| Structural highlights
Disease
[INS_HUMAN] Defects in INS are the cause of familial hyperproinsulinemia (FHPRI) [MIM:176730].[1] [2] [3] [4] Defects in INS are a cause of diabetes mellitus insulin-dependent type 2 (IDDM2) [MIM:125852]. IDDM2 is a multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical fetaures are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.[5] Defects in INS are a cause of diabetes mellitus permanent neonatal (PNDM) [MIM:606176]. PNDM is a rare form of diabetes distinct from childhood-onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy.[6] [7] Defects in INS are a cause of maturity-onset diabetes of the young type 10 (MODY10) [MIM:613370]. MODY10 is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.[8] [9] [10]
Function
[INS_HUMAN] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
Publication Abstract from PubMed
We have systematically explored three approaches based on 9-fluorenylmethoxycarbonyl (Fmoc) chemistry solid phase peptide synthesis (SPPS) for the total chemical synthesis of the key depsipeptide intermediate for the efficient total chemical synthesis of insulin. The approaches used were: stepwise Fmoc chemistry SPPS; the "hybrid method", in which maximally protected peptide segments made by Fmoc chemistry SPPS are condensed in solution; and, native chemical ligation using peptide-thioester segments generated by Fmoc chemistry SPPS. A key building block in all three approaches was a Glu[O-beta-(Thr)] ester-linked dipeptide equipped with a set of orthogonal protecting groups compatible with Fmoc chemistry SPPS. The most effective method for the preparation of the 51 residue ester-linked polypeptide chain of ester insulin was the use of unprotected peptide-thioester segments, prepared from peptide-hydrazides synthesized by Fmoc chemistry SPPS, and condensed by native chemical ligation. High-resolution X-ray crystallography confirmed the disulfide pairings and three-dimensional structure of synthetic insulin lispro prepared from ester insulin lispro by this route. Further optimization of these pilot studies could yield an efficient total chemical synthesis of insulin lispro (Humalog) based on peptide synthesis by Fmoc chemistry SPPS.
Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin.,Dhayalan B, Mandal K, Rege N, Weiss MA, Eitel SH, Meier T, Schoenleber RO, Kent SB Chemistry. 2016 Nov 30. doi: 10.1002/chem.201605578. PMID:27905149[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chan SJ, Seino S, Gruppuso PA, Schwartz R, Steiner DF. A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2194-7. PMID:3470784
- ↑ Barbetti F, Raben N, Kadowaki T, Cama A, Accili D, Gabbay KH, Merenich JA, Taylor SI, Roth J. Two unrelated patients with familial hyperproinsulinemia due to a mutation substituting histidine for arginine at position 65 in the proinsulin molecule: identification of the mutation by direct sequencing of genomic deoxyribonucleic acid amplified by polymerase chain reaction. J Clin Endocrinol Metab. 1990 Jul;71(1):164-9. PMID:2196279
- ↑ Shibasaki Y, Kawakami T, Kanazawa Y, Akanuma Y, Takaku F. Posttranslational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulinemia. J Clin Invest. 1985 Jul;76(1):378-80. PMID:4019786 doi:http://dx.doi.org/10.1172/JCI111973
- ↑ Yano H, Kitano N, Morimoto M, Polonsky KS, Imura H, Seino Y. A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto). J Clin Invest. 1992 Jun;89(6):1902-7. PMID:1601997 doi:http://dx.doi.org/10.1172/JCI115795
- ↑ Molven A, Ringdal M, Nordbo AM, Raeder H, Stoy J, Lipkind GM, Steiner DF, Philipson LH, Bergmann I, Aarskog D, Undlien DE, Joner G, Sovik O, Bell GI, Njolstad PR. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes. 2008 Apr;57(4):1131-5. doi: 10.2337/db07-1467. Epub 2008 Jan 11. PMID:18192540 doi:10.2337/db07-1467
- ↑ Stoy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15040-4. Epub 2007 Sep 12. PMID:17855560 doi:10.1073/pnas.0707291104
- ↑ Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, MacDonald MJ, Stoy J, Steiner DF, Philipson LH, Bell GI, Hattersley AT, Ellard S. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes. 2008 Apr;57(4):1034-42. Epub 2007 Dec 27. PMID:18162506 doi:10.2337/db07-1405
- ↑ Molven A, Ringdal M, Nordbo AM, Raeder H, Stoy J, Lipkind GM, Steiner DF, Philipson LH, Bergmann I, Aarskog D, Undlien DE, Joner G, Sovik O, Bell GI, Njolstad PR. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes. 2008 Apr;57(4):1131-5. doi: 10.2337/db07-1467. Epub 2008 Jan 11. PMID:18192540 doi:10.2337/db07-1467
- ↑ Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, MacDonald MJ, Stoy J, Steiner DF, Philipson LH, Bell GI, Hattersley AT, Ellard S. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes. 2008 Apr;57(4):1034-42. Epub 2007 Dec 27. PMID:18162506 doi:10.2337/db07-1405
- ↑ Boesgaard TW, Pruhova S, Andersson EA, Cinek O, Obermannova B, Lauenborg J, Damm P, Bergholdt R, Pociot F, Pisinger C, Barbetti F, Lebl J, Pedersen O, Hansen T. Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY). BMC Med Genet. 2010 Mar 12;11:42. doi: 10.1186/1471-2350-11-42. PMID:20226046 doi:10.1186/1471-2350-11-42
- ↑ Dhayalan B, Mandal K, Rege N, Weiss MA, Eitel SH, Meier T, Schoenleber RO, Kent SB. Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin. Chemistry. 2016 Nov 30. doi: 10.1002/chem.201605578. PMID:27905149 doi:http://dx.doi.org/10.1002/chem.201605578
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