Abstract
Inorganic polyphosphate (polyP) has been implicated in an astonishing array of biological functions, ranging from phosphorus storage to molecular chaperone activity to bacterial virulence. In bacteria, polyP is synthesized by polyphosphate kinase (PPK) enzymes, which are broadly subdivided into two families: PPK1 and PPK2. While both enzyme families are capable of catalyzing polyP synthesis, PPK1s preferentially synthesize polyP from nucleoside triphosphates, and PPK2s preferentially consume polyP to phosphorylate nucleoside mono- or diphosphates. Importantly, many pathogenic bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii encode at least one of each PPK1 and PPK2, suggesting these enzymes may be attractive targets for antibacterial drugs. Although the majority of bacterial polyP studies to date have focused on PPK1s, PPK2 enzymes have also begun to emerge as important regulators of bacterial physiology and downstream virulence. In this review, we specifically examine the contributions of PPK2s to bacterial polyP homeostasis. Beginning with a survey of the structures and functions of biochemically characterized PPK2s, we summarize the roles of PPK2s in the bacterial cell, with a particular emphasis on virulence phenotypes. Furthermore, we outline recent progress on developing drugs that inhibit PPK2 enzymes and discuss this strategy as a novel means of combatting bacterial infections.
Highlights
Inorganic Polyphosphate and Polyphosphate Kinase 1 (PPK1)Inorganic polyphosphate is an ancient and evolutionarily conserved biopolymer consisting of phosphate monomers linked together via high-energy phosphoanhydride bonds
Insoluble phosphate-containing granules—what we know to be polyP—have been documented in bacteria since the late 1800s [2]. The source of this mysterious phosphate polymer remained unclear until Arthur Kornberg and colleagues isolated an enzyme from Escherichia coli that could synthesize polyP, which they termed polyphosphate kinase (PPK; later disambiguated as PPK1) [3]. It was not until 1990 that E. coli PPK1 was purified to homogeneity [4], which allowed for the identification and cloning of the ppk1 gene, followed by overexpression and deletion studies [5,6,7]
We showed that relative to the P. aeruginosa ∆ppk1 strain, the ∆polyP strain was further attenuated in pyoverdine production, implicating PPK2 enzymes in pyoverdine virulence
Summary
Inorganic polyphosphate (polyP) is an ancient and evolutionarily conserved biopolymer consisting of phosphate monomers linked together via high-energy phosphoanhydride bonds. The source of this mysterious phosphate polymer remained unclear until Arthur Kornberg and colleagues isolated an enzyme from Escherichia coli that could synthesize polyP, which they termed polyphosphate kinase (PPK; later disambiguated as PPK1) [3]. It was not until 1990 that E. coli PPK1 was purified to homogeneity [4], which allowed for the identification and cloning of the ppk gene, followed by overexpression and deletion studies [5,6,7]. Several recent studies have demonstrated thatdemonstrated bacterial polyP canbacterial modulate the can modulate the mammalian immune response [30,31], suggesting an intriguing potenmammalian immune response [30,31], suggesting an intriguing potential for host–pathogen tial forcrosstalk host–pathogen crosstalk during polyP infection [32]. during infection [32]
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