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Trends in Biochemical Sciences Nov 2022Triterpenes are C30 organic compounds abundantly found in all living organisms. Although previously believed to be exclusively produced from squalene or oxidosqualene, a...
Triterpenes are C30 organic compounds abundantly found in all living organisms. Although previously believed to be exclusively produced from squalene or oxidosqualene, a recent report by Tao and colleagues describes a new triterpene biosynthetic route involving the cyclization of the precursor hexaprenyl diphosphate (HexPP) by unprecedented bifunctional terpene synthase (TS) enzymes.
Topics: Cyclization; Diphosphates; Squalene; Triterpenes
PubMed: 35914998
DOI: 10.1016/j.tibs.2022.07.004 -
Muscle & Nerve Feb 2023
Topics: Diphosphates; Muscle, Skeletal; Radionuclide Imaging
PubMed: 36382940
DOI: 10.1002/mus.27754 -
Cells Jan 2022Diacylglycerol pyrophosphate (DGPP) is an anionic phospholipid formed in plants, yeast, and parasites under multiple stress stimuli. It is synthesized by the...
Diacylglycerol pyrophosphate (DGPP) is an anionic phospholipid formed in plants, yeast, and parasites under multiple stress stimuli. It is synthesized by the phosphorylation action of phosphatidic acid (PA) kinase on phosphatidic acid, a signaling lipid with multifunctional properties. PA functions in the membrane through the interaction of its negatively charged phosphomonoester headgroup with positively charged proteins and ions. DGPP, like PA, can interact electrostatically via the electrostatic-hydrogen bond switch mechanism but differs from PA in its overall charge and shape. The formation of DGPP from PA alters the physicochemical properties as well as the structural dynamics of the membrane. This potentially impacts the molecular and ionic binding of cationic proteins and ions with the DGPP enriched membrane. However, the results of these important interactions in the stress response and in DGPP's overall intracellular function is unknown. Here, using P MAS NMR, we analyze the effect of the interaction of low DGPP concentrations in model membranes with the peptides KALP23 and WALP23, which are flanked by positively charged Lysine and neutral Tryptophan residues, respectively. Our results show a significant effect of KALP23 on the charge of DGPP as compared to WALP23. There was, however, no significant effect on the charge of the phosphomonoester of DGPP due to the interaction with positively charged lipids, dioleoyl trimethylammonium propane (DOTAP) and dioleoyl ethyl-phosphatidylcholine (EtPC). Divalent calcium and magnesium cations induce deprotonation of the DGPP headgroup but showed no noticeable differences on DGPP's charge. Our results lead to a novel model for DGPP-protein interaction.
Topics: Cations, Divalent; Diphosphates; Glycerol; Lysine; Magnetic Resonance Spectroscopy; Models, Molecular; Peptides; Phosphatidylcholines; Proteins; Static Electricity
PubMed: 35053406
DOI: 10.3390/cells11020290 -
PLoS Pathogens May 2021Bacteria inhabit diverse environmental niches and consequently must modulate their metabolism to adapt to stress. The nucleotide second messengers guanosine... (Review)
Review
Bacteria inhabit diverse environmental niches and consequently must modulate their metabolism to adapt to stress. The nucleotide second messengers guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) (collectively referred to as (p)ppGpp) are essential for survival during nutrient starvation. (p)ppGpp is synthesized by the RelA-SpoT homologue (RSH) protein family and coordinates the control of cellular metabolism through its combined effect on over 50 proteins. While the role of (p)ppGpp has largely been associated with nutrient limitation, recent studies have shown that (p)ppGpp and related nucleotides have a previously underappreciated effect on different aspects of bacterial physiology, such as maintaining cellular homeostasis and regulating bacterial interactions with a host, other bacteria, or phages. (p)ppGpp produced by pathogenic bacteria facilitates the evasion of host defenses such as reactive nitrogen intermediates, acidic pH, and the complement system. Additionally, (p)ppGpp and pyrophosphorylated derivatives of canonical adenosine nucleotides called (p)ppApp are emerging as effectors of bacterial toxin proteins. Here, we review the RSH protein family with a focus on its unconventional roles during host infection and bacterial competition.
Topics: Animals; Bacteria; Bacterial Infections; Bacterial Physiological Phenomena; Bacterial Proteins; Diphosphates; Gene Expression Regulation, Bacterial; Humans; Nucleotides; Phosphorylation; Stress, Physiological
PubMed: 33984072
DOI: 10.1371/journal.ppat.1009532 -
Journal of Nuclear Cardiology :... Oct 2022
Topics: Diphosphates; Heart; Humans; Technetium; Technetium Tc 99m Pyrophosphate
PubMed: 33409892
DOI: 10.1007/s12350-020-02498-2 -
Purinergic Signalling Jun 2023Conventionally, ATP is considered to be the principal energy source in cells. However, over the last few years, a novel role for ATP as a potent extracellular signaling... (Review)
Review
Conventionally, ATP is considered to be the principal energy source in cells. However, over the last few years, a novel role for ATP as a potent extracellular signaling molecule and the principal source of extracellular pyrophosphate, the main endogenous inhibitor of vascular calcification, has emerged. A large body of evidence suggests that two principal mechanisms are involved in the initiation and progression of ectopic calcification: high phosphate concentration and pyrophosphate deficiency. Pathologic calcification of cardiovascular structures, or vascular calcification, is a feature of several genetic diseases and a common complication of chronic kidney disease, diabetes, and aging. Previous studies have shown that the loss of function of several enzymes and transporters involved in extracellular ATP/pyrophosphate metabolism is associated with vascular calcification. Therefore, pyrophosphate homeostasis should be further studied to facilitate the design of novel therapeutic approaches for ectopic calcification of cardiovascular structures, including strategies to increase pyrophosphate concentrations by targeting the ATP/pyrophosphate metabolism cycle.
Topics: Humans; Diphosphates; Vascular Calcification; Homeostasis; Adenosine Triphosphate
PubMed: 35511317
DOI: 10.1007/s11302-022-09867-1 -
Scientific Reports Apr 2022The solid-state reaction was employed to synthesize CaCuPO by varying the mole ratio between Ca and Cu. The structure and crystallography of the pyrophosphate compounds...
The solid-state reaction was employed to synthesize CaCuPO by varying the mole ratio between Ca and Cu. The structure and crystallography of the pyrophosphate compounds were identified and confirmed by using X-ray diffraction (XRD). The Rietveld refinement method and the extended X-ray absorption fine structure (EXAFS) least-squares fitting technique were also applied to refine the sample crystal structure. The single phases of the obtained CaPO, CaCuPO, and CuPO samples and the mixing phases of the obtained CaCuPO and CaCuPO samples were identified, and then only a single phase of the samples was subjected to structural and dielectrical analyses. The structural results exhibit the tetragonal crystal system with the P4 space group for β-CaPO, the monoclinic crystal system with the P2/c space group for CaCuPO, and the C2/c space group for α-CuPO. The dielectric constant (ε) of the single metal pyrophosphates (CaPO and CuPO) was higher than that of binary metal pyrophosphates (CaCuPO). The image sensor result of the CuPO sample (x = 2.00) illustrated a yellowish-green color, while other compounds (x = 0.50-1.50) presented color tones that changed from blue-green to bluish-green. Raman and Fourier transform infrared (FTIR) spectrophotometers were employed to characterize and confirm the vibrational characteristics of the PO group, which contains the O-P-O radical ([PO]) and the P-O-P bride ([OPO]) and approximate M-O stretching modes. Furthermore, this work reports for the first time that the change in the crystal structure of CaCuPO (i.e., bond angle of P-O-P in PO and distortion phenomena in the M-O octahedral site) are cause the correlation between the structure, chromaticity, and dielectric properties of calcium copper pyrophosphates, CaCuPO.
Topics: Calcium; Calcium Pyrophosphate; Copper; Diphosphates; X-Ray Diffraction
PubMed: 35477985
DOI: 10.1038/s41598-022-11056-4 -
Nefrologia 2018Vascular calcification is a pathology characterized by the deposition of calcium-phosphate in cardiovascular structures, mainly in the form of hydroxyapatite crystals,... (Review)
Review
Vascular calcification is a pathology characterized by the deposition of calcium-phosphate in cardiovascular structures, mainly in the form of hydroxyapatite crystals, resulting in ectopic calcification. It is correlated with increased risk of cardiovascular disease and myocardial infarction in diabetic patients and in those with chronic kidney disease (CKD). Vascular smooth muscle cells are sensitive to changes in inorganic phosphate (Pi) levels. They are able to adapt and modify some of their functions and promote changes which trigger calcification. Pi is regulated by parathyroid hormone and 1,25-dihydroxyvitamin D. Changes in the transport of Pi are the primary factor responsible for the regulation of Pi homeostasis and the calcification process. Synthesis of calcification inhibitors is the main mechanism by which cells are able to prevent vascular calcification. Extracellular pyrophosphate (PPi) is a potent endogenous inhibitor of calcium-phosphate deposition both in vivo and in vitro. Patients with CKD show lower levels of PPi and increased activity of the enzyme alkaline phosphatase. Numerous enzymes implicated in the metabolism of PPi have been associated with vascular calcifications. PPi is synthesized from extracellular ATP by nucleotide pyrophosphatase/phosphodiesterase from extracellular ATP hydrolysis. PPi is hydrolyzed into Pi by tissue-nonspecific alkaline phosphatase. ATP can be hydrolyzed to Pi via the ectonucleoside triphosphate diphosphohydrolase family. All these enzymes must be in balance, thereby preventing calcifications. However, diseases like CKD or diabetes induce alterations in their levels. Administration of PPi could open up new treatment options for these patients.
Topics: Diphosphates; Humans; Renal Insufficiency, Chronic; Vascular Calcification
PubMed: 29137892
DOI: 10.1016/j.nefro.2017.07.005 -
Advances in Biological Regulation Jan 2022Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are a group of central eukaryotic metabolites and signaling molecules. Due to the diverse cellular functions and... (Review)
Review
Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are a group of central eukaryotic metabolites and signaling molecules. Due to the diverse cellular functions and widespread diseases InsPs and PP-InsPs are associated with, pharmacological targeting of the kinases involved in their biosynthesis has become a significant research interest in the last decade. In particular, the development of inhibitors for inositol hexakisphosphate kinases (IP6Ks) has leaped forward, while other inositol phosphate kinases have received scant attention. This review summarizes the efforts undertaken so far for discovering potent and selective inhibitors for this diverse group of small molecule kinases. The benefits of pharmacological inhibition are highlighted, given the multiple kinase-independent functions of inositol phosphate kinases. The distinct structural families of InsP and PP-InsP kinases are presented, and we discuss how compound availability for different inositol phosphate kinase families varies drastically. Lead compound discovery and optimization for the inositol kinases would benefit from detailed structural information on the ATP-binding sites of these kinases, as well as reliable biochemical and cellular read-outs to monitor inositol phosphate kinase activity in complex settings. Efforts to further tune well-established inhibitors, while simultaneously reviving tool compound development for the more neglected kinases from this family are indisputably worthwhile, considering the large potential therapeutic benefits.
Topics: Diphosphates; Eukaryotic Cells; Humans; Inositol Phosphates; Phosphorylation; Phosphotransferases (Phosphate Group Acceptor); Signal Transduction
PubMed: 34802993
DOI: 10.1016/j.jbior.2021.100836 -
Biochemistry Jun 2022Inositol pyrophosphates are signaling molecules containing at least one phosphoanhydride bond that regulate a wide range of cellular processes in eukaryotes. With a...
Inositol pyrophosphates are signaling molecules containing at least one phosphoanhydride bond that regulate a wide range of cellular processes in eukaryotes. With a cyclic array of phosphate esters and diphosphate groups around -inositol, these molecular messengers possess the highest charge density found in nature. Recent work deciphering inositol pyrophosphate biosynthesis in revealed important functions of these messengers in nutrient sensing, hormone signaling, and plant immunity. However, despite the rapid hydrolysis of these molecules in plant extracts, very little is known about the molecular identity of the phosphohydrolases that convert these messengers back to their inositol polyphosphate precursors. Here, we investigate whether Plant and Fungi Atypical Dual Specificity Phosphatases (PFA-DSP1-5) catalyze inositol pyrophosphate phosphohydrolase activity. We find that recombinant proteins of all five PFA-DSP homologues display phosphohydrolase activity with a high specificity for the 5-β-phosphate of inositol pyrophosphates and only minor activity against the β-phosphates of 4-InsP and 6-InsP. We further show that heterologous expression of PFA-DSP1-5 rescues wortmannin sensitivity and deranged inositol pyrophosphate homeostasis caused by the deficiency of the PFA-DSP-type inositol pyrophosphate phosphohydrolase Siw14 in yeast. Heterologous expression in leaves provided evidence that PFA-DSP1 also displays 5-β-phosphate-specific inositol pyrophosphate phosphohydrolase activity . Our findings lay the biochemical basis and provide the genetic tools to uncover the roles of inositol pyrophosphates in plant physiology and plant development.
Topics: Arabidopsis; Diphosphates; Dual-Specificity Phosphatases; Inositol Phosphates; Saccharomyces cerevisiae
PubMed: 35640071
DOI: 10.1021/acs.biochem.2c00145