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.
Highlights
Molybdenum and tungsten are redox-active transition metals and, when incorporated into enzymes, are able to mediate a variety of reactions including the oxidation of substrates using oxygen from water (Murray et al, 1966; Hille, 2005; Schwarz et al, 2009; Hille et al, 2014; Hagen, 2017)
Mo/W enzymes are evolutionarily old and likely already existed in the last universal common ancestor (Lebrun et al, 2003; Zhang and Gladyshev, 2008; Schoepp-Cothenet et al, 2012; Nitschke and Russell, 2013; Mayr et al, 2020; Wells et al, 2020). They are found in all domains of life and are abundant in bacteria, where more than 50 distinct types of enzymes have been identified (Leimkühler and Iobbi-Nivol, 2016; Maia et al, 2017), and physiological functions range from sulfur compound oxidation, degradation of aromatic compounds to supporting anaerobic respiration in bacteria (Hille et al, 2014; Maia et al, 2017)
Mo-PPT biosynthesis enzymes have been shown to be crucial for virulence in several pathogenic bacteria, including E. coli and Mycobacterium tuberculosis (Mtb) (Table 1) (MacGurn and Cox, 2007; Rosas-Magallanes et al, 2007; Brodin et al, 2010; Dutta et al, 2010; Winter et al, 2013b; Williams et al, 2014, 2015; Hughes et al, 2017; Levillain et al, 2017)
Summary
Molybdenum and tungsten are redox-active transition metals and, when incorporated into enzymes, are able to mediate a variety of reactions including the oxidation of substrates using oxygen from water (Murray et al, 1966; Hille, 2005; Schwarz et al, 2009; Hille et al, 2014; Hagen, 2017). Mo-PPT biosynthesis enzymes have been shown to be crucial for virulence in several pathogenic bacteria, including E. coli and Mtb (Table 1) (MacGurn and Cox, 2007; Rosas-Magallanes et al, 2007; Brodin et al, 2010; Dutta et al, 2010; Winter et al, 2013b; Williams et al, 2014, 2015; Hughes et al, 2017; Levillain et al, 2017).
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