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John B. Vincent - One of the best experts on this subject based on the ideXlab platform.
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The absorption and transport of chromium in the body
The Nutritional Biochemistry of Chromium (III), 2019Co-Authors: John B. Vincent, Kyle C. EdwardsAbstract:Abstract Understanding potential biological effects from chromium(3 +) requires establishing how chromium is transported and distributed in the body. Cr is believed to be absorbed from the gastrointestinal trace by passive diffusion, transported from the bloodstream to tissues by the iron transport protein transferrin, and transported from the tissues back to the bloodstream and ultimately to the urine for elimination by the peptide Low-Molecular-Weight Chromium-Binding Substance (LMWCr). However, each of these steps has been questioned, and data conflicting with this scheme have appeared. Transferrin and LMWCr have been proposed to function in chromium detoxification and to be associated with the pharmacological action of chromium at high doses.
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Encyclopedia of Inorganic and Bioinorganic Chemistry - Chromium: Biological Relevance
Encyclopedia of Inorganic and Bioinorganic Chemistry, 2011Co-Authors: John B. VincentAbstract:The biochemistry of CrIII has been a poorly understood field of endeavor; studies of the biochemistry of none of the other transition metals have been as problematic. Despite four decades of investigation, only recently has a clear picture of the role of Cr been defined potentially. The biologically important form is the trivalent ion, although not in the form of the purported glucose tolerance factor. Apparently, CrIII is required for proper carbohydrate and lipid metabolism in mammals, although Cr deficiency is difficult to achieve. Conditions that increase circulating glucose and insulin concentrations increase urinary chromium output. Cr is excreted after an insulin challenge, probably in the form of the oligopeptide chromodulin. Chromodulin may be the key to understanding the role of Cr at a molecular level as the molecule has been found to bind to the activated insulin receptor, stimulating its kinase activity. A mechanism for the action of chromodulin has been proposed recently. The popular nutritional supplement chromium picolinate has been associated with potentially deleterious effects. The mechanism of toxicity of chromate (CrVI) is still an area of intense investigation. Keywords: chromium; chromodulin; insulin receptor; diabetes; glucose tolerance factor; chromium picolinate; chromate; carcinogen; Low-Molecular-Weight Chromium-Binding Substance; transferrin
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Characterization of the Organic Component of Low-Molecular-Weight Chromium-Binding Substance and Its Binding of Chromium
The Journal of Nutrition, 2011Co-Authors: Yuan Chen, Carolyn J. Cassady, Heather M. Watson, Junjie Gao, Sarmistha Halder Sinha, John B. VincentAbstract:Chromium was proposed to be an essential element over 50 y ago and was shown to have therapeutic potential in treating the symptoms of type 2 diabetes; however, its mechanism of action at a molecular level is unknown. One Chromium-Binding biomolecule, low-molecular weight Chromium-Binding Substance (LMWCr or chromodulin), has been found to be biologically active in in vitro assays and proposed as a potential candidate for the in vivo biologically active form of chromium. Characterization of the organic component of LMWCr has proven difficult. Treating bovine LMWCr with trifluoroacetic acid followed by purification on a graphite powder micro-column generates a heptapeptide fragment of LMWCr. The peptide sequence of the fragment was analyzed by MS and tandem MS (MS/MS and MS/MS/MS) using collision-induced dissociation and post-source decay. Two candidate sequences, pEEEEGDD and pEEEGEDD (where pE is pyroglutamate), were identified from the MS/MS experiments; additional tandem MS suggests the sequence is pEEEEGDD. The N-terminal glutamate residues explain the inability to sequence LMWCr by the Edman method. Langmuir isotherms and Hill plots were used to analyze the binding constants of chromic ions to synthetic peptides similar in composition to apoLMWCr. The sequence pEEEEGDD was found to bind 4 chromic ions per peptide with nearly identical cooperativity and binding constants to those of apoLMWCr. This work should lead to further studies elucidating or eliminating a potential role for LMWCr in treating the symptoms of type 2 diabetes and other conditions resulting from improper carbohydrate and lipid metabolism.
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Quest for the Molecular Mechanism of Chromium Action and Its Relationship to Diabetes
Nutrition Reviews, 2009Co-Authors: John B. VincentAbstract:Despite forty years of research on the potential role of chromium in carbohydrate and lipid metabolism, significant progress has only recently been made regarding the mode of action of chromium at a molecular level. The oligopeptide Low-Molecular-Weight Chromium-Binding Substance (LMWCr) may function as part of a novel insulin-signaling autoamplification mechanism. The proposed mechanism of action also sheds some light on the potential of chromium-containing compounds as nutritional supplements or in the treatment of adult-onset diabetes and other conditions. The potential relationship between the results of recent studies on diabetic patients and the proposed mode of action of LMWCr are discussed.
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Low-Molecular-Weight Chromium-Binding Substance from chicken liver and American alligator liver
Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 2006Co-Authors: M. Jason Hatfield, Shanna Gillespie, Yuan Chen, Carolyn J. Cassady, John B. VincentAbstract:Low-Molecular-Weight Chromium-Binding Substance (LMWCr), also known as chromodulin, is a Chromium-Binding oligopeptide proposed to have a function in chromium transport and insulin signaling in mammals. In this work, LMWCr has been isolated and purified for the first time from non-mammalian sources: chicken and American alligator. Milligram quantities of the oligopeptide can be obtained from kilogram quantities of liver. The LMWCr's from both sources are asparatate- and glutamate-rich oligopeptides which possess multinuclear chromium assemblies. The composition and physical and spectroscopic properties of the avian and reptilian LMWCr's are extremely similar to those of their mammalian analogues, suggesting the multinuclear sites of the biomolecule from all three classes of animal possess very similar structures. The chicken and alligator oligopeptides may possess intrinsic phosphotyrosine phosphatase activity.
J. B. Vincent - One of the best experts on this subject based on the ideXlab platform.
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The binding of trivalent chromium to Low-Molecular-Weight Chromium-Binding Substance (LMWCr) and the transfer of chromium from transferrin and chromium picolinate to LMWCr
JBIC Journal of Biological Inorganic Chemistry, 2000Co-Authors: Yanjie Sun, J Ramirez, S. A. Woski, J. B. VincentAbstract:-transferrin and the nutritional supplement chromium picolinate, Cr(pic)_3, was examined. These results are consistent with the model of the mode of action of LMWCr; a Hill study indicates the four chromic ions bind to apoLMWCr in a highly cooperative fashion ( n =3.47) with a binding constant of 1.54×10^21. Chromium is readily transferred from transferrin to apoLMWCr at near neutral pH. The results also suggest that reduction of the chromic center of Cr(pic)_3 may be required for the supplement to release chromium; thus, release of chromium is related to a mechanism by which Cr(pic)_3 may generate hydroxyl radicals in cells.
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The biomimetic [Cr_3O(O_2CCH_2CH_3)_6(H_2O)_3]^+ decreases plasma cholesterol and triglycerides in rats: towards chromium-containing therapeutics
JBIC Journal of Biological Inorganic Chemistry, 1999Co-Authors: Yanjie Sun, Kavita Mallya, Juliet Ramirez, J. B. VincentAbstract:O(O_2CCH_2CH_3)_6 (H_2O)_3]^+ 1 and a naturally occurring, biologically active form of chromium, Low-Molecular-Weight Chromium-Binding Substance (LMWCr), to rats are described. Given that the complexes are proposed to function by interacting with insulin receptor, trapping it in its active conformation, in contrast to current chromium-containing nutrition supplements, which only serve as sources of absorbable chromium, changes in lipid and carbohydrate metabolism would be expected. After 12 weeks administration (20 μg/kg body mass), compound 1 results in 40% lower levels of blood plasma LDL cholesterol, 33% lower levels of total cholesterol, and significantly lower HDL cholesterol and triglyceride; these results are in stark contrast to those of administration of other forms of Cr(III) to rats, which have no effect on these parameters. LMWCr, in contrast to 1 , has no effect as it probably is degraded in vivoor excreted. These results are interpreted in terms of the mechanism of chromium action in response to insulin and the activation of insulin receptor, and the potential for the rational design of chromium-containing therapeutics is discussed.
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Chromium in carbohydrate and lipid metabolism
JBIC Journal of Biological Inorganic Chemistry, 1997Co-Authors: C. Michele Davis, J. B. VincentAbstract:Since the discovery in the 1950s that mammals have a nutritional requirement for chromium, the biological function of chromium has been sought. Candidates for the naturally-occurring biologically active form of chromium have been proposed, but, until recently, all have been shown to be artifacts. Recent studies examining the properties of the oligopeptide Low-Molecular-Weight Chromium-Binding Substance (LMWCr) suggest that this material may have a role in carbohydrate and lipid metabolism as part of a novel insulin-signaling amplification mechanism and may have implications in the treatment of diabetes and related conditions.
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Chromium oligopeptide activates insulin receptor tyrosine kinase activity.
Biochemistry, 1997Co-Authors: C. Michele Davis, J. B. VincentAbstract:A possible new mechanism for the amplification of insulin receptor tyrosine kinase activity in response to insulin has been identified. The chromium-containing oligopeptide low molecular weight Chromium-Binding Substance (LMWCr) does not effect the tyrosine protein kinase activity of rat adipocytic membrane fragments in the absence of insulin; however, insulin-stimulated kinase activity in the membrane fragments is increased up to 8-fold by the oligopeptide. Using isolated rat insulin receptor, LMWCr has been shown to bind to insulin-activated insulin receptor with a dissociation constant of circa 250 pM, resulting in the increase of its tyrosine protein kinase activity. The ability of LMWCr to stimulate insulin receptor tyrosine kinase activity is dependent on its chromium content. The results appear to explain the previously poorly understood relationship between chromium and adult-onset diabetes and cardiovascular disease.
Yanjie Sun - One of the best experts on this subject based on the ideXlab platform.
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the binding of trivalent chromium to low molecular weight chromium binding Substance lmwcr and the transfer of chromium from transferrin and chromium picolinate to lmwcr
Journal of Biological Inorganic Chemistry, 2000Co-Authors: Yanjie Sun, Stephen A. Woski, J Ramirez, John B. VincentAbstract:A recent model for the role of chromium in insulin signaling requires that the oligopeptide Low-Molecular-Weight Chromium-Binding Substance (LMWCr) tightly bind four chromic ions before the oligopeptide obtains a conformation required for binding to the tyrosine kinase active site of the insulin receptor. To test this model, the Chromium-Binding constant of LMWCr was determined, and the ability of LMWCr to remove chromium from Cr2-transferrin and the nutritional supplement chromium picolinate, Cr(pic)3, was examined. These results are consistent with the model of the mode of action of LMWCr; a Hill study indicates the four chromic ions bind to apoLMWCr in a highly cooperative fashion (n =3.47) with a binding constant of 1.54x 10(21). Chromium is readily transferred from transferrin to apoLMWCr at near neutral pH. The results also suggest that reduction of the chromic center of Cr(pic)3 may be required for the supplement to release chromium; thus, release of chromium is related to a mechanism by which Cr(pic)3 may generate hydroxyl radicals in cells.
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The binding of trivalent chromium to Low-Molecular-Weight Chromium-Binding Substance (LMWCr) and the transfer of chromium from transferrin and chromium picolinate to LMWCr
JBIC Journal of Biological Inorganic Chemistry, 2000Co-Authors: Yanjie Sun, J Ramirez, S. A. Woski, J. B. VincentAbstract:-transferrin and the nutritional supplement chromium picolinate, Cr(pic)_3, was examined. These results are consistent with the model of the mode of action of LMWCr; a Hill study indicates the four chromic ions bind to apoLMWCr in a highly cooperative fashion ( n =3.47) with a binding constant of 1.54×10^21. Chromium is readily transferred from transferrin to apoLMWCr at near neutral pH. The results also suggest that reduction of the chromic center of Cr(pic)_3 may be required for the supplement to release chromium; thus, release of chromium is related to a mechanism by which Cr(pic)_3 may generate hydroxyl radicals in cells.
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The biomimetic [Cr_3O(O_2CCH_2CH_3)_6(H_2O)_3]^+ decreases plasma cholesterol and triglycerides in rats: towards chromium-containing therapeutics
JBIC Journal of Biological Inorganic Chemistry, 1999Co-Authors: Yanjie Sun, Kavita Mallya, Juliet Ramirez, J. B. VincentAbstract:O(O_2CCH_2CH_3)_6 (H_2O)_3]^+ 1 and a naturally occurring, biologically active form of chromium, Low-Molecular-Weight Chromium-Binding Substance (LMWCr), to rats are described. Given that the complexes are proposed to function by interacting with insulin receptor, trapping it in its active conformation, in contrast to current chromium-containing nutrition supplements, which only serve as sources of absorbable chromium, changes in lipid and carbohydrate metabolism would be expected. After 12 weeks administration (20 μg/kg body mass), compound 1 results in 40% lower levels of blood plasma LDL cholesterol, 33% lower levels of total cholesterol, and significantly lower HDL cholesterol and triglyceride; these results are in stark contrast to those of administration of other forms of Cr(III) to rats, which have no effect on these parameters. LMWCr, in contrast to 1 , has no effect as it probably is degraded in vivoor excreted. These results are interpreted in terms of the mechanism of chromium action in response to insulin and the activation of insulin receptor, and the potential for the rational design of chromium-containing therapeutics is discussed.
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The biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ decreases plasma cholesterol and triglycerides in rats: towards chromium-containing therapeutics.
JBIC Journal of Biological Inorganic Chemistry, 1999Co-Authors: Yanjie Sun, Kavita Mallya, Juliet Ramirez, John B. VincentAbstract:O(O2CCH2CH3)6 (H2O)3]+1 and a naturally occurring, biologically active form of chromium, Low-Molecular-Weight Chromium-Binding Substance (LMWCr), to rats are described. Given that the complexes are proposed to function by interacting with insulin receptor, trapping it in its active conformation, in contrast to current chromium-containing nutrition supplements, which only serve as sources of absorbable chromium, changes in lipid and carbohydrate metabolism would be expected. After 12 weeks administration (20 μg/kg body mass), compound 1 results in 40% lower levels of blood plasma LDL cholesterol, 33% lower levels of total cholesterol, and significantly lower HDL cholesterol and triglyceride; these results are in stark contrast to those of administration of other forms of Cr(III) to rats, which have no effect on these parameters. LMWCr, in contrast to 1, has no effect as it probably is degraded in vivoor excreted. These results are interpreted in terms of the mechanism of chromium action in response to insulin and the activation of insulin receptor, and the potential for the rational design of chromium-containing therapeutics is discussed.
Stephen A. Woski - One of the best experts on this subject based on the ideXlab platform.
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the binding of trivalent chromium to low molecular weight chromium binding Substance lmwcr and the transfer of chromium from transferrin and chromium picolinate to lmwcr
Journal of Biological Inorganic Chemistry, 2000Co-Authors: Yanjie Sun, Stephen A. Woski, J Ramirez, John B. VincentAbstract:A recent model for the role of chromium in insulin signaling requires that the oligopeptide Low-Molecular-Weight Chromium-Binding Substance (LMWCr) tightly bind four chromic ions before the oligopeptide obtains a conformation required for binding to the tyrosine kinase active site of the insulin receptor. To test this model, the Chromium-Binding constant of LMWCr was determined, and the ability of LMWCr to remove chromium from Cr2-transferrin and the nutritional supplement chromium picolinate, Cr(pic)3, was examined. These results are consistent with the model of the mode of action of LMWCr; a Hill study indicates the four chromic ions bind to apoLMWCr in a highly cooperative fashion (n =3.47) with a binding constant of 1.54x 10(21). Chromium is readily transferred from transferrin to apoLMWCr at near neutral pH. The results also suggest that reduction of the chromic center of Cr(pic)3 may be required for the supplement to release chromium; thus, release of chromium is related to a mechanism by which Cr(pic)3 may generate hydroxyl radicals in cells.
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Low-Molecular-Weight Chromium-Binding Substance AND BIOMIMETIC CR3O(O2CCH2CH3)6(H2O)3+ DO NOT CLEAVE DNA UNDER PHYSIOLOGICALLY-RELEVANT CONDITIONS
Polyhedron, 1999Co-Authors: J.kristopher Speetjens, John B. Vincent, Ali Parand, Michael W. Crowder, Stephen A. WoskiAbstract:Abstract Chromium(III) tris(picolinate), Cr(pic)3, is currently a very popular nutritional supplement; however, at physiologically-relevant concentrations, it has recently been demonstrated to cleave DNA [J.K. Speetjens, R.A. Collins, J.B. Vincent, S.A. Woski, Chem. Res. Toxicol. 12 (1999) 483]. A number of other chromium-containing compounds have been proposed as substitutes for Cr(pic)3. Of particular interest are Low-Molecular-Weight Chromium-Binding Substance (LMWCr) and [Cr3O(O2CCH2CH3)6(H2O)3]+ 1. The former compound has recently been identified as the biologically active form of chromium in mammals, activating the kinase activity of insulin receptor in the presence of insulin. Complex 1 is a functional biomimetic for LMWCr. Both compounds have been proposed as possible nutritional supplements and therapeutics for adult-onset diabetes. This work demonstrates that these complexes, unlike Cr(pic)3, are poor DNA-cleaving agents and may represent safer materials for human consumption.
C. Michele Davis - One of the best experts on this subject based on the ideXlab platform.
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Chromium in carbohydrate and lipid metabolism
JBIC Journal of Biological Inorganic Chemistry, 1997Co-Authors: C. Michele Davis, J. B. VincentAbstract:Since the discovery in the 1950s that mammals have a nutritional requirement for chromium, the biological function of chromium has been sought. Candidates for the naturally-occurring biologically active form of chromium have been proposed, but, until recently, all have been shown to be artifacts. Recent studies examining the properties of the oligopeptide Low-Molecular-Weight Chromium-Binding Substance (LMWCr) suggest that this material may have a role in carbohydrate and lipid metabolism as part of a novel insulin-signaling amplification mechanism and may have implications in the treatment of diabetes and related conditions.
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Synthetic Multinuclear Chromium Assembly Activates Insulin Receptor Kinase Activity: Functional Model for Low-Molecular-Weight Chromium-Binding Substance
Inorganic Chemistry, 1997Co-Authors: C. Michele Davis, And April C. Royer, John B. VincentAbstract:The biologically-active form of chromium, Low-Molecular-Weight Chromium-Binding Substance (LMWCr), activates the insulin-dependent tyrosine protein kinase activity of insulin receptor (IR). The site of activation was shown to be on the active site fragment of the β subunit of IR. As LMWCr previously has been proposed to contain a multinuclear chromic assembly, the ability of multinuclear chromium assemblies to activate IR kinase activity has been probed. The trinuclear cation [Cr3O(O2CCH2CH3)6(H2O)3]+ (1) has been found to activate IR activity in a fashion almost identical to that of LMWCr using rat adipocytic membrane fragments and an active site fragment of IR, while a variety of other chromic complexes have in contrast been found to be ineffective or to inhibit kinase activity. The activation of IR kinase activity by complex 1, its stability in aqueous and strongly acidic solution, and its low molecular weight suggest that it potentially could be used in a treatment for adult-onset diabetes.
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Isolation and Characterization of a Biologically Active Chromium Oligopeptide from Bovine Liver
Archives of Biochemistry and Biophysics, 1997Co-Authors: C. Michele Davis, John B. VincentAbstract:Low-Molecular-Weight Chromium-Binding Substance (LMWCr), the only known naturally occurring Cr-containing polypeptide from mammals and candidate for the biologically active form of chromium, has been isolated for the first time in yields sufficient for spectroscopic studies capable of providing structural and mechanistic data on a molecular level. The results of paramagnetic1H NMR, electron paramagnetic resonance, and electronic spectroscopic studies indicate that the four chromic ions per polypeptide are probably arranged in an integer-spin tetranuclear assembly, although an alternate possibility, the presence of two dinuclear assemblies, could not be ruled out. This assembly (or assemblies) is bridged by anionic ligands and supported by carboxylates provided by the polypeptide.
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Chromium oligopeptide activates insulin receptor tyrosine kinase activity.
Biochemistry, 1997Co-Authors: C. Michele Davis, J. B. VincentAbstract:A possible new mechanism for the amplification of insulin receptor tyrosine kinase activity in response to insulin has been identified. The chromium-containing oligopeptide low molecular weight Chromium-Binding Substance (LMWCr) does not effect the tyrosine protein kinase activity of rat adipocytic membrane fragments in the absence of insulin; however, insulin-stimulated kinase activity in the membrane fragments is increased up to 8-fold by the oligopeptide. Using isolated rat insulin receptor, LMWCr has been shown to bind to insulin-activated insulin receptor with a dissociation constant of circa 250 pM, resulting in the increase of its tyrosine protein kinase activity. The ability of LMWCr to stimulate insulin receptor tyrosine kinase activity is dependent on its chromium content. The results appear to explain the previously poorly understood relationship between chromium and adult-onset diabetes and cardiovascular disease.
