Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

Morrissey, James H.; Choi, Sharon H.; Smith, Stephanie A.

doi:10.1182/blood-2012-03-306605

Cited by 324 publications

(303 citation statements)

References 108 publications

(99 reference statements)

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“…Artificial surfaces that are used in catheters or cardiopulmonary bypass will also lead to activation of the contact system and, over recent years, more and more physiological surfaces have been identified, such as RNA, polyphosphates, neutrophil extracellular traps, and misfolded proteins. [6][7][8][9][10] Factor XII binds directly to these surfaces. HK also binds directly and, because it is in the circulation in complex with PK and factor XI, the complete contact system becomes assembled on the surface.…”

Section: Biochemistry Of the Contact Systemmentioning

confidence: 99%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecularweight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy. Learning Objectives• To understand that the contact system consists of 4 proteins: factor XI, factor XII, PK, and HK • To understand that deficiency of factor XII, PK, or HK is not associated with a bleeding tendency in humans • To understand that targeting the contact system is an effective method to prevent thrombosis in mice •

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Section: Biochemistry Of the Contact Systemmentioning

confidence: 99%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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“…Besides these common roles, many specific functions have been attributed to polyP in eukaryotes (see reviews in refs. [9][10][11]. Recently its ability to function as a protein-folding chaperone (12) and to drive a newly discovered posttranslational protein modification, protein polyphosphorylation (13), have provided further insight into the mechanism of action of this simple polymer.…”

mentioning

confidence: 99%

Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum

Livermore

Chubb

Saiardi

2016

Proc. Natl. Acad. Sci. U.S.A.

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Inorganic polyphosphate (polyP) is composed of linear chains of phosphate groups linked by high-energy phosphoanhydride bonds. However, this simple, ubiquitous molecule remains poorly understood. The use of nonstandardized analytical methods has contributed to this lack of clarity. By using improved polyacrylamide gel electrophoresis we were able to visualize polyP extracted from Dictyostelium discoideum. We established that polyP is undetectable in cells lacking the polyphosphate kinase (DdPpk1). Generation of this ppk1 null strain revealed that polyP is important for the general fitness of the amoebae with the mutant strain displaying a substantial growth defect. We discovered an unprecedented accumulation of polyP during the developmental program, with polyP increasing more than 100-fold. The failure of ppk1 spores to accumulate polyP results in a germination defect. These phenotypes are underpinned by the ability of polyP to regulate basic energetic metabolism, demonstrated by a 2.5-fold decrease in the level of ATP in vegetative ppk1. Finally, the lack of polyP during the development of ppk1 mutant cells is partially offset by an increase of both ATP and inositol pyrophosphates, evidence for a model in which there is a functional interplay between inositol pyrophosphates, ATP, and polyP.inorganic polyphosphate | phosphate | metabolism | inositol pyrophosphate | mitochondria T he simplest biological polymer is inorganic polyphosphate (polyP), which consists of a linear chain of phosphates linked by high-energy phosphoanhydride bonds (1). Regardless of its origin, polyP is ubiquitously present in today's living organisms. The synthesis, enzymology, and role of polyP are best characterized in the bacteria Escherichia coli (2). However, polyP is also present in archaea (3), eukaryotes (4), and human cells (5). Whilst polyP is present in virtually all cellular compartments (6), it accumulates in acidocalcisomes, organelles common to bacteria and mammalian cells (7).PolyP has been implicated in a range of cellular processes over recent years, but its most basic proposed function is to act as a buffer for the level of free phosphate (8). Phosphate buffering is essential for general metabolism, and the synthesis or degradation of polyP is able to safeguard the level of free phosphate in cells. In addition, the polyanionic nature of polyP makes it a strong chelator of bivalent cations; thus polyP plays a key role in cation homeostasis. The chelation of calcium by polyP might even play a role as a calcium sink, regulating calcium signaling (8). Besides these common roles, many specific functions have been attributed to polyP in eukaryotes (see reviews in refs. 9-11). Recently its ability to function as a protein-folding chaperone (12) and to drive a newly discovered posttranslational protein modification, protein polyphosphorylation (13), have provided further insight into the mechanism of action of this simple polymer.Little is known about the synthesis or metabolism of polyP in eukaryotes. The yeast Saccharomyces c...

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“…The recent discoveries that polyP can be released from some mammalian cells, such as blood platelets (3) and mast cells (4), and has potent modulatory activity on blood coagulation (5) and inflammation (6) have renewed interest in this polymer. Interestingly, polyP with chain lengths characteristic of microorganisms modulates coagulation and inflammation differently than polyP with chain lengths typically found in mammalian cells (7).…”

mentioning

confidence: 99%

Trypanosoma brucei Vacuolar Transporter Chaperone 4 (TbVtc4) Is an Acidocalcisome Polyphosphate Kinase Required for in Vivo Infection

Lander

Ulrich²,

Docampo

2013

Journal of Biological Chemistry

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Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

Cited by 324 publications

References 108 publications

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum

Trypanosoma brucei Vacuolar Transporter Chaperone 4 (TbVtc4) Is an Acidocalcisome Polyphosphate Kinase Required for in Vivo Infection

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