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Quelle: Uldry and Thorens 2004 Seite(n): 481, 482, Zeilen: 481: r.col: 2ff; 482: l.col: 1ff |
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| GLUT1 is found in almost every tissue with different levels of expression in different cell types. The expression level usually correlates with the rate of cellular glucose metabolism. As mentioned above, it is also expressed highly in blood-tissue barriers, in particular in the endothelial cells forming the blood-brain barrier. Several heterozygous mutations resulting in GLUT1 haploinsufficiency have been identified. These cause hypoglycorrachia, a condition characterized by seizures, developmental delay, acquired microcephaly, and hypotonia, and which is due to a decrease rate of glucose transport from the blood into cerebrospinal fluid.
The topological arrangement of GLUT1 within the plasma membrane has been confirmed using several experimental approaches. Recently, two models have been proposed for the tertiary structure of GLUT1. The first is based on data obtained from cysteine scanning mutagenesis of five of the α-helices of GLUT1 together with information from site-directed mutagenesis (32). The second is based primarily on the proposed helical bundle arrangement of the Lac permease and has been refined using energy minimization algorithm (33) These two models describe a key role for helix 7 in the formation of a water-filled channel which may form the path for glucose across the plasma membrane. The transport of glucose may be described as an alternating confirmation model in which the transporter has mutually exclusive binding sites located on the extracellular (import site) and on the intracellular face (export site) of the transporter (Figure 4). Binding of glucose to one site induces the transporter to switch to the opposite conformation, a process that is accompanied by a movement of the substrate across the plasma membrane (34). In human erythrocytes, GLUT1 is thought to be present as homodimers or homotetramers, with the conversion between both oligomeric forms being dependent on the redox state, . GLUT1 transports glucose with an affinity constant (Km) of ~3 mM. Other transported substrates are galactose (30mM) (34), mannose (35) (20mM) and glucosamine 2.1±0.5mM (36). Glucose transport by GLUT1 is sensitive to several inhibitors that also block transport by other isoforms. Many of them are competitive inhibitors of sugar binding, either to the extracellular or the cytosolic sugar binding sites. Cytochalasin B binds to the inner surface of GLUT1 and inhibits its glucose transport activity with an IC50 of 0.44 μM. Binding of cytochalasin B is to a site which contains tryptophan 388 and 412. Also acting on the same intracellular site is the diterpene toxin forskolin. Forskolin has been used as a photoaffinity label with some specificity for the glucose transporter and its affinity is increased in the 3-iodo4-azidophenethylamido-7-O-succinyldeacetyl (IAPS) derivative. 32. Keymeulen,B, Ling,Z, Gorus,FK, Delvaux,G, Bouwens,L, Grupping,A, Hendrieckx,C, Pipeleers-Marichal,M, Van Schravendijk,C, Salmela,K, Pipeleers,DG: Implantation of standardized beta-cell grafts in a liver segment of IDDM patients: graft and recipients characteristics in two cases of insulin-independence under maintenance immunosuppression for prior kidney graft. Diabetologia 41:452-459, 1998 33. Fischbarg,J, Cheung,M, Li,J, Iserovich,P, Czegledy,F, Kuang,K, Garner,M: Are most transporters and channels beta barrels? Mol.Cell Biochem. 140:147-162, 1994 34. Joost,HG, Thorens,B: The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). Mol.Membr.Biol. 18:247-256, 2001 35. Palfreyman,RW, Clark,AE, Denton,RM, Holman,GD, Kozka,IJ: Kinetic resolution of the separate GLUT1 and GLUT4 glucose transport activities in 3T3-L1 cells. Biochem.J. 284 ( Pt 1):275-282, 1992 36. Robinson,KA, Sens,DA, Buse,MG: Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. Diabetes 42:1333-1346, 1993 |
[page 481]
GLUT1 is found in almost every tissue with different levels of expression in different cell types. The expression level usually correlates with the rate of cellular glucose metabolism. It is also expressed highly in blood-tissue barriers, in particular in the endothelial cells forming the blood-brain barrier [45]. The topological arrangement of GLUT1 within the plasma membrane has been confirmed using several experimental approaches. Recently, two models have been proposed for the tertiary structure of GLUT1. The first is based on data obtained from cysteine scanning mutagenesis of five of the α-helices of GLUT1 together with information from site-directed mutagenesis [52]. The second is based primarily on the proposed helical bundle arrangement of the Lac permease and has been refined using energy minimization algorithm [79]. These two models describe a key role for helix 7 in the formation of a water-filled channel which may form the path for glucose across the plasma membrane. The transport of glucose may be described as an alternating conformer model in which the transporter has mutually exclusive binding sites located on the extracellular (import site) and on the intracellular face (export site) of the transporter. Binding of glucose to one site induces the transporter to switch to the opposite conformation, a process that is accompanied by a movement of the substrate across the plasma membrane. In human erythrocytes, GLUT1 is thought to be present as homodimers or homotetramers, with the conversion between both oligomeric forms being dependent on the redox state [27, 28]. GLUT1 transports glucose with a Km of ~3 mM. Other transported substrates are galactose, mannose and glucosamine [75]. Glucose transport by GLUT1 is sensitive to several inhibitors that also block transport by other isoforms. Many of them are competitive inhibitors of sugar binding, either to the extracellular or the cytosolic sugar binding sites. Cytochalasin B binds to the inner surface of GLUT1 [4] and inhibits its glucose transport activity with an IC50 of 0.44 μM. Binding of cytochalasin B is to a site which contains tryptophan 388 and 412 (see Fig. 2). Also acting on the same intracellular site is the diterpene toxin forskolin. Forskolin has been used as a photoaffinity label with some specificity for the glucose transporter and its affinity is increased in the 3-iodo4-azidophenethylamido-7-O-succinyldeacetyl (IAPS) derivative. [...] [...] Several heterozygous mutations resulting in GLUT1 haploinsufficiency have been identified. These cause [page 482] hypoglycorrachia, a condition characterized by seizures, developmental delay, acquired microcephaly, and hypotonia, and which is due to a decrease rate of glucose transport from the blood into cerebrospinal fluid [42, 67]. 4. Baldwin SA, Lienhard GE (1989) Purification and reconstitution of glucose transporter from human erythrocytes. Methods Enzymol 174:39–50 27. Hamill S, Cloherty EK, Carruthers A (1999) The human erythrocyte sugar transporter presents two sugar import sites. Biochemistry 38:16974–16983 28. Hebert DN, Carruthers A (1992) Glucose transporter oligomeric structure determines transporter function. Reversible redoxdependent interconversions of tetrameric and dimeric GLUT1. J Biol Chem 267:23829–23838 42. Klepper J, Voit T (2002) Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain—a review. Eur J Pediatr 161:295–304 45. Maher F, Vannucci SJ, Simpson IA (1994) Glucose transporter proteins in brain. FASEB J 8:1003–1011 52. Mueckler M, Makepeace C (2002) Analysis of transmembrane segment 10 of the Glut1 glucose transporter by cysteinescanning mutagenesis and substituted cysteine accessibility. J Biol Chem 277:3498–3503 67. Seidner G, Alvarez MG, Yeh JI, O’Driscoll KR, Klepper J, Stump TS, Wang D, Spinner NB, Birnbaum MJ, De Vivo DC (1998) GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 18:188–191 75. Uldry M, Ibberson M, Hosokawa M, Thorens B (2002) GLUT2 is a high affinity glucosamine transporter. FEBS Lett 524:199–203 79. Zuniga FA, Shi G, Haller JF, Rubashkin A, Flynn DR, Iserovich P, Fischbarg J (2001) A three-dimensional model of the human facilitative glucose transporter Glut1. J Biol Chem 276:44970–44975 |
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