Mutation Annotation, Peptide Designing and Targeting of V 383 Position in GLUT4, an Important Enzyme Involved in Glucose Metabolism

Author Name: *Aditi Jain, Naveen Veeragani
Author Email: aditijain.lucknow@gmail.com

Abstract

Diabetes mellitus a well known disorder of current era has several direct and indirect causes for its onset. Glucose transporter type 4, also known as GLUT4, is a protein encoded by the GLUT4gene which is an insulin-regulated glucose transporter involved in insulin-regulated glucose transport into the cell. This protein is expressed primarily in muscle and fat cells which are the major tissues in the body that respond to insulin. The current work involves the analysis of the GLUT4 protein and its Mutational study. The work involves the targeting of the site 383 Valine in the protein sequence which is the most mutable site in the sequence as inferred from the literature. The site was replaced by all the other possible 19 amino acids using various insilico tools and softwares and the effect of these substitutions on the protein’s stability and function have been analyzed. The results concluded that the substitution of Valine with Histidine or Tryptophan at 383 is probably more damaging when compared to the other 17 combinations. Due to the most deleterious effect of these two mutated peptides, the current work aimed at designing the 3D structure of the two followed by selecting a potent drug that can act against these two mutant peptides and can control the diseased condition. Docking studies were performed in order to select the best drug among the study ligands. The study also concluded that among the study chemical saxagliptin gave good docking results with lowest docking energy, indicating the importance of it in treating the condition.

Keywords

GLUT4, Glucose Transporter, Mutational Analysis, Docking, Saxagliptin.

Introduction

Diabetes mellitus type 2
Diabetes mellitus type 2 occurs when the cells in the body do not respond to the insulin produced (insulin resistance) or sometimes combined with inadequate insulin production. It is also referred to as non Insulin-dependent diabetes mellitus (NIDDM) or “Adult-Onset Diabetes”. Some of the common causes known to all are: Living a sedentary lifestyle, obesity, junk foods and heredity. But most of the people are unaware of the actual causes of the condiotion [1] Approximately 90% of all cases of diabetes worldwide are of this type [2]. Some individuals may control the symptoms of their diabetes mellitus type 2 by following a healthy diet, losing weight, doing plenty of exercise, and monitoring their blood glucose levels. Overweight and obese people have a much higher risk of developing type 2 diabetes compared to those with a healthy body weight. The risk of developing type 2 diabetes is also greater with the onset of age. Men whose testosterone levels are low have been found to have a higher risk of developing type 2 diabetes. Major symptoms of type 2 diabetes include Frequent urination Disproportionate thirst Intense hunger, Unusual weight loss, Increased fatigue, Blurred vision.
Glucose Transporter Type 4 and Its Importance:
Type 2 diabetes has genetic and environmental factors that increase the chances of an individual of being attached. Among the environmental factors are high cholesterol and obesity, and among the genetic factors are genes involved in glucose metabolism or glucose intake signaling such as GLUT4 [3] The GLUT4 gene (aka SLC2A4) is a member of the solute carrier family 2 (facilitated glucose transporter) family and it and encodes a 509 amino acid long protein called GLUT4 also termed as glucose transporter 4 that functions as an insulin-regulated facilitative glucose transporter [4]. There are several glucose transporters such as GLUT1, GLUT2, etc in the cell that help keep the blood glucose level low, but GLUT4 is the only one that responds to insulin. GLUT4 is in the family of solute carriers and is responsible for facilitating the transport of glucose into the cells in response to insulin [5]. For this reason, mutations in GLUT4 have been associated with Type 2 diabetes [6]. The GLUT4 gene has been mapped to the region 13 in the short arm of chromosome 17 (17p13) [7]. Also it has been determined that the gene is 6314 bp long and contains 11 exons.

Conclusion

From the above work it can be concluded that the (V->H) type of mutations at position 383 in GLUT-4 can be targeted with the ligand saxagliptin(CID 66576989). Saxagliptin being an inhibitor of the enzyme DPP-4, which breaks down incretin hormones that are responsible for the beneficial actions of Saxagliptin, including increasing insulin production in response to meals and decreasing the amount of glucose (sugar) that the liver produces. Because incretin hormones are more active in response to higher blood sugar levels (and are less active in response to low blood sugar), the risk of dangerously low blood sugar (hypoglycemia) is low with Saxagliptin. Thus saxagliptin could prove to be of great help to the patients of Diabetes Mellitus Type-2.

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