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Journal articles on the topic 'Calcium cofactor'

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Published: 4 June 2021
Last updated: 28 January 2023

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1

Chaturvedi, Madhu, and Arun K. Shukla. "Calcium as a biased cofactor." Science 368, no. 6489 (April 23, 2020): 369–70. http://dx.doi.org/10.1126/science.abb4393.

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2

Khatun, Mita, Md Mamun Monir, Ting Xu, Haiming Xu, and Jun Zhu. "Genome-wide conditional association study reveals the influences of lifestyle cofactors on genetic regulation of body surface area in MESA population." PLOS ONE 16, no. 6 (June 18, 2021): e0253167. http://dx.doi.org/10.1371/journal.pone.0253167.

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Body surface area (BSA) is an important trait used for many clinical purposes. People’s BSA may vary due to genetic background, race, and different lifestyle factors (such as walking, exercise, reading, smoking, transportation, etc.). GWAS of BSA was conducted on 5,324 subjects of four ethnic populations of European-American, African-American, Hispanic-American, and Chinese-American from the Multi-Ethnic Study of Atherocloris (MESA) data using unconditional and conditional full genetic models. In this study, fifteen SNPs were identified (Experiment-wise PEW < 1×10−5) using unconditional full genetic model, of which thirteen SNPs had individual genetic effects and seven SNPs were involved in four pairs of epistasis interactions. Seven single SNPs and eight pairs of epistasis SNPs were additionally identified using exercise, smoking, and transportation cofactor-conditional models. By comparing association analysis results from unconditional and cofactor conditional models, we observed three different scenarios: (i) genetic effects of several SNPs did not affected by cofactors, e.g., additive effect of gene CREB5 (a≙ –0.013 for T/T and 0.013 for G/G, −Log10 PEW = 8.240) did not change in the cofactor models; (ii) genetic effects of several SNPs affected by cofactors, e.g., the genetic additive effect (a≙ 0.012 for A/A and –0.012 for G/G, −Log10 PEW = 7.185) of SNP of the gene GRIN2A was not significant in transportation cofactor model; and (iii) genetic effects of several SNPs suppressed by cofactors, e.g., additive (a≙ –0.018 for G/G and 0.018 for C/C, −Log10 PEW = 19.737) and dominance (d≙ –0.038 for G/C, −Log10 PEW = 27.734) effects of SNP of gene ERBB4 was identified using only transportation cofactor model. Gene ontology analysis showed that several genes are related to the metabolic pathway of calcium compounds, coronary artery disease, type-2 Diabetes, Alzheimer disease, childhood obesity, sleeping duration, Parkinson disease, and cancer. This study revealed that lifestyle cofactors could contribute, suppress, increase or decrease the genetic effects of BSA associated genes.
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3

Yong, S. C., P. Roversi, J. Lillington, F. Rodriguez, M. Krehenbrink, O. B. Zeldin, E. F. Garman, S. M. Lea, and B. C. Berks. "A complex iron-calcium cofactor catalyzing phosphotransfer chemistry." Science 345, no. 6201 (September 4, 2014): 1170–73. http://dx.doi.org/10.1126/science.1254237.

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4

Hayakawa, Yumiko, Toshimitsu Hayashi, Jung-Bum Lee, Tetsuo Ozawa, and Nobuo Sakuragawa. "Activation of Heparin Cofactor II by Calcium Spirulan." Journal of Biological Chemistry 275, no. 15 (April 6, 2000): 11379–82. http://dx.doi.org/10.1074/jbc.275.15.11379.

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5

Grinnell, BW, JD Walls, C. Marks, AL Glasebrook, DT Berg, SB Yan, and NU Bang. "Gamma-carboxylated isoforms of recombinant human protein S with different biologic properties." Blood 76, no. 12 (December 15, 1990): 2546–54. http://dx.doi.org/10.1182/blood.v76.12.2546.2546.

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Abstract Human protein S (HPS), a regulator of hemostasis, is a vitamin K- dependent plasma protein with potential clinical utility. We have obtained high-level expression of the cDNA for HPS in two mammalian cell lines. Both cell lines secreted single chain recombinant HPS (rHPS) in serum-free medium as determined by Western blot analysis. The ability of the rHPS from both cell lines to act as a cofactor for human protein C (HPC) was determined; the rHPS secreted from the human 293 cell line had an activity six times that of the rHPS from the AV12–664 Syrian hamster cell line. Furthermore, the relative specific cofactor activity of rHPS from the 293 cell line was actually 2.5-fold higher than that of single-chain human plasma-derived HPS. Essentially all of the rHPS secreted from the 293 cell line exhibited a calcium-dependent elution profile on anion exchange chromatography, whereas only 25% to 35% of the hamster cell-derived rHPS exhibited this profile. However, the calcium-eluted rHPS from the AV12 cell line had a high specific cofactor activity, equivalent to that of the 293-derived rHPS. A NaCl- elutable rHPS fraction (calcium nondependent) was isolated from the recombinant AV12–664 cell line, further purified, and found to have reduced activity, only 40% that of the calcium-dependent rHPS. The only observable difference in the calcium-dependent and nondependent rHPS molecules was in the content of gamma-carboxyglutamic acid (Gla); the calcium-dependent material contained approximately 10 mol Gla/mol protein whereas the calcium-nondependent material contained only approximately 8 mol Gla/mol of protein. In addition, the calcium- nondependent rHPS had reduced ability to interact with phospholipid vesicles as evidenced by an eightfold increase in the apparent kd. Our data demonstrate the isolation of rHPS with high specific activity, and show that a reduction in as few as two Gla residues dramatically decreases its functional cofactor activity for HPC, due to a reduction in ability to interact with the phospholipid bilayer.
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6

Grinnell, BW, JD Walls, C. Marks, AL Glasebrook, DT Berg, SB Yan, and NU Bang. "Gamma-carboxylated isoforms of recombinant human protein S with different biologic properties." Blood 76, no. 12 (December 15, 1990): 2546–54. http://dx.doi.org/10.1182/blood.v76.12.2546.bloodjournal76122546.

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Human protein S (HPS), a regulator of hemostasis, is a vitamin K- dependent plasma protein with potential clinical utility. We have obtained high-level expression of the cDNA for HPS in two mammalian cell lines. Both cell lines secreted single chain recombinant HPS (rHPS) in serum-free medium as determined by Western blot analysis. The ability of the rHPS from both cell lines to act as a cofactor for human protein C (HPC) was determined; the rHPS secreted from the human 293 cell line had an activity six times that of the rHPS from the AV12–664 Syrian hamster cell line. Furthermore, the relative specific cofactor activity of rHPS from the 293 cell line was actually 2.5-fold higher than that of single-chain human plasma-derived HPS. Essentially all of the rHPS secreted from the 293 cell line exhibited a calcium-dependent elution profile on anion exchange chromatography, whereas only 25% to 35% of the hamster cell-derived rHPS exhibited this profile. However, the calcium-eluted rHPS from the AV12 cell line had a high specific cofactor activity, equivalent to that of the 293-derived rHPS. A NaCl- elutable rHPS fraction (calcium nondependent) was isolated from the recombinant AV12–664 cell line, further purified, and found to have reduced activity, only 40% that of the calcium-dependent rHPS. The only observable difference in the calcium-dependent and nondependent rHPS molecules was in the content of gamma-carboxyglutamic acid (Gla); the calcium-dependent material contained approximately 10 mol Gla/mol protein whereas the calcium-nondependent material contained only approximately 8 mol Gla/mol of protein. In addition, the calcium- nondependent rHPS had reduced ability to interact with phospholipid vesicles as evidenced by an eightfold increase in the apparent kd. Our data demonstrate the isolation of rHPS with high specific activity, and show that a reduction in as few as two Gla residues dramatically decreases its functional cofactor activity for HPC, due to a reduction in ability to interact with the phospholipid bilayer.
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7

Armstrong, C. M., and G. Cota. "Calcium ion as a cofactor in Na channel gating." Proceedings of the National Academy of Sciences 88, no. 15 (August 1, 1991): 6528–31. http://dx.doi.org/10.1073/pnas.88.15.6528.

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8

Hayakawa, Y., T. Hayashi, K. Hayashi, T. Hayashi, T. Ozawa, K. Niiya, and N. Sakuragawa. "Heparin cofactor II-dependent antithrombin activity of calcium spirulan." Blood Coagulation & Fibrinolysis 7, no. 5 (July 1996): 554–60. http://dx.doi.org/10.1097/00001721-199607000-00007.

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9

Saif, Muhammad Wasif, Nektaria Makrilia, and Kostas Syrigos. "CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy." Journal of Oncology 2010 (2010): 1–5. http://dx.doi.org/10.1155/2010/934359.

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Intracellular reduced folate exists as a “pool” of more than 6 interconvertable forms. One of these forms, 5,10 methylenetetrahydrofolic acid (CH2THF), is the key one-carbon donor and reduced folate substrate for thymidylate synthase (TS). This pathway has been an important target for chemotherapy as it provides one of the necessary nucleotide substrates for DNA synthesis. The fluoropyrimidine 5-fluorouracil (5-FU) exerts its main cytotoxic activity through TS inhibition. Leucovorin (5-formyltetrahydrofolate; LV) has been used to increase the intracellular reduced folate pools and enhance TS inhibition. However, it must be metabolized within the cell through multiple intracellular enzymatic steps to form CH2THF. CoFactor (USAN fotrexorin calcium, (dl)-5,10,-methylenepteroyl-monoglutamate calcium salt) is a reduced folate that potentiates 5-FU cytotoxicity. According to early clinical trials, when 5-FU is modulated by CoFactor instead of LV, there is greater anti-tumor activity and less toxicity. This review presents the emerging role of CoFactor in colorectal and nongastrointestinal malignancies.
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10

Hayakawa, Yumiko, Yutaka Hirashima, Hiromichi Yamamoto, Masanori Kurimoto, Toshimitsu Hayashi, Jung-Bum Lee, and Shunro Endo. "Mechanism of activation of heparin cofactor II by calcium spirulan." Archives of Biochemistry and Biophysics 416, no. 1 (August 2003): 47–52. http://dx.doi.org/10.1016/s0003-9861(03)00289-3.

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11

Haberland, Annekathrin, Thomas Knaus, Sergei V. Zaitsev, Renate Stahn, Ajay R. Mistry, Charles Coutelle, Hermann Haller, and Michael Böttger. "Calcium ions as efficient cofactor of polycation-mediated gene transfer." Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1445, no. 1 (April 1999): 21–30. http://dx.doi.org/10.1016/s0167-4781(99)00017-2.

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12

George, Nelson, Megha Changtoo, Aru Singh, Srinivasan Muthuswamy, and Bandana Chakraborthy. "Hormonal Regulation of Calcium Signaling in Endocrine Cancers." World Journal of Endocrine Surgery 6, no. 2 (2014): 77–80. http://dx.doi.org/10.5005/jp-journals-10002-1141.

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ABSTRACT The calcium ion (Ca2+) plays a fundamental role in a number of physiological functions including bone formation, muscle contraction, secretion, enzyme cofactor, stabilization of membrane potentials, blood coagulation, etc. Calcium is homeostatically regulated by hormones that determines calcium balance within the body. The hormones PTH, 1,25-(OH)2D3 and calcitonin are altered in endocrine cancers which are in turn regulated by calcium. The main focus of this review is how hormones can regulate calcium homeostasis in endocrine cancers. How to cite this article George N, Changtoo M, Singh A, Kumar P, Muthuswamy S, Chakraborthy B. Hormonal Regulation of Calcium Signaling in Endocrine Cancers. World J Endoc Surg 2014;6(2):77-80.
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13

Camp, Carl E., and Sam S. Sofer. "Calcium alginate-Immobilized hepatic microsomes: Effect of NADPH cofactor on oxidation rates." Enzyme and Microbial Technology 9, no. 11 (November 1987): 685–89. http://dx.doi.org/10.1016/0141-0229(87)90128-1.

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14

Soria, J., C. Soria, M. Samama, S. Tabori, M. Kehl, A. Henschen, W. Nieuwenhuizen, A. Rimon, and I. Tatarski. "Fibrinogen Haifa: Fibrinogen Variant with Absence of Protective Effect of Calcium on Plasmin Degradation of Gamma Chains." Thrombosis and Haemostasis 57, no. 03 (1987): 310–13. http://dx.doi.org/10.1055/s-0038-1651123.

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SummaryThe abnormal fibrinogen Haifa is characterized by the fact that calcium present during enzymatic digestion by plasmin does not protect the Haifa D gamma chain against further plasmin attack as it does in normal molecules.Since calcium binding to fibrinogen, ADP - platelet aggregation cofactor activity and gamma dimerization process induced by factor XIIIa are normal for fibrinogen Haifa, the corresponding sequences in the gamma chain are not involved. It seems rather that the anomaly resides near the gamma 302 plasmin cleavage site that is protected when calcium is bound to the gamma chain and that this affects the availability of the polymerization site located in the C terminal part of the chain.
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15

Hultin, MB. "Modulation of thrombin-mediated activation of factor VIII:C by calcium ions, phospholipid, and platelets." Blood 66, no. 1 (July 1, 1985): 53–58. http://dx.doi.org/10.1182/blood.v66.1.53.53.

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Abstract The activation of factor VIII:C by thrombin appears to be an important prerequisite for the function of factor VIII:C as a cofactor in factor X activation in coagulation. The possible modulation of factor VIII:C activation by potential cofactors such as calcium ions, phospholipid, and platelets was studied systematically. Factor VIII:C activation could not be studied in the complete absence of Ca2+, since factor VIII:C activity decayed rapidly in calcium-free buffers, EDTA, or ethylene glycol tetra-acetic acid (EGTA), with only partial or no recovery of activity after readdition of Ca2+, Mn2+, or Mg2+. Added calcium chloride at 1.25, 2.5, 4, 10, 50, and 200 mmol/L produced progressive inhibition of factor VIII:C activation, with complete inhibition achieved by 50 mmol/L. Crude phospholipid preparations gave varying results, while purified phospholipids either had no effect or inhibited activation. This paper reports the new finding that fresh washed human platelets markedly potentiated factor VIII:C activation by a low concentration of thrombin (0.02 U/mL), even with prostaglandin E1 (PGE1) or dibutyryl cyclic AMP (cAMP) added to the washed platelets. However, the activity of platelets in factor VIII:C activation was inhibited by inclusion of PGE1 or dibutyryl cAMP during platelet washing, and ionophore A23187 increased this platelet activity; these data suggest that platelet stimulation is involved in the development of this activity. When platelets were maximally stimulated by thrombin (0.5 U/mL), the external calcium concentration increased 55 to 160 mumol/L, as measured with murexide, supporting the possible modulation of factor VIII:C activation by a transient increase in Ca2+ at the platelet surface.
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16

Hultin, MB. "Modulation of thrombin-mediated activation of factor VIII:C by calcium ions, phospholipid, and platelets." Blood 66, no. 1 (July 1, 1985): 53–58. http://dx.doi.org/10.1182/blood.v66.1.53.bloodjournal66153.

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The activation of factor VIII:C by thrombin appears to be an important prerequisite for the function of factor VIII:C as a cofactor in factor X activation in coagulation. The possible modulation of factor VIII:C activation by potential cofactors such as calcium ions, phospholipid, and platelets was studied systematically. Factor VIII:C activation could not be studied in the complete absence of Ca2+, since factor VIII:C activity decayed rapidly in calcium-free buffers, EDTA, or ethylene glycol tetra-acetic acid (EGTA), with only partial or no recovery of activity after readdition of Ca2+, Mn2+, or Mg2+. Added calcium chloride at 1.25, 2.5, 4, 10, 50, and 200 mmol/L produced progressive inhibition of factor VIII:C activation, with complete inhibition achieved by 50 mmol/L. Crude phospholipid preparations gave varying results, while purified phospholipids either had no effect or inhibited activation. This paper reports the new finding that fresh washed human platelets markedly potentiated factor VIII:C activation by a low concentration of thrombin (0.02 U/mL), even with prostaglandin E1 (PGE1) or dibutyryl cyclic AMP (cAMP) added to the washed platelets. However, the activity of platelets in factor VIII:C activation was inhibited by inclusion of PGE1 or dibutyryl cAMP during platelet washing, and ionophore A23187 increased this platelet activity; these data suggest that platelet stimulation is involved in the development of this activity. When platelets were maximally stimulated by thrombin (0.5 U/mL), the external calcium concentration increased 55 to 160 mumol/L, as measured with murexide, supporting the possible modulation of factor VIII:C activation by a transient increase in Ca2+ at the platelet surface.
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17

Weber. "The Role of Vitamins in the Prevention of Osteoporosis – a Brief Status Report." International Journal for Vitamin and Nutrition Research 69, no. 3 (May 1, 1999): 194–97. http://dx.doi.org/10.1024/0300-9831.69.3.194.

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This papers summarizes the main role vitamins are believed to play in the prevention of osteoporosis, a common disease which is anticipated to rapidly increase because of the aging of the population. Vitamin D, the classical vitamin related to bone health, improves bone strength mainly by increasing intestinal calcium absorption and reabsorption of calcium by the kidney. Several intervention studies demonstrated in humans that vitamin D can improve bone status as measured by bone density. Vitamin C is considered an essential cofactor of collagen formation. Epidemiological studies report a positive association between vitamin C intake and bone density. Intervention studies on the effect of vitamin C on bone status are missing. Vitamin B6 could function as a cofactor to build up cross-links. In humans, however, there is little evidence to support this. Vitamin K is required for the biological activity of several coagulation factors; the classical function of vitamin K. Recent research also points to a role of vitamin K in bone metabolism. Vitamin K mediates the ¨-carboxylation of glutamyl residues on several bone proteins, notably osteocalcin. Epidemiological studies and results from first intervention trials are consistently suggesting that vitamin K may improve bone health.
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18

Ubarretxena-Belandia, Iban, Jan-Willem P. Boots, Hubertus M. Verheij, and Niek Dekker. "Role of the Cofactor Calcium in the Activation of Outer Membrane Phospholipase A†." Biochemistry 37, no. 45 (November 1998): 16011–18. http://dx.doi.org/10.1021/bi9814181.

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19

Shin, Sooim, Manliang Feng, Yan Chen, Lyndal M. R. Jensen, Hiroyasu Tachikawa, Carrie M. Wilmot, Aimin Liu, and Victor L. Davidson. "The Tightly Bound Calcium of MauG Is Required for Tryptophan Tryptophylquinone Cofactor Biosynthesis." Biochemistry 50, no. 1 (January 11, 2011): 144–50. http://dx.doi.org/10.1021/bi101819m.

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20

Bartlett, John E., Sergei V. Baranov, Gennady M. Ananyev, and G. Charles Dismukes. "Calcium controls the assembly of the photosynthetic water-oxidizing complex: a cadmium(II) inorganic mutant of the Mn 4 Ca core." Philosophical Transactions of the Royal Society B: Biological Sciences 363, no. 1494 (October 17, 2007): 1253–61. http://dx.doi.org/10.1098/rstb.2007.2222.

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Perturbation of the catalytic inorganic core (Mn 4 Ca 1 O x Cl y ) of the photosystem II-water-oxidizing complex (PSII-WOC) isolated from spinach is examined by substitution of Ca 2+ with cadmium(II) during core assembly. Cd 2+ inhibits the yield of reconstitution of O 2 -evolution activity, called photoactivation, starting from the free inorganic cofactors and the cofactor-depleted apo-WOC-PSII complex. Ca 2+ affinity increases following photooxidation of the first Mn 2+ to Mn 3+ bound to the ‘high-affinity’ site. Ca 2+ binding occurs in the dark and is the slowest overall step of photoactivation (IM 1 →IM 1 * step). Cd 2+ competitively blocks the binding of Ca 2+ to its functional site with 10- to 30-fold higher affinity, but does not influence the binding of Mn 2+ to its high-affinity site. By contrast, even 10-fold higher concentrations of Cd 2+ have no effect on O 2 -evolution activity in intact PSII-WOC. Paradoxically, Cd 2+ both inhibits photoactivation yield, while accelerating the rate of photoassembly of active centres 10-fold relative to Ca 2+ . Cd 2+ increases the kinetic stability of the photooxidized Mn 3+ assembly intermediate(s) by twofold (mean lifetime for dark decay). The rate data provide evidence that Cd 2+ binding following photooxidation of the first Mn 3+ , IM 1 →IM 1 * , causes three outcomes: (i) a longer intermediate lifetime that slows IM 1 decay to IM 0 by charge recombination, (ii) 10-fold higher probability of attaining the degrees of freedom (either or both cofactor and protein d.f.) needed to bind and photooxidize the remaining 3 Mn 2+ that form the functional cluster, and (iii) increased lability of Cd 2+ following Mn 4 cluster assembly results in (re)exchange of Cd 2+ by Ca 2+ which restores active O 2 -evolving centres. Prior EPR spectroscopic data provide evidence for an oxo-bridged assembly intermediate, Mn 3+ (μ-O 2− )Ca 2+ , for IM 1 * . We postulate an analogous inhibited intermediate with Cd 2+ replacing Ca 2+ .
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21

Yu, Peilin, Xiaobo Cai, Yan Liang, Mingxiang Wang, and Wei Yang. "Roles of NAD+ and Its Metabolites Regulated Calcium Channels in Cancer." Molecules 25, no. 20 (October 20, 2020): 4826. http://dx.doi.org/10.3390/molecules25204826.

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Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for redox enzymes, but also moonlights as a regulator for ion channels, the same as its metabolites. Ca2+ homeostasis is dysregulated in cancer cells and affects processes such as tumorigenesis, angiogenesis, autophagy, progression, and metastasis. Herein, we summarize the regulation of the most common calcium channels (TRPM2, TPCs, RyRs, and TRPML1) by NAD+ and its metabolites, with a particular focus on their roles in cancers. Although the mechanisms of NAD+ metabolites in these pathological processes are yet to be clearly elucidated, these ion channels are emerging as potential candidates of alternative targets for anticancer therapy.
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22

Shea, Lei, Xuhua He, and Björn Dahlbäck. "Synergistic Cofactor Function of Factor V and Protein S to Activated Protein C in the Inactivation of the Factor Villa – Factor IXa Complex." Thrombosis and Haemostasis 78, no. 03 (1997): 1030–36. http://dx.doi.org/10.1055/s-0038-1657682.

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SummaryHuman factor V has been shown not only to be a precursor to procoagulant factor Va but also to express anticoagulant properties. Thus, factor V was recently found to potentiate the effect of protein S as cofactor to activated protein C (APC) in the inactivation of the factor VIIIa-factor IXa complex. The purpose of this study was to determine whether the APC-cofactor function of factor V was also expressed in the bovine protein C system and to elucidate the molecular background for the species specificity of APC. For this purpose, the effects of protein S and factor V on APC-mediated inactivation of factor VIIIa were studied using purified APC, protein S and factor V of human and bovine.origin. The factor VIIIa investigated here was part of a Xase complex (i.e. factor IXa, factor VIIIa, phospholipid and calcium) and the APC-mediated inhibition of factor VIIIa was monitored by the ability of the Xase complex to activate factor X. Synergistic APC-cofactor function of factor V and protein S was demonstrated in the bovine system. The effect of bovine APC was potentiated by bovine protein S but not by human protein S, whereas both human or bovine protein S stimulated the function of human APC. Factor V did not express species specificity in its APC-cofactor activity even though bovine factor V was more potent than its human counterpart. Recombinant human/bovine protein S chimeras were used to demonstrate that the thrombin sensitive region and first epidermal growth factor-like module of protein S determine the species specificity of the APC-protein S interaction. In conclusion, both human and bovine factor V were found to express APC-cofactor activity which depends on the presence of protein S. The species specificity of APC was shown to be caused by the interaction between APC and protein S.
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23

Irimia, Adriana, Hong Zang, Lioudmila V. Loukachevitch, Robert L. Eoff, F. Peter Guengerich, and Martin Egli. "Calcium Is a Cofactor of Polymerization but Inhibits Pyrophosphorolysis by theSulfolobus solfataricusDNA Polymerase Dpo4†." Biochemistry 45, no. 19 (May 2006): 5949–56. http://dx.doi.org/10.1021/bi052511+.

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24

Niu, Zhiyv, Dinakar Iyer, Simon J. Conway, James F. Martin, Kathryn Ivey, Deepak Srivastava, Alfred Nordheim, and Robert J. Schwartz. "Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart." Proceedings of the National Academy of Sciences 105, no. 46 (November 12, 2008): 17824–29. http://dx.doi.org/10.1073/pnas.0805491105.

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Our conditional serum response factor (SRF) knockout, Srf Cko, in the heart-forming region blocked the appearance of rhythmic beating myocytes, one of the earliest cardiac defects caused by the ablation of a cardiac-enriched transcription factor. The appearance of Hand1 and Smyd1, transcription and chromatin remodeling factors; Acta1, Acta2, Myl3, and Myom1, myofibril proteins; and calcium-activated potassium-channel gene activity (KCNMB1), the channel protein, were powerfully attenuated in the SrfCKO mutant hearts. A requisite role for combinatorial cofactor interactions with SRF, as a major determinant for regulating the appearance of organized sarcomeres, was shown by viral rescue of SRF-null ES cells with SRF point mutants that block cofactor interactions. In the absence of SRF genes associated with biomineralization, GATA-6, bone morphogenetic protein 4 (BMP4), and periostin were strongly up-regulated, coinciding with the down regulation of many SRF dependent microRNA, including miR1, which exerted robust silencer activity over the induction of GATA-6 leading to the down regulation of BMP4 and periostin.
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25

Zweifach, A., and R. S. Lewis. "Calcium-dependent potentiation of store-operated calcium channels in T lymphocytes." Journal of General Physiology 107, no. 5 (May 1, 1996): 597–610. http://dx.doi.org/10.1085/jgp.107.5.597.

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The depletion of intracellular Ca2+ stores triggers the opening of Ca2+ release-activated Ca2+ (CRAC) channels in the plasma membrane of T lymphocytes. We have investigated the additional role of extracellular Ca2+ (Ca02+) in promoting CRAC channel activation in Jurkat leukemic T cells. Ca2+ stores were depleted with 1 microM thapsigargin in the nominal absence of Ca02+ with 12 mM EGTA or BAPTA in the recording pipette. Subsequent application of Ca02+ caused ICRAC to appear in two phases. The initial phase was complete within 1 s and reflects channels that were open in the absence of Ca02+. The second phase consisted of a severalfold exponential increase in current amplitude with a time constant of 5-10 s; we call this increase Ca(2+)-dependent potentiation, or CDP. The shape of the current-voltage relation and the inferred single-channel current amplitude are unchanged during CDP, indicating that CDP reflects an alteration in channel gating rather than permeation. The extent of CDP is modulated by voltage, increasing from approximately 50% at +50 mV to approximately 350% at -75 mV in the presence of 2 mM Ca02+. The voltage dependence of CDP also causes ICRAC to increase slowly during prolonged hyperpolarizations in the constant presence of Ca02+. CDP is not affected by exogenous intracellular Ca2+ buffers, and Ni2+, a CRAC channel blocker, can cause potentiation. Thus, the underlying Ca2+ binding site is not intracellular. Ba2+ has little or no ability to potentiate CRAC channels. These results demonstrate that the store-depletion signal by itself triggers only a small fraction of capacitative Ca2+ entry and establish Ca2+ as a potent cofactor in this process. CDP confers a previously unrecognized voltage dependence and slow time dependence on CRAC channel activation that may contribute to the dynamic behavior of ICRAC.
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26

Lumpe, Henning, and Lena J. Daumann. "Studies of Redox Cofactor Pyrroloquinoline Quinone and Its Interaction with Lanthanides(III) and Calcium(II)." Inorganic Chemistry 58, no. 13 (June 11, 2019): 8432–41. http://dx.doi.org/10.1021/acs.inorgchem.9b00568.

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27

van de Ven, T. G. M., M. Abdallah Qasaimeh, C. Pigeon, and J. Paris. "The effect of calcium ions on the efficiency of polyethylene oxide–cofactor retention aid systems." Colloids and Surfaces A: Physicochemical and Engineering Aspects 297, no. 1-3 (April 2007): 79–83. http://dx.doi.org/10.1016/j.colsurfa.2006.10.026.

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28

Pena, Florentina, Annemieke Jansens, Guus van Zadelhoff, and Ineke Braakman. "Calcium as a Crucial Cofactor for Low Density Lipoprotein Receptor Folding in the Endoplasmic Reticulum." Journal of Biological Chemistry 285, no. 12 (January 20, 2010): 8656–64. http://dx.doi.org/10.1074/jbc.m110.105718.

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29

Togashi, H., C. A. Hirshman, and C. W. Emala. "Qualitative immunoblot analysis of PKC isoforms expressed in airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 272, no. 4 (April 1, 1997): L603—L607. http://dx.doi.org/10.1152/ajplung.1997.272.4.l603.

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Protein kinase C (PKC) was originally identified as a single serine/ threonine protein kinase with calcium- and phospholipid-dependent activity, but more recently PKC has been found to consist of a family of multiple isoenzymes with different biochemical characteristics, substrates, and cofactor requirements. PKC is particularly important in regulating airway smooth muscle (ASM) tone. Although a previous investigation has demonstrated PKC-beta, -delta, -epsilon, -theta and -zeta in canine trachealis muscle, additional PKC isoforms have not been characterized in ASM. Therefore, immunoblot analysis using nine isotype-specific antibodies was used to further characterize the expression of PKC isoforms in porcine ASM. In addition to the previously described beta-, delta-, epsilon-, and zeta-isoforms in ASM, the calcium-dependent alpha-isoform, and the calcium- and diacylglycerol-independent isoforms iota/lambda and mu were identified. This study demonstrates multiple PKC isoforms in porcine ASM that can participate in intracellular signaling pathways in this tissue.
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30

Pradhan, Shaili, and P. Mishra. "Gingival Enlargement in Antihypertensive Medication." Journal of Nepal Medical Association 48, no. 174 (April 1, 2009): 149–52. http://dx.doi.org/10.31729/jnma.232.

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Introduction: Drug-induced gingival enlargement is a well documented side effect with the use of phenytoin, cyclosporine and calcium channel blockers. The prevalence of gingival enlargement induced by calcium channel blockers is uncertain. Several studies show confl icting results ranging from 20% to 83%. This study was conducted to determine the prevalence of gingival enlargement in patients taking antihypertensive medication. Methods: All consecutive patients on antihypertensive agents attending the Dental OPD were studied. The prevalence of drug induced gingival enlargement was determined. The periodontal condition of all subjects were assessed including plaque index and probing depth. Results: Total 81.2% of subjects taking antihypertensive were seen to have signifi cant enlargement. Among them 71.1% were taking calcium channel blocker, 21.5% were taking ACE Inhibitors, and 7.4% were taking β- blockers. Conclusions:Patients taking antihypertensive agents are at increased risk for gingival enlargement and infl ammation is an important cofactor for the expression of this effect.Key Words: anti-hypertensive drugs, gingival enlargement
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31

Grinnell, B. W., B. Gerlitz, and D. T. Berg. "Identification of a region in protein C involved in thrombomodulin-stimulated activation by thrombin: potential repulsion at anion-binding site I in thrombin." Biochemical Journal 303, no. 3 (November 1, 1994): 929–33. http://dx.doi.org/10.1042/bj3030929.

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During coagulation human protein C is activated by thrombin; however, this cleavage reaction is slow unless thrombin is complexed with a cofactor, thrombomodulin. Near the thrombin cleavage site in protein C is a cluster of basic residues, at positions P5′ (Lys-174), P8′ (Arg-177) and P9′ (Arg-178). We have explored the role of this basic cluster in the activation of protein C by thrombin, and by thrombin-thrombomodulin complex, by substitution of glutamic acid at each position to generate the acidic protein C derivative P′-EEE. The activation rate of P′-EEE by free alpha-thrombin was approx. 12-fold faster than that observed for wild-type (wt) human protein C zymogen (HPC) in the presence of calcium, but unchanged in the absence of calcium. While the thrombin-catalysed activation of wt-HPC was stimulated approx. 300-fold by thrombomodulin, we observed no effect of thrombomodulin on thrombin-catalysed activation of the P′-EEE derivative. Using synthetic peptides that bind to anion-binding site I of thrombin (thrombin-receptor sequence 52-66 and hirudin sequence 54-65 SO4 Tyr), we found that the rate of thrombin-catalysed activation of wt-HPC in the presence of calcium could be increased severalfold in a dose-dependent manner. However, the enhanced rate of thrombin-catalysed activation of P′-EEE could be progressively reduced to wt-HPC levels with increasing concentrations of both synthetic peptides. Our data suggest that the P′ basic cluster in protein C reduces interaction with free alpha-thrombin through electrostatic repulsion with anion-binding site I, a site that is masked when thrombomodulin binds thrombin. Further, the lack of thrombomodulin cofactor activity with thrombin-catalysed activation of P′-EEE suggests that the basic cluster in protein C forms a contact site with thrombomodulin.
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32

McNally, T., S. E. Cotterell, I. J. Mackie, D. A. Isenberg, and S. J. Machin. "The Interaction of β2 Glycoprotein-I and Heparin and Its Effect on β2 Glycoprotein-I Antiphospholipid Antibody Cofactor Function in Plasma." Thrombosis and Haemostasis 72, no. 04 (1994): 578–81. http://dx.doi.org/10.1055/s-0038-1648918.

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Summaryβ2 glycoprotein-I (β2GPI), a cofactor for antiphospholipid antibody (aPA) binding, binds to many anionic macromolecules including heparin. The nature of this interaction with heparin is not well understood and its effect on the purported biological functions of β2GPI is unknown.We have examined the interactions of dermatan sulphate (DS) and different pharmaceutical preparations of heparin with β2GPI by crossed immunoelectrophoresis (CIE) and investigated the effect of these agents on plasma levels of p2GPI antigen (β2GPI: Ag) by a standardised enzyme linked immunosorbent assay (ELISA). P2GPI aPA cofactor activity (β2GPI:Cof) was also measured using a modified solid phase an-ti-phosphatidylserine (aPS) ELISA. CIE results confirmed a heparin-β2GPI interaction with unfractionated (UF) heparin. β2GPI:Ag levels were unaffected by any of the preparations investigated. There were no significant differences in β2GPI:Cof activities of the samples containing LMW heparins or DS but levels of β2GPI:Cof were increased in samples containing UF sodium and calcium heparin preparations (0.5 IU/ml Monoparin, p <0.05, and 10 IU/ml Liquemin and Calcipa-rine, p <0.05).
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Rao, LV, and SI Rapaport. "The effect of platelets upon factor Xa-catalyzed activation of factor VII in vitro." Blood 72, no. 2 (August 1, 1988): 396–401. http://dx.doi.org/10.1182/blood.v72.2.396.396.

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Abstract The authors have investigated the ability of platelets to enhance factor Xa-catalyzed activation of factor VII. Unstimulated platelets were without effect, whereas freeze/thawed platelets substantially enhanced activation. Antifactor V antibodies did not diminish the enhancement. Platelets activated by thrombin, collagen, or calcium ionophore A23187 also enhanced factor Xa-catalyzed activation of factor VII. In contrast to their lack of effect upon freeze/thawed platelets, antifactor V antibodies abolished augmented factor VII activation induced by activated platelets. Adding exogenous factor Va to unstimulated platelets failed to enhance factor Xa-catalyzed activation of factor VII, nor did adding exogenous factor Va to activated platelets augment activation beyond that observed with activated platelets alone. These observations can be interpreted as follows: (1) factor Va does not function as a cofactor for factor Xa-catalyzed activation of factor VII; (2) anionic phospholipids are a known cofactor for factor Xa-catalyzed activation of factor VII, and freeze/thawed platelets probably enhance activation by making anionic phospholipids on disrupted platelet membranes available to function as a cofactor; (3) the presumed binding of factor Xa to exogenous factor Va on unstimulated platelets is insufficient in itself to augment factor Xa-catalyzed activation of factor VII; (4) activated platelets augment factor Xa-catalyzed factor VII activation because activation allows both factor Xa to bind to released platelet factor V(a) and makes available a surface membrane component, probably anionic phospholipids, with which the bound factor Xa interacts.
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Rao, LV, and SI Rapaport. "The effect of platelets upon factor Xa-catalyzed activation of factor VII in vitro." Blood 72, no. 2 (August 1, 1988): 396–401. http://dx.doi.org/10.1182/blood.v72.2.396.bloodjournal722396.

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The authors have investigated the ability of platelets to enhance factor Xa-catalyzed activation of factor VII. Unstimulated platelets were without effect, whereas freeze/thawed platelets substantially enhanced activation. Antifactor V antibodies did not diminish the enhancement. Platelets activated by thrombin, collagen, or calcium ionophore A23187 also enhanced factor Xa-catalyzed activation of factor VII. In contrast to their lack of effect upon freeze/thawed platelets, antifactor V antibodies abolished augmented factor VII activation induced by activated platelets. Adding exogenous factor Va to unstimulated platelets failed to enhance factor Xa-catalyzed activation of factor VII, nor did adding exogenous factor Va to activated platelets augment activation beyond that observed with activated platelets alone. These observations can be interpreted as follows: (1) factor Va does not function as a cofactor for factor Xa-catalyzed activation of factor VII; (2) anionic phospholipids are a known cofactor for factor Xa-catalyzed activation of factor VII, and freeze/thawed platelets probably enhance activation by making anionic phospholipids on disrupted platelet membranes available to function as a cofactor; (3) the presumed binding of factor Xa to exogenous factor Va on unstimulated platelets is insufficient in itself to augment factor Xa-catalyzed activation of factor VII; (4) activated platelets augment factor Xa-catalyzed factor VII activation because activation allows both factor Xa to bind to released platelet factor V(a) and makes available a surface membrane component, probably anionic phospholipids, with which the bound factor Xa interacts.
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35

Johnson, J. L., R. E. London, and K. V. Rajagopalan. "Covalently bound phosphate residues in bovine milk xanthine oxidase and in glucose oxidase from Aspergillus niger: a reevaluation." Proceedings of the National Academy of Sciences 86, no. 17 (September 1989): 6493–97. http://dx.doi.org/10.1073/pnas.86.17.6493.

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The reported presence of covalently bound phosphate residues in flavoproteins has significant implications with regard to the catalytic mechanisms and structural stability of the specific enzymes themselves and in terms of general cellular metabolic regulation. These considerations have led to a reevaluation of the presence of covalently bound phosphorus in the flavoproteins xanthine oxidase (xanthine: oxygen oxidoreductase, EC 1.1.3.22) and glucose oxidase (beta-D-glucose: oxygen 1-oxidoreductase, EC 1.1.3.4). Milk xanthine oxidase purified by a procedure that includes anion-exchange chromatography is shown to contain three phosphate residues. All three are noncovalently associated with the protein, two with the FAD cofactor, and one with the molybdenum cofactor. Results of chemical analysis and 31P NMR spectroscopy indicate that enzyme purified by this method contains no phosphoserine residues. Xanthine oxidase preparations purified by chromatography on calcium phosphate gel in place of DEAE-Sephadex yielded higher phosphate-to-protein ratios, which could be reduced to the expected values by additional purification on a folate affinity column. Highly active, highly purified preparations of glucose oxidase are shown to contain only the two phosphate residues of the FAD cofactor. The covalently bound bridging phosphate reported by others may arise in aged or degraded preparations of the enzyme but appears not to be a constituent of functional glucose oxidase. These results suggest that the presence of covalent phosphate residues in other flavoproteins should be rigorously reevaluated as well.
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36

Crabtree, Mark J., Caroline L. Smith, George Lam, Michael S. Goligorsky, and Steven S. Gross. "Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 4 (April 2008): H1530—H1540. http://dx.doi.org/10.1152/ajpheart.00823.2007.

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5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOSs). Oxidation of BH4, in the setting of diabetes and other chronic vasoinflammatory conditions, can cause cofactor insufficiency and uncoupling of endothelial NOS (eNOS), manifest by a switch from nitric oxide (NO) to superoxide production. Here we tested the hypothesis that eNOS uncoupling is not simply a consequence of BH4insufficiency, but rather results from a diminished ratio of BH4vs. its catalytically incompetent oxidation product, 7,8-dihydrobiopterin (BH2). In support of this hypothesis, [3H]BH4binding studies revealed that BH4and BH2bind eNOS with equal affinity ( Kd≈ 80 nM) and BH2can rapidly and efficiently replace BH4in preformed eNOS-BH4complexes. Whereas the total biopterin pool of murine endothelial cells (ECs) was unaffected by 48-h exposure to diabetic glucose levels (30 mM), BH2levels increased from undetectable to 40% of total biopterin. This BH2accumulation was associated with diminished calcium ionophore-evoked NO activity and accelerated superoxide production. Since superoxide production was suppressed by NOS inhibitor treatment, eNOS was implicated as a principal superoxide source. Importantly, BH4supplementation of ECs (in low and high glucose-containing media) revealed that calcium ionophore-evoked NO bioactivity correlates with intracellular BH4:BH2and not absolute intracellular levels of BH4. Reciprocally, superoxide production was found to negatively correlate with intracellular BH4:BH2. Hyperglycemia-associated BH4oxidation and NO insufficiency was recapitulated in vivo, in the Zucker diabetic fatty rat model of type 2 diabetes. Together, these findings implicate diminished intracellular BH4:BH2, rather than BH4depletion per se, as the molecular trigger for NO insufficiency in diabetes.
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Wang, Yuxiao, Walter Huynh, Taylor D. Skokan, Wen Lu, Arthur Weiss, and Ronald D. Vale. "CRACR2a is a calcium-activated dynein adaptor protein that regulates endocytic traffic." Journal of Cell Biology 218, no. 5 (February 27, 2019): 1619–33. http://dx.doi.org/10.1083/jcb.201806097.

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Cytoplasmic dynein is a minus end–directed microtubule motor that transports intracellular cargoes. Transport is initiated by coiled-coil adaptors that (a) join dynein and its cofactor dynactin into a motile complex and (b) interact with a cargo-bound receptor, which is frequently a Rab GTPase on an organelle. Here, we report two novel dynein adaptors, CRACR2a and Rab45, that have a coiled-coil adaptor domain, a pair of EF-hands, and a Rab GTPase fused into a single polypeptide. CRACR2a-mediated, but not Rab45-mediated, dynein motility is activated by calcium in vitro. In Jurkat T cells, elevation of intracellular calcium activates CRACR2a-mediated dynein transport. We further found that T cell receptor activation induces the formation of CRACR2a puncta at the plasma membrane, which initially associate with the actin cortex and subsequently detach and travel along microtubules, suggestive of an endocytic process. These results provide the first examples of Rab GTPases that directly act as dynein adaptors and implicate CRACR2a–dynein in calcium-regulated endocytic trafficking.
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Dhungana, Arun, Naveen Shreevastva, Subash Pant, and Baburam Pokharel. "A study of serum calcium, phosphorous and magnesium level in hypothyroid cases." Journal of Pathology of Nepal 12, no. 1 (March 31, 2022): 1933–37. http://dx.doi.org/10.3126/jpn.v12i1.40422.

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Background: Hypothyroidism is an endocrine disorder occurred either due to its impaired activity or hormonal deficiency. Trace elements are required as a cofactor for many enzymes in various metabolic pathways which are regulated by thyroid hormone. Hence, thyroid disorders are linked with disturbances in various metabolisms. So, the purpose of this study is to evaluate whether serum calcium, magnesium, and phosphorus level are deranged or not in hypothyroid cases. Materials and Methods: A prospective study was carried out in a total of 112 cases of hypothyroid and euthyroid subjects aged 20-50 years involving both male and female individuals. Thyroid function test, serum calcium, phosphorous and magnesium activities were measured in both the study population. Results: Serum calcium was significantly lower while serum phosphorous and magnesium levels were significantly higher in hypothyroidism (p<0.001). There was a significant negative correlation between Thyroid Stimulating Hormone (TSH) and calcium (r-value -0.282, p0.035) while, there was a significant positive correlation between TSH and serum phosphorous and magnesium (r-value 0.593, p<0.001) and (r-value 0.513, p<0.001) respectively. Conclusions: Our study, suggests that there was a significant change in the levels of serum calcium, phosphorous, and magnesium in thyroid dysfunction. Assessing the level of serum calcium and phosphorous can be fairly used as an index of bone resorption. So, preventive measures like supplementation of minerals can be initiated early in those who are at risk of rapid bone loss and to prevent osteoporotic fractures.
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39

Song, Jina, Kimberley Talbot, Jeffrey Hewitt, Rodney M. Camire, Ross T. A. MacGillivray, and Ed L. Pryzdial. "Single Amino Acid Substitution (Asp111Ala) in Coagulation Factor Va Causes Subunit Dissociation and Disrupted Calcium and Copper Binding." Blood 110, no. 11 (November 16, 2007): 2699. http://dx.doi.org/10.1182/blood.v110.11.2699.2699.

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Abstract Factor V (FV) is the essential inactive precursor of blood coagulation cofactor Va (FVa). FV is synthesized as a single chain protein that is activated at sites of injury by thrombin to FVa. As a ternary complex with the serine protease factor Xa and an anionic phospholipid (aPL) membrane in the presence of calcium (prothrombinase), FVa functions to accelerate the rate of prothrombin to thrombin conversion, the critical step in hemostasis. FVa is a non-covalent heterodimer composed of a heavy (FVaH) and a light subunit (FVaL). It has been well established that FVa requires calcium to stabilize a functional subunit interaction, although copper is also known to bind. A 1:1 divalent cation:FVa stoichiometry has been reported for both metals. Despite the importance of FV few studies have investigated the specific amino acids and divalent cations that mediate the FVaH-FVaL association. In order to understand the role of divalent cations in maintaining the FVa subunit interaction and consequent function, we investigated the effect of mutating FV Asp111 to Ala (D111A), which was suggested by our previous work, others’ crystallography studies and homology to coagulation factor VIII, to potentially participate in calcium binding. Compared to wild type recombinant FV (wtFV), there was no difference in the kinetics of thrombin-mediated conversion of purified FVD111A to FVaD111A assessed by gel electrophoresis. Binding to small unilamellar aPL-containing vesicles was followed by light scattering and also showed no change. However, the cofactor activity of FVD111A was observed in clotting and purified prothrombinase chromogenic assays to be significantly inhibited (39% and 27% reduction, respectively). When the wtFV or FVD111A was pre-activated by thrombin (i.e. 2-stage assay), markedly greater inhibition was observed (94% and 73% reduction, respectively). The 1-stage/2-stage discrepancy seen here can be explained by spontaneous dissociation of subunits in FVD111A upon activation. Indeed, thrombin activation of FVD111A was shown by light scattering to result in rapid dissociation of subunits even in the presence of excess calcium. To quantitatively investigate the direct effect of the mutation on divalent cation coordination, graphite furnace atomic absorption spectrometry was utilized to measure the amount of bound calcium and copper. As predicted, calcium binding to FVD111A was severely inhibited resulting in a stoichiometry of <0.16:1. Interestingly, the stoichiometry of copper binding was also appreciably reduced to ∼0.5:1. These data demonstrate for the first time that a single point mutation can result in the spontaneous subunit dissociation of purified FVa. The finding that mutation of Asp111 disrupted not only the coordination of calcium but also that of copper, suggests that interdependent metal ion binding sites may contribute to FVa configuration and function.
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40

Lumpe, Henning, Peter Mayer, and Lena J. Daumann. "Crystal structure of a calcium(II)–pyrroloquinoline quinone (PQQ) complex outside a protein environment." Acta Crystallographica Section C Structural Chemistry 76, no. 12 (November 5, 2020): 1051–56. http://dx.doi.org/10.1107/s2053229620014278.

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Pyrroloquinoline quinone (PQQ) is an important cofactor of calcium- and lanthanide-dependent alcohol dehydrogenases, and has been known for over 30 years. Crystal structures of Ca–MDH enzymes (MDH is methanol dehydrogenase) have been known for some time; however, crystal structures of PQQ with biorelevant metal ions have been lacking in the literature for decades. We report here the first crystal structure analysis of a Ca–PQQ complex outside the protein environment, namely, poly[[undecaaquabis(μ-4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylato)tricalcium(II)] dihydrate], {[Ca3(C14H3N2O8)2(H2O)11]·2H2O} n . The complex crystallized as Ca3PQQ2·13H2O with Ca2+ in three different positions and PQQ3−, including an extensive hydrogen-bond network. Similarities and differences to the recently reported structure with biorelevant europium (Eu2PQQ2) are discussed.
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41

Brzęczek, Maciej, Lidia Hyla-Klekot, Franciszek Kokot, and Marek Synder. "Contribution of Bone Tissue to Regulation of Calcium and Phosphate Metabolism. Role of FGF23 and Klotho Protein." Ortopedia Traumatologia Rehabilitacja 22, no. 2 (April 30, 2020): 69–76. http://dx.doi.org/10.5604/01.3001.0014.1153.

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Bone tissue actively contributes to the regulation of systemic homoeostasis, and particularly the maintenance of calcium-phosphate balance. The parathyroid hormone-vitamin D feedback axis is balanced by the recently discovered bone-FGF23-kidney hormonal axis. An active complex consisting of FGF23, a receptor and Klotho protein blocks phosphate reabsorption in the proximal tubules, increasing urine phosphate levels and decreasing blood phosphate levels. Mutations of the gene mediating FGF23 transcription lead to a number of diseases, examples including autosomal dominant hypophosphataemic rickets. Klotho protein is a cofactor for FGF23 displaying cardio-, vaso- and nephroprotective activity. It increases calcium reabsorption in the kidneys and inhibits phosphate reabsorption. It also exerts antioxidative and anti-insulin effects and inhibits tissue calcification and apoptosis. As an inhibitor of bone resorption, osteoprotegerin becomes an important contributor to bone remodelling, while RANK/RANKL signalling inhibition is used in the treatment of postmenopausal osteoporosis. Osteocalcin plays an important role in energy metabolism in the human body. Sclerostin exerts a strong catabolic effect on bone tissue. Newly identified contributors to the regulation of calcium and phosphate homoeostasis suggest that bone tissue plays a complex role in the systemic metabolism.
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42

Giri, Tusar, Bruno Villoutreix, Anders Wallqvist, Björn Dahlbäck, and Pablo García de Frutos. "Topological Studies of the Amino Terminal Modules of Vitamin K-dependent Protein S Using Monoclonal Antibody Epitope Mapping and Molecular Modeling." Thrombosis and Haemostasis 80, no. 11 (1998): 798–804. http://dx.doi.org/10.1055/s-0037-1615361.

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SummaryProtein S is an important anticoagulant protein acting as cofactor to activated protein C (APC) in the degradation of membrane-bound factors Va and VIIIa. Binding of protein S to the membrane depends on the Gla-domain, whereas sites for APC-interaction are located in the thrombin-sensitive region (TSR) and the first EGF domain. The aims of the present investigation were to localize the sites on protein S which are involved in APC-cofactor function and to elucidate possible orientations of the TSR in relation to the membrane. For these purposes, we determined the epitope for a calcium-dependent monoclonal antibody (HPS67) against the TSR, which inhibits APC cofactor activity even though it does not impede protein S binding to the membrane. HPS67 did not recognize wild-type mouse protein S but gained reactivity against a recombinant mouse protein in which G49 and R52 were mutated to R and Q (found in human protein S), respectively, suggesting these two residues to be part of a surface exposed epitope for HPS67. This information helped in the validation and refinement of the structural model for the Gla-TSR-EGF1-modules of protein S. The X-ray structure of a Fab-fragment mimicking HPS67 was docked onto the protein S model. The observation that HPS67 did not inhibit phospholipid binding of protein S has implications for the possible orientation of protein S on the membrane surface. In the proposed model for membrane-bound protein S, there is no contact between the TSR and the membrane. Rather, the TSR is free to interact with membrane-bound APC.
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Elnatan, Daniel, and David A. Agard. "Calcium binding to a remote site can replace magnesium as cofactor for mitochondrial Hsp90 (TRAP1) ATPase activity." Journal of Biological Chemistry 293, no. 35 (July 10, 2018): 13717–24. http://dx.doi.org/10.1074/jbc.ra118.003562.

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44

Zhang, Shu, Hanzhong Gao, Lixia Wang, Yihui Zhang, Dandan Zhou, Ali Anwar, Jingjuan Li, et al. "Comparative Transcriptome and Co-Expression Network Analyses Reveal the Molecular Mechanism of Calcium-Deficiency-Triggered Tipburn in Chinese Cabbage (Brassica rapa L. ssp. Pekinensis)." Plants 11, no. 24 (December 16, 2022): 3555. http://dx.doi.org/10.3390/plants11243555.

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Chinese cabbage tipburn is characterized by the formation of necrotic lesions on the margin of leaves, including on the insides of the leafy head. This physiological disorder is associated with a localized calcium deficiency during leaf development. However, little information is available regarding the molecular mechanisms governing Ca-deficiency-triggered tipburn. This study comprehensively analysed the transcriptomic comparison between control and calcium treatments (CK and 0 mM Ca) in Chinese cabbage to determine its molecular mechanism in tipburn. Our analysis identified that the most enriched gene ontology (GO) categories are photosynthesis, thylakoid and cofactor binding. Moreover, the KEGG pathway was most enriched in photosynthesis, carbon metabolism and carbon fixation. We also analyzed the co-expression network by functional categories and identified ten critical hub differentially expressed genes (DEGs) in each gene regulatory network (GRN). These DEGs might involve abiotic stresses, developmental processes, cell wall metabolism, calcium distribution, transcription factors, plant hormone biosynthesis and signal transduction pathways. Under calcium deficiency, CNX1, calmodulin-binding proteins and CMLs family proteins were downregulated compared to CK. In addition, plant hormones such as GA, JA, BR, Auxin and ABA biosynthesis pathways genes were downregulated under calcium treatment. Likewise, HATs, ARLs and TCP transcription factors were reported as inactive under calcium deficiency, and potentially involved in the developmental process. This work explores the specific DEGs’ significantly different expression levels in 0 mM Ca and the control involved in plant hormones, cell wall developments, a light response such as chlorophylls and photosynthesis, transport metabolism and defence mechanism and redox. Our results provide critical evidence of the potential roles of the calcium signal transduction pathway and candidate genes governing Ca-deficiency-triggered tipburn in Chinese cabbage.
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Tfelt-Hansen, Jacob, Ana Ferreira, Shozo Yano, Deephti Kanuparthi, Jose R. Romero, Edward M. Brown, and Naibedya Chattopadhyay. "Calcium-sensing receptor activation induces nitric oxide production in H-500 Leydig cancer cells." American Journal of Physiology-Endocrinology and Metabolism 288, no. 6 (June 2005): E1206—E1213. http://dx.doi.org/10.1152/ajpendo.00492.2004.

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Nitric oxide (NO) is a versatile second messenger. NO is produced by Leydig cells, where NO is a negative regulator of steroidogenesis. In cancer cells, NO is thought to have mutagenic and proliferative effects. We have previously shown that the calcium-sensing receptor (CaR) has promalignant effects in rat H-500 Leydig cancer cells, a model for humoral hypercalcemia of malignancy. Calcium, the major physiological ligand of the CaR, is a recognized intracellular cofactor in the process of NO production by virtue of its positive modulation of neuronal and endothelial nitric oxide synthase (NOS), but importantly, not of inducible (i) NOS activity. iNOS activity is regulated by changes in its expression level. Therefore, we investigated whether CaR activation changes iNOS expression. We found that high extracellular calcium (Ca[Formula: see text]) upregulates the level of mRNA for iNOS, whereas no change was seen in neuronal or endothelial NOS, as assessed by microarray and real-time PCR, respectively. The high Ca[Formula: see text]-induced iNOS upregulation was also detected by Northern and Western blotting. By quantitative real-time PCR, we showed that calcium maximally upregulates iNOS at 18 h. The effect of calcium was abolished by overexpression of a dominant-negative CaR (R185Q), confirming that the effect of Ca[Formula: see text] was mediated by the CaR. Cells treated with high calcium had higher NO production than those treated with low calcium, as detected with the NO-specific DAF2-AM dye. This was confirmed in single-cell fluorescence determinations using confocal microscopy. In conclusion, high calcium upregulates the levels of iNOS mRNA and protein as well as NO production in H-500 cells, and the effect of Ca[Formula: see text] on iNOS expression is mediated by the CaR.
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Okada, Hiroyuki, Koji Okabe, and Sakae Tanaka. "Finely-Tuned Calcium Oscillations in Osteoclast Differentiation and Bone Resorption." International Journal of Molecular Sciences 22, no. 1 (December 26, 2020): 180. http://dx.doi.org/10.3390/ijms22010180.

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Calcium (Ca2+) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclastogenesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca2+ storage. Ryanodine receptor, inositol trisphosphate receptor, and sarco/endoplasmic reticulum Ca2+ ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains to be examined.
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47

NAKAZAWA, Fumie, Christian KANNEMEIER, Aya SHIBAMIYA, Yutong SONG, Eleni TZIMA, Uwe SCHUBERT, Takatoshi KOYAMA, et al. "Extracellular RNA is a natural cofactor for the (auto-)activation of Factor VII-activating protease (FSAP)." Biochemical Journal 385, no. 3 (January 24, 2005): 831–38. http://dx.doi.org/10.1042/bj20041021.

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FSAP (Factor VII-activating protease) is a new plasma-derived serine protease with putative dual functions in haemostasis, including activation of coagulation Factor VII and generation of urinary-type plasminogen activator (urokinase). The (auto-)activation of FSAP is facilitated by polyanionic glycosaminoglycans, such as heparin or dextran sulphate, whereas calcium ions stabilize the active form of FSAP. In the present study, extracellular RNA was identified and characterized as a novel FSAP cofactor. The conditioned medium derived from various cell types such as smooth muscle cells, endothelial cells, osteosarcoma cells or CHO (Chinese-hamster ovary) cells contained an acidic factor that initiated (auto-)activation of FSAP. RNase A, but not other hydrolytic enzymes (proteases, glycanases and DNase), abolished the FSAP cofactor activity, which was subsequently isolated by anion-exchange chromatography and unequivocally identified as RNA. In purified systems, as well as in plasma, different forms of natural RNA (rRNA, tRNA, viral RNA and artificial RNA) were able to (auto-)activate FSAP into the two-chain enzyme form. The specific binding of FSAP to RNA (but not to DNA) was shown by mobility-shift assays and UV crosslinking, thereby identifying FSAP as a new extracellular RNA-binding protein, the KD estimated to be 170–350 nM. Activation of FSAP occurred through an RNA-dependent template mechanism involving a nucleic acid size of at least 100 nt. In a purified system, natural RNA augmented the FSAP-dependent Factor VII activation several-fold (as shown by subsequent Factor Xa generation), as well as the FSAP-mediated generation of urokinase. Our results provide evidence for the first time that extracellular RNA, present at sites of cell damage or vascular injury, can serve an important as yet unrecognized cofactor function in haemostasis by inducing (auto-)activation of FSAP through a novel surface-dependent mechanism.
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48

Chen, Rong, Qiuhui Wei, Xin Wei, Yuheng Liu, Xiaomin Zhang, Xiabin Chen, Xiaopu Yin, and Tian Xie. "Stable and efficient immobilization of bi-enzymatic NADPH cofactor recycling system under consecutive microwave irradiation." PLOS ONE 15, no. 11 (November 18, 2020): e0242564. http://dx.doi.org/10.1371/journal.pone.0242564.

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One of the challenges in biocatalysis is the development of stable and efficient bi-enzymatic cascades for bio-redox reactions coupled to the recycling of soluble cofactors. Aldo-keto reductase (LEK) and glucose dehydrogenase (GDH) can be utilized as the NADPH recycling system for economic and efficient biocatalysis of (R)-4-chloro-3-hydroxybutanoate ((R)-CHBE), an important chiral pharmaceutical intermediate. The LEK and GDH was efficiently co-immobilized in mesocellular siliceous foams (MCFs) under microwave irradiation (CoLG-MIA). while they were also co-immobilized by entrapment in calcium alginate without MIA as control (CoLG-CA). The relative activity of CoLG-MIA was increased to 140% compared with that of free LEK. The CoLG-MIA exhibited a wider range of pH and temperature stabilities compared with other preparations. The thermal, storage and batch operational stabilities of microwave-assisted immobilized LEK-GDH were also improved. The NADPH recycling system exhibited the potential as the stable and efficient catalyst for the industrial preparation of (R)-CHBE.
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49

Perry, Susan M. "Investigations on the Relationship Between the Autonomic Nervous System and the Triggering of Malignant Hyperthermia: A State-of-the-Science Review." Annual Review of Nursing Research 32, no. 1 (October 2014): 135–54. http://dx.doi.org/10.1891/0739-6686.32.135.

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Early research in malignant hyperthermia (MH) focused on the autonomic nervous system (ANS) as a primary trigger of the syndrome. This hypothesis was based on the initial signs and symptoms of MH such as tachycardia, cardiac arrhythmias, hypertension, and signs of increased metabolism in patients who developed MH. Supporting these early links between MH and the ANS were case reports from anesthesia providers who reported that patients who subsequently developed MH after a nontriggering previous anesthetic had appeared unusually stressed prior to the surgical procedure in which they triggered. There is no disagreement in the scientific community that a primary disorder in MH lies in the inability to control myoplasmic calcium levels in skeletal muscles. However, considering the variability in genetic and clinical presentation, the timing of intraoperative triggering, and the unexplained phenomenon of nonanesthetic triggering, the identification of cofactors in MH triggering remains paramount. A careful review of existing research supports the hypothesis that the autonomic nervous system plays a significant role as a cofactor in the triggering and progression of an MH episode. If a differentiation can be made and a link can be demonstrated between abnormalities in receptor sensitivity for or release, reuptake, or metabolism of catecholamines in malignant hyperthermia susceptible individuals, we may be able to use these as additional markers/predictors of disease.
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50

Steinberg, Susan F. "Structural Basis of Protein Kinase C Isoform Function." Physiological Reviews 88, no. 4 (October 2008): 1341–78. http://dx.doi.org/10.1152/physrev.00034.2007.

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Protein kinase C (PKC) isoforms comprise a family of lipid-activated enzymes that have been implicated in a wide range of cellular functions. PKCs are modular enzymes comprised of a regulatory domain (that contains the membrane-targeting motifs that respond to lipid cofactors, and in the case of some PKCs calcium) and a relatively conserved catalytic domain that binds ATP and substrates. These enzymes are coexpressed and respond to similar stimulatory agonists in many cell types. However, there is growing evidence that individual PKC isoforms subserve unique (and in some cases opposing) functions in cells, at least in part as a result of isoform-specific subcellular compartmentalization patterns, protein-protein interactions, and posttranslational modifications that influence catalytic function. This review focuses on the structural basis for differences in lipid cofactor responsiveness for individual PKC isoforms, the regulatory phosphorylations that control the normal maturation, activation, signaling function, and downregulation of these enzymes, and the intra-/intermolecular interactions that control PKC isoform activation and subcellular targeting in cells. A detailed understanding of the unique molecular features that underlie isoform-specific posttranslational modification patterns, protein-protein interactions, and subcellular targeting (i.e., that impart functional specificity) should provide the basis for the design of novel PKC isoform-specific activator or inhibitor compounds that can achieve therapeutically useful changes in PKC signaling in cells.
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