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]
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]
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]
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]