Low-molecular-weight chromium-binding substance

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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 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]

Related Research Articles

Chromium Chemical element with atomic number 24

Chromium is a chemical element with the symbol Cr and atomic number 24. It is the first element in group 6. It is a steely-grey, lustrous, hard and brittle transition metal. Chromium is the main additive in stainless steel, to which it adds anti-corrosive properties. Chromium is also highly valued as a metal that is able to be highly polished while resisting tarnishing. Polished chromium reflects almost 70% of the visible spectrum, with almost 90% of infrared light being reflected. The name of the element is derived from the Greek word χρῶμα, chrōma, meaning color, because many chromium compounds are intensely colored.

Insulin Peptide hormone

Insulin is a peptide hormone produced by beta cells of the pancreatic islets; it is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

Protein kinase enzyme that adds phosphate groups to other proteins

A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction.

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

Kinase Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the substrate gains a phosphate group and the high-energy ATP molecule donates a phosphate group. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

Glucagon mammalian protein found in human, mouse, and rat

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Insulin receptor mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of tyrosine kinase receptors. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

GSK-3 class of enzymes

Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase, GSK-3 has since been identified as a kinase for over 100 different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two paralogous genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes, Alzheimer's disease, inflammation, cancer, and bipolar disorder.

Chromium(III) picolinate chemical compound

Chromium(III) picolinate (CrPic3) is a chemical compound sold as a nutritional supplement to treat type 2 diabetes and promote weight loss. This bright-red coordination compound is derived from chromium(III) and picolinic acid. Small quantities of chromium are needed for glucose utilization by insulin in normal health, but deficiency is extremely rare and has only been observed in people receiving 100% of their nutrient needs intravenously, i.e., total parenteral nutrition diets. Chromium has been identified as regulating insulin by increasing the sensitivity of the insulin receptor. As such, chromium(III) picolinate has been proposed as a treatment for type 2 diabetes, although its effectiveness remains controversial due to conflicting evidence from human trials.

Branched-chain amino acid chemical compound

A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch. Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and valine. Non-proteinogenic BCAAs include 2-aminoisobutyric acid.

Glucose transporter type 4 (GLUT-4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

Insulin-like growth factor 1 receptor protein-coding gene in the species Homo sapiens

The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults – meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. This testifies to the strong growth-promoting effect of this receptor.

Receptor tyrosine kinase class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non receptor tyrosine kinases which do not possess transmembrane domains.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2, Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's Disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

IRS1 protein-coding gene in the species Homo sapiens

Insulin receptor substrate 1 (IRS-1) is a signaling adapter protein that in humans is encoded by the IRS-1 gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies.

PTPN1 protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the PTPN1 gene. PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes. It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well.

The Walker A and Walker B motifs are protein sequence motifs, known to have highly conserved three-dimensional structures. These were first reported in ATP-binding proteins by Walker and co-workers in 1982.

Phonemic neurological hypochromium therapy (PNHT) is a technique that uses insemination devices to implement chromium (Cr3+) into the hypothalamic regions of the brain. It has been proposed by Dr. Nicole Kim to offset delayed phonemic awareness in children between the ages of 3 and 8. The causes of delayed phonemic awareness have been linked to an inability to break down chromium triastenitephosphate. PNHT has been successfully implemented into in vivo mice with some controversial side effects, including; polydactyly, regurgitation, fatigue, and nausea. While Russia, Poland, and Ukraine have approved this procedure, the United States Food and Drug Administration (USFDA) has not yet granted its approval.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

Chromium is claimed to be an essential element involved in the regulation of blood glucose levels within the body. More recent reviews have questioned this however.

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. 1 2 3 4 5 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. 1 2 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. 1 2 3 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. 1 2 3 4 5 6 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. 1 2 3 4 5 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. 1 2 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. 1 2 3 4 5 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.
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