Metabolism and Function of Polyphosphates in Bacteria and Yeast

Kulaev, I. S.; Kulakovskaya, T. V.; Андреева, Н. И.; Lichko, L. P.

doi:10.1007/978-3-642-58444-2_3

Cited by 21 publications

(18 citation statements)

References 55 publications

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“…PolyP has been widely described in unicellular organisms such as bacteria, fungi, algae, and protozoa, where it plays diverse physiologic roles, including regulating growth, stress responses, and virulence. 1,7 Comparatively less is known about the metabolism or physiologic roles of polyP in mammalian cells, 8 although polyP is reported to induce apoptosis in plasma cells, 9 promote calcification in osteoblasts, 10 block metastasis of melanoma cells in a mouse model, 11 and possibly serve as a regulatory factor in proliferative signaling pathways. 12 PolyP is present at high concentrations in dense granules of human platelets and is secreted upon platelet activation.…”

Section: Introductionmentioning

confidence: 99%

Polyphosphate exerts differential effects on blood clotting, depending on polymer size

Smith¹,

Choi²,

Davis-Harrison³

et al. 2010

Blood

266

423

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Polyphosphate, a linear polymer of inorganic phosphate, is secreted by activated platelets and accumulates in many infectious microorganisms. We recently showed that polyphosphate modulates the blood coagulation cascade at 3 steps: it triggers the contact pathway, it accelerates factor V activation, and it enhances fibrin polymerization. We now report that polyphosphate exerts differential effects on blood clotting, depending on polymer length. Very long polymers (> 500mers, such as those present in microorganisms) were required for optimal activation of the contact pathway, while shorter polymers (ϳ 100mers, similar to the polymer lengths released by platelets) were sufficient to accelerate factor V activation and abrogate the anticoagulant function of the tissue factor pathway inhibitor. Optimal enhancement of fibrin clot turbidity by polyphosphate required > 250mers. Pyrophosphate, which is also secreted by activated platelets, potently blocked polyphosphate-mediated enhancement of fibrin clot structure, suggesting that pyrophosphate is a novel regulator of fibrin function. In conclusion, polyphosphate of the size secreted by platelets is very efficient at accelerating blood clotting reactions but is less efficient at initiating them or at modulating clot structure. Microbial polyphosphate, which is highly procoagulant, may function in host responses to pathogens. IntroductionPolyphosphate (polyP)-a linear polymer of inorganic phosphateaccumulates in a variety of microorganisms 1 and is secreted by activated human platelets. 2,3 We recently showed that polyP is a potent modulator of the human blood-clotting system. [3][4][5][6] The polymer lengths of polyP are known to vary substantially among different organisms and cell types, with relatively short polymers being secreted by human platelets (ϳ 60-100 phosphate units long) 2,3 and very long polymers accumulating in microorganisms (many hundreds to more than 1000 phosphate units long). 1 In this study, we demonstrate that shorter versus longer polymers of polyP have differential effects on the blood clotting system, with important physiologic/pathophysiologic implications. PolyP has been widely described in unicellular organisms such as bacteria, fungi, algae, and protozoa, where it plays diverse physiologic roles, including regulating growth, stress responses, and virulence. 1,7 Comparatively less is known about the metabolism or physiologic roles of polyP in mammalian cells, 8 although polyP is reported to induce apoptosis in plasma cells, 9 promote calcification in osteoblasts, 10 block metastasis of melanoma cells in a mouse model, 11 and possibly serve as a regulatory factor in proliferative signaling pathways. 12 PolyP is present at high concentrations in dense granules of human platelets and is secreted upon platelet activation. 2,3 PolyP has a half-life in plasma of approximately 90 minutes, because of degradation by phosphatases. 4,13 We recently showed that polyP is a potent hemostatic regulator, acting at 3 points in the blood clotting cascade: it...

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Section: Introductionmentioning

confidence: 99%

Polyphosphate exerts differential effects on blood clotting, depending on polymer size

Smith¹,

Choi²,

Davis-Harrison³

et al. 2010

Blood

266

423

View full text Add to dashboard Cite

show abstract

“…In such organisms, polyP plays essential roles in stress responses and virulence. 12 Although polyP has been studied less extensively in mammalian cells, 13 it has been reported to induce apoptosis in plasma cells, 14 promote calcification in osteoblasts, 15 and block metastasis of melanoma cells in a mouse model. 16 It has also been proposed to serve as a regulatory factor in proliferative signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Polyphosphate enhances fibrin clot structure

Smith

Morrissey

2008

Blood

192

185

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Polyphosphate, a linear polymer of inorganic phosphate, is present in platelet dense granules and is secreted on platelet activation. We recently reported that polyphosphate is a potent hemostatic regulator, serving to activate the contact pathway of blood clotting and accelerate factor V activation. Because polyphosphate did not alter thrombin clotting times, it appeared to exert all its procoagulant actions upstream of thrombin. We now report that polyphosphate enhances fibrin clot structure in a calciumdependent manner. Fibrin clots formed in the presence of polyphosphate had up to 3-fold higher turbidity, had higher masslength ratios, and exhibited thicker fibers in scanning electron micrographs. The ability of polyphosphate to enhance fibrin clot turbidity was independent of factor XIIIa activity. When plasmin or a combination of plasminogen and tissue plasminogen activators were included in clotting reactions, fibrin clots formed in the presence of polyphosphate exhibited prolonged clot lysis times. Release of polyphosphate from activated platelets or infectious microorganisms may play an important role in modulating fibrin clot structure and increasing its resistance to fibrinolysis. Polyphosphate may also be useful in enhancing the structure of surgical fibrin sealants. (Blood. 2008;112: 2810-2816) IntroductionA fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel. Factor XIIIa, a transglutaminase activated by thrombin, covalently crosslinks these fibers to increase the strength and elasticity of the resulting clot. 1 Variables known to influence fibrin clot structure include fibrinogen and thrombin concentrations, 1 pH, 2,3 ionic strength, 3 chloride ion concentration, 2 and presence of calcium ions. 4 A variety of molecules are reported to affect fibrin clot structure, including homocysteine, 5 decorin core protein, 6 heparins, 7,8 dextran, 9 and hydroxyethylstarch. 10 In this study, we demonstrate that inorganic polyphosphate (polyP) strongly modulates fibrin clot structure.polyP is a negatively charged, linear polymer of phosphate units linked by high-energy phosphoanhydride bonds. polyP has a wide biologic distribution, 11 but its functions have been studied most extensively in prokaryotes and unicellular eukaryotes, in which high levels of polyP accumulate in organelles known as acidocalcisomes. In such organisms, polyP plays essential roles in stress responses and virulence. 12 Although polyP has been studied less extensively in mammalian cells, 13 it has been reported to induce apoptosis in plasma cells, 14 promote calcification in osteoblasts, 15 and block metastasis of melanoma cells in a mouse model. 16 It has also been proposed to serve as a regulatory factor in proliferative signaling pathways. 17 Dense granules of human...

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“…Based on its chemical composition, rich in PP i and polyP (a linear polymer of hundreds of orthophosphate residues linked by high energy phosphoanhydride bonds), one possible function could be as an energy and phosphate reservoir. PolyP has been shown to have a function in the cellular response to nutrient limitation during the stationary phase of growth and in the chelation of metals (17)(18)(19). A critical role for the acidocalcisomal polyP in the adaptation processes of Trypanosoma cruzi to environmental changes has been demonstrated (20).…”

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confidence: 99%

Characterization of Isolated Acidocalcisomes from Toxoplasma gondii Tachyzoites Reveals a Novel Pool of Hydrolyzable Polyphosphate

Rodrigues¹,

Ruiz²,

Rohloff

et al. 2002

Journal of Biological Chemistry

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Toxoplasma gondii tachyzoites were fractionated by modification of an iodixanol density gradient method previously used for acidocalcisome isolation from Trypanosoma cruzi epimastigotes. Fractions were characterized using electron microscopy, x-ray microanalysis, and enzymatic markers, and it was demonstrated that the heaviest (pellet) fraction contains electron-dense vacuoles rich in phosphorus, calcium, and magnesium, as found before for acidocalcisomes. Staining with 4,6-diamidino-2-phenylindole (DAPI) indicated that polyphosphate (polyP) was preferentially localized in this fraction together with pyrophosphate (PP i ). Using an enzyme-based method, millimolar levels (in terms of P i residues) of polyP chains of less than 50 residues long and micromolar levels in polyP chains of about 700 -800 residues long were found to be preferentially localized in this fraction. The fraction also contained the pyrophosphatase and polyphosphatase activities characteristic of acidocalcisomes. Western blot analysis using antibodies against proteins from micronemes, dense granules, rhoptries, and plasma membrane showed that the acidocalcisomal fraction was not contaminated by these other organelles. T. gondii polyP levels rapidly decreased upon exposure of the parasites to a calcium ionophore (ionomycin), to an inhibitor of the V-H ؉ -ATPase (bafilomycin A 1 ), or to the alkalinizing agent NH 4 Cl. These changes were in parallel to an increase in intracellular Ca 2؉ concentration, suggesting a close association between polyP hydrolysis and Ca 2؉ release from the acidocalcisome. These results provide a useful method for the isolation and characterization of acidocalcisomes, showing that they are distinct from other previously recognized organelles present in T. gondii, and provide evidence for the role of polyP metabolism in response to cellular stress.

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Metabolism and Function of Polyphosphates in Bacteria and Yeast

Cited by 21 publications

References 55 publications

Polyphosphate exerts differential effects on blood clotting, depending on polymer size

Polyphosphate exerts differential effects on blood clotting, depending on polymer size

Polyphosphate enhances fibrin clot structure

Characterization of Isolated Acidocalcisomes from Toxoplasma gondii Tachyzoites Reveals a Novel Pool of Hydrolyzable Polyphosphate

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