	^[35]
Archaea	ELY35639	Haloferax volcanii	HVO_2763	278	Zn-dependent hydrolases of the β-lactamase fold	Membrane transport; Static and dynamic osmo-response	^[36]
	851225341	Methanosarcina barkeri	MetbaB	214	MβL fold metallo-hydrolase	β-lactamase; Ribonuclease; and D-lactate hydrolase	^[37]
	15623131	Sulfolobus tokodaii	-	200	Putative hydrolase	Quorum sensing activity	^[38]
	AAM30391	Methanosarcina mazei	-	638	Metal-dependent RNase, contains metallo-β-lactamase and KH domains	Cleavage and Polyadenylation of mRNA	^[39]
	BAD70075	Thermus thermophilus	TTHA0252		Metallo-β-lactamase superfamily	Ribonuclease (RNase)	^[40]
	NA	Methanocaldococcus jannaschii	MjRNase J1		Ribonuclease Rnase J	Ribonuclease (RNase)	^[41]
	NA	Methanocaldococcus jannaschii	MjRNase J2		Ribonuclease Rnase J	Ribonuclease (RNase); Nuclease
	NA	Methanocaldococcus jannaschii	MjRNase J3		Ribonuclease Rnase J	Ribonuclease (RNase); Nuclease
Human	NP_981951	Homo sapiens	MβLAC2	280	Metallo-β-lactamase domain	Exosome biogenesis enzyme; β-lactamase	^[42]^[43]
	Q6PJP8	Homo sapiens	SNM1A	365	DNA cross-link repair 1A	Cisplatin or Mitomycin hydrolase; β-lactamase	^[43]^[44]
	Q9H816	Homo sapiens	SNM1B	335	5′ exonuclease Apollo isoform X1	β-lactamase	^[43]
Giant viruses	AUL78925	Tupanvirus deep ocean	TupBlac	322	β-lactamase superfamily domain	β-lactamase; Ribonuclease	^[45]
Candidate Phyla Radiation (CPR)	KKR15801	Candidatus Levybacteria	-	287	β-lactamase class A-like protein	β-lactamase; Ribonuclease	^[46]
	KKR17584	Candidatus Levybacteria	-	303	β-lactamase class A-like protein	β-lactamase; Ribonuclease
	OGK62163	Candidatus Roizmanbacteria	-	263	Hypothetical protein	β-lactamase; Ribonuclease
	OGZ64179	Candidatus Staskawiczbacteria	-	251	Hypothetical protein	β-lactamase; Ribonuclease
	QHU90009	Candidatus Saccharibacteria	-	722	RNase J family beta-CASP ribonuclease	β-lactamase; Ribonuclease

Recently, another atypical enzymatic activity of two MβL fold proteins has also been described from a functional metagenomic study of forest soil ^[33]. In this study, while the authors performed a function-based screening of libraries generated from the whole metagenomic sequence data of forest soil to identify positive phytase activity in E. coli clones, two clones were positive for this phytase activity. Surprisingly, while phytic acid degradation activity has been restricted to only four protein superfamilies, including histidine phosphatases, tyrosine phosphatases, purple acid phosphatases, and β-propeller phosphatases ^[47]^[48], the two obtained proteins (MβLp01 and MβLp02) from this metagenome were annotated and identified as genes encoding for metallo-β-lactamase proteins. Sequence analysis confirmed their membership of the MβL fold superfamily of proteins due to their close protein structure homology with the MβL ZipD from E. coli, a zinc phosphodiesterase with a tRNA-processing endonuclease activity ^[49]. Based on this discovery, the two proteins were subcloned, expressed, and enzymatically tested. As expected, the enzymatic characterisation revealed for both purified proteins an activity on the majority of tested phosphorylated substrates including phytate. Moreover, both purified enzymes were able to confer to recombinant E. coli strains less sensitivity to β-lactam antibiotics, suggestive of a β-lactamase activity, and qualified by the authors as promiscuous activity ^[33]. This promiscuous β-lactamase activity was also reported from the discovered and identified subclass B3 MβL protein, PNGM-1 from a conducted functional metagenomic analyses of deep-sea sediments predating the era of antibiotics ^[34]^[50]. Indeed, the phylogenetic and protein structure analyses of the PNGM-1 protein revealed its membership of the MβL fold superfamily and its structural similarity with the tRNA Z enzyme, and the activities test confirmed a dual enzymatic β-lactamase and ribonuclease activity of this PNGM-1 protein ^[34].

Another example of bacterial MβL fold enzymes with activities other than β-lactam hydrolase is that of lactonase enzymes. Recognised as members of the metallo-β-lactamase superfamily as a result of their conserved HxHxDH MβL motif ^[51]^[52], these enzymes are involved in the bacterial quorum sensing mechanism, especially by disrupting bacterial signalling via the enzymatic degradation of acyl homoserine lactone (AHL) molecules ^[13]^[52]. The quorum sensing mechanism is described as a communication system used by bacteria to manage large panels of biological processes often related to pathogenicity, such as the production of proteases, or antimicrobial compounds, such as violacein ^[53]. These enzymes have been reported in various and atypical bacterial species such as thermoacidophilic bacteria including Alicyclobacter acidoterrestris, Geobacillus caldoxylosilyticus, Chromobacterium spp., Bacillus thuringiensis, Escherichia coli, Ruegeria mobilis, Microbacterium testaceum, Muricauda olearia, Arthrobacter sp. and Chryseobacterium spp. ^[27]^[51]^[52]^[53]^[54]^[55]^[56]^[57]^[58]^[59].

This entry is adapted from the peer-reviewed paper 10.3390/cells12131752

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