Promiscuous Enzyme Activity as a Driver of Allo and Iso Convergent Evolution, Lessons from the β-Lactamases

Abstract

The probability of the evolution of a character depends on two factors: the probability of moving from one character state to another character state and the probability of the new character state fixation. The more the evolution of a character is probable, the more the convergent evolution will be witnessed, and consequently, convergent evolution could mean that the convergent character evolution results as a combination of these two factors. We investigated this phenomenon by studying the convergent evolution of biochemical functions. For the investigation we used the case of β-lactamases. β-lactamases hydrolyze β-lactams, which are antimicrobials able to block the DD-peptidases involved in bacterial cell wall synthesis. β-lactamase activity is present in two different superfamilies: the metallo-β-lactamase and the serine β-lactamase. The mechanism used to hydrolyze the β-lactam is different for the two superfamilies. We named this kind of evolution an allo-convergent evolution. We further showed that the β-lactamase activity evolved several times within each superfamily, a convergent evolution type that we named iso-convergent evolution. Both types of convergent evolution can be explained by the two evolutionary mechanisms discussed above. The probability of moving from one state to another is explained by the promiscuous β-lactamase activity present in the ancestral sequences of each superfamily, while the probability of fixation is explained in part by positive selection, as the organisms having β-lactamase activity allows them to resist organisms that secrete β-lactams. Indeed, an organism that has a mutation that increases the β-lactamase activity will be selected, as the organisms having this activity will have an advantage over the others.

Could β-Lactam Antibiotics Block Humoral Immunity?

“…Thus a landscape of cross enzymatic activities among MBLs enzyme superfamily was reported (31,77,(80)(81)(82)(83). Therefore, MBLs' cross enzymatic activities (hydrolase and nuclease) among different domains of the living were identified, whereas different enzymatic activities observed may be related to divergent host substrates (17). The interspecies common enzymatic activities can be explained by the highly conserved MBLs catalytic site (Figure 4) (81,84,85).…”

“…First of all, it works by inhibiting the bacterial peptidoglycan cell wall synthesis (16). b-lactamases enzymes hydrolyse the b-lactam antibiotics and may also have different nuclease and hydrolases activities (17)(18)(19)(20)(21)(22)(23)(24). Two mechanistically distincts superfamilies of b-lactamases with two distincts ancestors are described, the nucleophilic serine b-lactamases (class A/C/D); and the zinc ion dependent metallo-b-lactamases (class B) (17,(25)(26)(27).…”

Dual RNase and β-lactamase Activity of a Single Enzyme Encoded in Archaea

“…Finally, the existence of enzymes in the world of archaea with multiple activities such as β-lactamase, ribonuclease, and glyoxalase II shows that β-lactamase enzymes are not only a defense system against β-lactam antibiotics. These multiple activities appear as promiscuous activities of these MBL fold enzymes, as suggested in the literature through sequence similarity network analysis [25,27]. Moreover, very recently, RNA-hydrolysis activity of bacterial class B metallo-β-lactamase IMP-1 has been reported experimentally [28].…”

PBP-A, a cyanobacterial DD-peptidase with high specificity for amidated muropeptides, exhibits pH-dependent promiscuous activity harmful to Escherichia coli

“…Since the PG and its biosynthetic enzymes are probably more ancient than the inhibitory penicillins which are themselves probably more ancient than their inactivating enzymes, it is generally accepted that serine b-lactamases evolved from ancestral PBPs. This evolutionary relationship is supported by a conserved acylation mechanism by β-lactams and, despite a barely detectable sequence similarity, a conserved structural fold (Medeiros 1997;Hall and Barlow 2004;Keshri et al 2020;Fröhlich et al 2021). To date, the highest (~ 30%) sequence identity is found between a family of cyanobacterial low molecular weight PBPs and class A SBLs (Urbach et al 2008;Fröhlich et al 2021).…”