Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

Abstract

Mononuclear molybdoenzymes are highly versatile catalysts that occur in organisms in all domains of life, where they mediate essential cellular functions such as energy generation and detoxification reactions. Molybdoenzymes are particularly abundant in bacteria, where over 50 distinct types of enzymes have been identified to date. In bacterial pathogens, all aspects of molybdoenzyme biology such as molybdate uptake, cofactor biosynthesis, and function of the enzymes themselves, have been shown to affect fitness in the host as well as virulence. Although current studies are mostly focused on a few key pathogens such as Escherichia coli, Salmonella enterica, Campylobacter jejuni, and Mycobacterium tuberculosis, some common themes for the function and adaptation of the molybdoenzymes to pathogen environmental niches are emerging. Firstly, for many of these enzymes, their role is in supporting bacterial energy generation; and the corresponding pathogen fitness and virulence defects appear to arise from a suboptimally poised metabolic network. Secondly, all substrates converted by virulence-relevant bacterial Mo enzymes belong to classes known to be generated in the host either during inflammation or as part of the host signaling network, with some enzyme groups showing adaptation to the increased conversion of such substrates. Lastly, a specific adaptation to bacterial in-host survival is an emerging link between the regulation of molybdoenzyme expression in bacterial pathogens and the presence of immune system-generated reactive oxygen species. The prevalence of molybdoenzymes in key bacterial pathogens including ESKAPE pathogens, paired with the mounting evidence of their central roles in bacterial fitness during infection, suggest that they could be important future drug targets.

The DmsABC Sulfoxide Reductase Supports Virulence in Non-typeable Haemophilus influenzae

“…One of the most common types of biomolecular damage caused by oxidative stress is the oxidation of sulfur compounds including amino acids. Both cysteine and methionine are highly susceptible to oxidative damage, and there is increasing evidence that both thiol-based and molybdenum-containing methionine sulfoxide reductases protect bacterial pathogens from hostinduced oxidative stress and thus support bacterial virulence (Ezraty et al, 2005(Ezraty et al, , 2017Denkel et al, 2013;Nasreen et al, 2020;Zhong et al, 2020).…”

Bis‐molybdopterin guanine dinucleotide modulates hemolysin expression under anaerobiosis and contributes to fitness in vivo in uropathogenic Escherichia coli

“…Indeed, previous reports indicate that energy generation defects are one of the two major physiological impacts caused by dysfunctional DMSOR molybdoenzymes (Zhong et al, 2020). Our RNA-seq analysis identified that GlnA, an indicator of nitrogen availability, was upregulated in the mobA mutant (Table S1), suggesting nitrogen limitation.…”

“…Defects in bis-MGD biosynthesis extensively impact the transcriptome and UPEC fitness in vivo. Given that DMSOR occurs only in prokaryotes (e.g., dissimilatory nitrate reductase and formate dehydrogenase; Zhong et al, 2020), our study has provided potential drug targets for treating UPEC infections.…”

Evolutionary barriers to horizontal gene transfer in macrophage associated Salmonella

“…Substantial dependency of fitness effects of genes on environmental niches has been well documented in studies of antibiotic resistance genes and metabolic enzymes (Zhong et al, 2020, Melnyk et al, 2015). There are three possible outcomes for how the environment shapes the DFEs of newly transferred genes.…”