Low-molecular-weight chromium-binding substance

Low-molecular-weight chromium-binding substance (LMWCr; also known as chromodulin) is an oligopeptide that seems to transport chromium in the body.[1] It consists of four amino acid residues; aspartate, cysteine, glutamate, and glycine, bonded with four (Cr3+) centers. It interacts with the insulin receptor, by prolonging kinase activity through stimulating the tyrosine kinase pathway, thus leading to improved glucose absorption.[2][3] and has been confused with glucose tolerance factor.[4]

The exact mechanisms underlying this process are currently unknown.[3] Evidence for the existence of this protein comes from the fact that the removal of 51Cr in the blood exceeds the rate of 51Cr formation in the urine.[5] This indicates that the transport of Cr3+ must involve an intermediate (i.e. chromodulin) and that Cr3+ is moved from the blood to tissues in response to increased levels of insulin.[3][5] Subsequent protein isolations in rats, dogs, mice and cows have shown the presence of a similar substance, suggesting that it is found extensively in mammals.[6][7][8] This oligopeptide is small, having a molecular weight of around 1 500 g/mol and the predominant amino acids present are aspartic acid, glutamic acid, glycine, and cysteine.[6][7][8] Despite recent efforts to characterize the exact structure of chromodulin, it is still relatively unknown.[3][9]

Nature of binding

From spectroscopic data, it has been shown that Cr3+ binds tightly to chromodulin (Kf = 1021 M−4), and that the binding is highly cooperative (Hill Coefficient = 3.47).[7] It has been shown that holochromodulin binds 4 equivalents of Cr3+.[6][7][8] Evidence for this comes from in vitro studies which showed that apochromodulin exerts its maximal activity on insulin receptors when titrated with 4 equivalents of Cr3+.[7][8][10] Chromodulin is highly specific for Cr3+ as no other metals are able to stimulate tyrosine kinase activity. It is believed to stimulate the phosphorylation of the 3 tyrosine residues of the β subunits of the insulin receptor.[7][8][10][11] From electronic studies, the crystal field stabilization energy was determined to be 1.74 x 103 while the Racah parameter B was 847 cm−1. This indicates that chromium binds to chromodulin in the trivalent form.[11] In addition, magnetic susceptibility studies have shown that chromium does not coordinate to any N-terminal amine groups but rather to carboxylates (although the exact the amino acids involved are still unknown).[3] These magnetic susceptibility studies are consistent with the presence of a mononuclear Cr3+ center and an unsymmetric trinuclear Cr3+ assembly with bridging oxo ligands.[11] In chromodulin isolated from bovine liver, x-ray absorption spectroscopy studies have shown that the chromium (III) atoms are surrounded by 6 oxygen atoms with an average Cr—O distance of 1.98 Å, while the distance between 2 chromium (III) atoms is 2.79 Å. These results are indicative of a multinuclear assembly.[11] No sulfur ligands coordinate to chromium and instead, it has been proposed that a disulfide linkage between 2 cysteine residues occurs owing to a characteristic peak at 260 nm.[11]

References

  1. ^ Viera M, Davis-McGibony CM (2008). "Isolation and characterization of low-molecular-weight chromium-binding substance (LMWCr) from chicken liver". Protein J. 27 (6): 371–5. doi:10.1007/s10930-008-9146-z. PMID 18769887.
  2. ^ Clodfelder BJ, Emamaullee J, Hepburn DD, Chakov NE, Nettles HS, Vincent JB (2001). "The trail of chromium(III) in vivo from the blood to the urine: the roles of transferrin and chromodulin". J. Biol. Inorg. Chem. 6 (5–6): 608–17. doi:10.1007/s007750100238. PMID 11472024.
  3. ^ a b c d e Vincent, John (2015). "Is the Pharmacological Mode of Action of Chromium (III) as a secondary messenger?". Biological Trace Element Research. 166 (1): 7–12. doi:10.1007/s12011-015-0231-9. PMID 25595680.
  4. ^ Vincent JB (1994). "Relationship between glucose tolerance factor and low-molecular-weight chromium-binding substance" (PDF). J. Nutr. 124 (1): 117–9. doi:10.1093/jn/124.1.117. PMID 8283288.
  5. ^ a b Vincent, John (2012). "The binding and transport of alternative metals by transferrin". Biochimica et Biophysica Acta (BBA) - General Subjects. 1820 (3): 362–378. doi:10.1016/j.bbagen.2011.07.003. PMID 21782896.
  6. ^ a b c Feng, Weiyue (2007). "Chapter 6—The Transport of chromium (III) in the body: Implications for Function" (PDF). In Vincent, John (ed.). The Nutritional Biochemistry of Chromium (III). Amsterdam: Elsevier B.V. pp. 121–137. ISBN 978-0-444-53071-4. Retrieved 20 March 2015.
  7. ^ a b c d e f Vincent, John (2004). "Recent advances in the nutritional biochemistry of trivalent chromium". Proceedings of the Nutrition Society. 63 (1): 41–47. doi:10.1079/PNS2003315. PMID 15070438.
  8. ^ a b c d e Vincent, John (2000). "The Biochemistry of Chromium". The Journal of Nutrition. 130 (4): 715–718. doi:10.1093/jn/130.4.715. PMID 10736319. Retrieved 20 March 2015.
  9. ^ Levina, Aviva; Lay, Peter (2008). "Chemical Properties and Toxcity of Chromium (III) Nutritional Supplements". Chemical Research in Toxicology. 21 (3): 563–571. doi:10.1021/tx700385t. PMID 18237145.
  10. ^ a b Cefalu, William; Hu, Frank (2004). "Role of Chromium in Human Health and in Diabetes". Diabetes Care. 27 (11): 2741–2751. doi:10.2337/diacare.27.11.2741. PMID 15505017. Retrieved 20 March 2015.
  11. ^ a b c d e Vincent, John (2012). "Biochemical Mechanisms". In Vincent, John (ed.). The Bioinorganic Chemistry of Chromium. Chichester, UK: John Wiley & Sons. pp. 125–167. doi:10.1002/9781118458891.ch6. ISBN 9780470664827.