| Structural highlights
Disease
[HXK4_HUMAN] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:125851]; also shortened MODY-2. MODY 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:602485]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.[14]
Function
[HXK4_HUMAN] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.
Publication Abstract from PubMed
Human glucokinase (GK) is a principal regulating sensor of plasma glucose levels. Mutations that inactivate GK are linked to diabetes, and ones that activate it are associated with hypoglycemia. Unique kinetic properties equip GK for its regulatory role: although it has weak basal affinity for glucose, positive cooperativity in its binding of glucose causes a rapid increase in catalytic activity when plasma glucose concentrations rise above euglycemic levels. In clinical trials, small molecule GK activators (GKA) have been efficacious in lowering plasma glucose and enhancing glucose-stimulated insulin secretion (GSIS), but they carry a risk of overly activating GK and causing hypoglycemia. The theoretical models proposed to date attribute the positive cooperativity of GK to the existence of distinct protein conformations that interconvert slowly and exhibit different affinities for glucose. Here we report the respective crystal structures of the catalytic complex of GK and of a GK/glucose complex in a wide-open conformation. To assess conformations of GK in solution, we also carried out small angle X-ray scattering (SAXS) experiments. The results showed that glucose dose-dependently converts GK from an apo conformation to an active open conformation. Compared to wild type GK, activating mutants required notably lower concentrations of glucose to be converted to the active open conformation. GKAs decreased the level of glucose required for GK activation, and different compounds demonstrated distinct activation profiles. These results lead us to propose a modified mnemonic model to explain cooperativity in GK. Our findings may offer new approaches for designing GKA with reduced hypoglycemic risk.
Insights into the mechanism of glucokinase activation: observation of multiple distinct protein conformations.,Liu S, Ammirati MJ, Song X, Knafels JD, Zhang J, Greasley SE, Pfefferkorn JA, Qiu X J Biol Chem. 2012 Feb 1. PMID:22298776[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Stoffel M, Froguel P, Takeda J, Zouali H, Vionnet N, Nishi S, Weber IT, Harrison RW, Pilkis SJ, Lesage S, et al.. Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7698-702. PMID:1502186
- ↑ Sakura H, Eto K, Kadowaki H, Simokawa K, Ueno H, Koda N, Fukushima Y, Akanuma Y, Yazaki Y, Kadowaki T. Structure of the human glucokinase gene and identification of a missense mutation in a Japanese patient with early-onset non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1992 Dec;75(6):1571-3. PMID:1464666
- ↑ Stoffel M, Patel P, Lo YM, Hattersley AT, Lucassen AM, Page R, Bell JI, Bell GI, Turner RC, Wainscoat JS. Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nat Genet. 1992 Oct;2(2):153-6. PMID:1303265 doi:https://dx.doi.org/10.1038/ng1092-153
- ↑ Stoffel M, Bell KL, Blackburn CL, Powell KL, Seo TS, Takeda J, Vionnet N, Xiang KS, Gidh-Jain M, Pilkis SJ, et al.. Identification of glucokinase mutations in subjects with gestational diabetes mellitus. Diabetes. 1993 Jun;42(6):937-40. PMID:8495817
- ↑ Takeda J, Gidh-Jain M, Xu LZ, Froguel P, Velho G, Vaxillaire M, Cohen D, Shimada F, Makino H, Nishi S, et al.. Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. J Biol Chem. 1993 Jul 15;268(20):15200-4. PMID:8325892
- ↑ Gidh-Jain M, Takeda J, Xu LZ, Lange AJ, Vionnet N, Stoffel M, Froguel P, Velho G, Sun F, Cohen D, et al.. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1932-6. PMID:8446612
- ↑ Hager J, Blanche H, Sun F, Vaxillaire NV, Poller W, Cohen D, Czernichow P, Velho G, Robert JJ, Cohen N, et al.. Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique. Diabetes. 1994 May;43(5):730-3. PMID:8168652
- ↑ Velho G, Blanche H, Vaxillaire M, Bellanne-Chantelot C, Pardini VC, Timsit J, Passa P, Deschamps I, Robert JJ, Weber IT, Marotta D, Pilkis SJ, Lipkind GM, Bell GI, Froguel P. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia. 1997 Feb;40(2):217-24. PMID:9049484 doi:10.1007/s001250050666
- ↑ Guazzini B, Gaffi D, Mainieri D, Multari G, Cordera R, Bertolini S, Pozza G, Meschi F, Barbetti F. Three novel missense mutations in the glucokinase gene (G80S; E221K; G227C) in Italian subjects with maturity-onset diabetes of the young (MODY). Mutations in brief no. 162. Online. Hum Mutat. 1998;12(2):136. PMID:10694920 doi:<136::AID-HUMU11>3.0.CO;2-0 10.1002/(SICI)1098-1004(1998)12:2<136::AID-HUMU11>3.0.CO;2-0
- ↑ Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet. 1998 Jul;19(3):268-70. PMID:9662401 doi:10.1038/953
- ↑ Ng MC, Cockburn BN, Lindner TH, Yeung VT, Chow CC, So WY, Li JK, Lo YM, Lee ZS, Cockram CS, Critchley JA, Bell GI, Chan JC. Molecular genetics of diabetes mellitus in Chinese subjects: identification of mutations in glucokinase and hepatocyte nuclear factor-1alpha genes in patients with early-onset type 2 diabetes mellitus/MODY. Diabet Med. 1999 Nov;16(11):956-63. PMID:10588527
- ↑ Nam JH, Lee HC, Kim YH, Cha BS, Song YD, Lim SK, Kim KR, Huh KB. Identification of glucokinase mutation in subjects with post-renal transplantation diabetes mellitus. Diabetes Res Clin Pract. 2000 Dec;50(3):169-76. PMID:11106831
- ↑ Njolstad PR, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001 May 24;344(21):1588-92. PMID:11372010 doi:10.1056/NEJM200105243442104
- ↑ Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, Herold KC. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998 Jan 22;338(4):226-30. PMID:9435328 doi:10.1056/NEJM199801223380404
- ↑ Liu S, Ammirati MJ, Song X, Knafels JD, Zhang J, Greasley SE, Pfefferkorn JA, Qiu X. Insights into the mechanism of glucokinase activation: observation of multiple distinct protein conformations. J Biol Chem. 2012 Feb 1. PMID:22298776 doi:10.1074/jbc.M111.274126
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