Flavin associated Sulfhydryl oxidase and Ero1β in Insulin activity in Type 2 Diabetes Mellitus
Main Article Content
Abstract
DM is proving to be a global public health burden as this number is expected to rise to another 200 million by 2040. Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycaemia. It may be due to impaired insulin secretion, resistance to peripheral actions of insulin, or both.
Type 1 diabetes mellitus accounts for 5% to 10% of DM and is characterized by autoimmune destruction of insulin-producing beta cells in the islets of the pancreas.
Type 2 diabetes mellitus accounts for around 90% of all cases of diabetes. In Type 2 diabetes mellitus the response to insulin is diminished, and this is defined as insulin resistance. During this state, insulin is ineffective and we now hypothesize that this ineffectiveness of Insulin is due to its improper folding affecting its activity.
Insulin consists of two chains: A chain with 21 amino acids and B chain consists of 30 amino acids with intra and interchain disulphide bonds. These disulphide linkages help to stabilize the structure of insulin thus resulting in its proper biological activity.
The flavin-dependent Endoplasmic Reticulum oxidoreductase 1 beta family of sulfhydryl oxidase enzymes Quiescin-sulfhydryl oxidase rapidly inserts disulfide bonds into unfolded proteins thereby stabilising their tertiary and quaternary structures. As this enzyme is Flavin dependent, a dietary deficiency of Riboflavin leads to improper activity of Sulfhydryl oxidase resulting in abnormal folding of proteins affecting their biological activity.
Riboflavin is one of the most common vitamin deficiencies seen in Indian population. The overall prevalence of deficiency of vitamin B2 (Riboflavin) was strikingly high as documented in various studies.
Looking at the rising trend of Type 2 Diabetes Mellitus cases in worldwide and in India, it is always the need of time to look into the pathophysiology of Insulin inactivity in these cases. Sulfhydryl oxidase can be the target molecule and improving its actions with Riboflavin supplementation can prove to be an easy and cost-effective way for the target population to overall improve the Insulin activity. For this the biochemical link has to be established between Sulfhydryl oxidase, Riboflavin and Insulin.
Hence, this study aims to establish the mechanistic link between serum Sulfhydryl oxidase and Ero1β with serum Riboflavin and Insulin in Type 2 Diabetes Mellitus patients.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Weiss M, Steiner DF, Philipson LH. Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships. Nih.gov. Published February 2014. https://www.ncbi.nlm.nih.gov/books/NBK279029/
3. Chang SG, Choi KD, Jang SH, Shin HC. Role of disulfide bonds in the structure and activity of human insulin. Mol Cells. 2003;16(3):323-330.
4. Guo ZY, Feng YM. Effects of Cysteine to Serine Substitutions in the Two Inter-Chain Disulfide Bonds of Insulin. Biological Chemistry. 2001;382(3). doi:https://doi.org/10.1515/bc.2001.054
5. Guo ZY, Jia XY, Feng YM. Replacement of the interchain disulfide bridge-forming amino acids A7 and B7 by glutamate impairs the structure and activity of insulin. Biological chemistry. 2004;385 (12):1171-1175. doi:https://doi.org/10.1515/bc.2004.151
6. Vinther TN, Kjeldsen TB, Jensen KJ, Hubálek F. The road to the first, fully active and more stable human insulin variant with an additional disulfide bond. Journal of Peptide Science. 2015;21(11):797-806. doi:https://doi.org/10.1002/psc.2822
7. Heckler EJ, Alon A, Fass D, Thorpe C. Human Quiescin-Sulfhydryl Oxidase, QSOX1: Probing Internal Redox Steps by Mutagenesis†. Biochemistry. 2008;47 (17):4955-4963. doi:https://doi.org/10.1021/bi702522q
8. Hoober KL, Glynn NM, Burnside J, Coppock DL, Thorpe C. Homology between egg white sulfhydryl oxidase and quiescin Q6 defines a new class of flavin-linked sulfhydryl oxidases. J Biol Chem. 1999;274(45):31759-31762. doi:10.1074/jbc.274.45.31759
9. Chakravarthi S, Jessop Catherine E, Willer M, Stirling Colin J, Bulleid Neil J. Intracellular catalysis of disulfide bond formation by the human sulfhydryl oxidase, QSOX1. Biochemical Journal. 2007;404(3):403-411. doi:https://doi.org/10.1042/bj20061510
10. Kodali VK, Thorpe C. Oxidative Protein Folding and the Quiescin–Sulfhydryl Oxidase Family of Flavoproteins. Antioxidants & Redox Signaling. 2010;13(8):1217-1230. doi:https://doi.org/10.1089/ars.2010.3098
11. Hoober KL, Sheasley SL, Gilbert HF, Thorpe C. Sulfhydryl Oxidase from Egg White. Journal of Biological Chemistry. 1999;274(32):22147-22150. doi:https://doi.org/10.1074/jbc.274.32.22147
12. E. Yu. Klyosova, Shkurat EA, Azarova YE, Polonikov AV. Polymorphism rs1046495 of the GFER Gene as a New Genetic Marker of Preposition to Type 2 Diabetes Mellitus. Bulletin of experimental biology and medicine. 2022;172(5):587-591. doi:https://doi.org/10.1007/s10517-022-05441-2
13. Zito E, Chin KT, Blais J, Harding HP, Ron D. ERO1-beta, a pancreas-specific disulfide oxidase, promotes insulin biogenesis and glucose homeostasis [published correction appears in J Cell Biol. 2010 May 17;189(4):769]. J Cell Biol. 2010;188(6):821-832. doi:10.1083/jcb.200911086
14. Motoharu Awazawa, Takashi Futami, Michinori Sakada, et al. Deregulation of Pancreas-Specific Oxidoreductin ERO1β in the Pathogenesis of Diabetes Mellitus. Molecular and cellular biology. 2014;34(7):1290-1299. doi:https://doi.org/10.1128/mcb.01647-13
15. Shergalis AG, Hu S, Bankhead A 3rd, Neamati N. Role of the ERO1-PDI interaction in oxidative protein folding and disease. Pharmacol Ther. 2020;210:107525. doi:10.1016/j.pharmthera.2020.107525
16. Sivaprasad M, Shalini T, Reddy PY, et al. Prevalence of vitamin deficiencies in an apparently healthy urban adult population: Assessed by subclinical status and dietary intakes. Nutrition. 2019;63-64:106-113. doi:10.1016/j.nut.2019.01.017
17. Hartl FU, Hayer-Hartl M. Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol. 2009;16(6):574-581. doi:10.1038/nsmb.1591
18. Manthey KC, Rodriguez-Melendez R, Hoi JT, Zempleni J. Riboflavin deficiency causes protein and DNA damage in HepG2 cells, triggering arrest in G1 phase of the cell cycle. J Nutr Biochem. 2006;17(4):250-256. doi:10.1016/j.jnutbio.2005.05.004
19. Liu M, Weiss MA, Arunagiri A, et al. Biosynthesis, structure, and folding of the insulin precursor protein. Diabetes Obes Metab. 2018;20 Suppl 2(Suppl 2):28-50. doi:10.1111/dom.13378
20. Alam MM, Iqbal S, Naseem I. Ameliorative effect of riboflavin on hyperglycemia, oxidative stress and DNA damage in type-2 diabetic mice: Mechanistic and therapeutic strategies. Arch Biochem Biophys. 2015;584:10-19. doi:10.1016/j.abb.2015.08.013