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词汇介绍
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解析
Glycogen 英 /'glaɪkədʒ(ə)n/ 美 /'glaɪkodʒən/
释 义 n. 糖原;动物淀粉
同根词 adj. glycogenic 生糖原的;糖原的
n. glycogenesis [生化] 糖原生成(作用)
例 句 The sugars will turn into glycogen, which will help your body hold onto its water supply.这些糖类会转化为糖原,能够帮助你保证体内得水分供应。
Phosphorylase 英 /fɒs'fɒrɪleɪz/
释 义 n. [生化] 磷酸化酶
例 句 The results indicated that starch degradation was the result of synergism of amylase and starch phosphorylase.结果表明:淀粉的降解是淀粉酶和淀粉磷酸化酶综合作用的结果。
概述
概述
糖原磷酸化酶是一种磷酸化酶,糖原磷酸化酶通过从末端α-1,4-糖苷键释放1-磷酸葡萄糖来催化动物糖原分解的限速步骤。糖原磷酸化酶也被研究为模型蛋白,受可逆磷酸化和变构作用调节。
结构
糖原磷酸化酶单体是一种大蛋白,在肌肉细胞中由842个氨基酸组成,质量为97.434 kDa。尽管该酶可以以无活性单体或四聚体的形式存在,但具有两个相同亚基的二聚体的生物活性。AMP结合在糖原磷酸化酶的肌肉同工型上的变构位点接近亚基界面,就像Ser14一样。AMP在此位点的结合(对应于从酶的T状态到R状态的变化)导致亚基界面处三级结构的细微变化,从而导致四级结构的大变化。AMP结合通过更大的组织和亚基间的相互作用使两个亚基50′的塔螺旋(残基262-278)彼此相对旋转。塔螺旋的这种旋转导致两个亚基相对于彼此旋转10°,更重要的是扰乱了残基282-286(280s回路),这些残基在T状态下阻止进入催化位点,但不会R状态。
糖原磷酸化酶蛋白上的最后一个也许是最奇怪的位点是所谓的糖原存储位点。残基397-437形成此结构,从而使蛋白质从催化位点开始以全30Å的价格共价结合到糖原链上。该位点很可能是酶在开始切割末端葡萄糖分子之前与酶原颗粒结合的位点。实际上,细胞中70%的二聚磷酸化酶与糖原颗粒结合,而不是自由漂浮。
临床意义
已经提出抑制糖原磷酸化酶作为治疗2型糖尿病的一种方法。由于已显示2型糖尿病患者肝脏中的葡萄糖产生增加,抑制从肝脏糖原供应中释放葡萄糖似乎是有效的方法。糖原磷酸化酶(PYGM)的肌肉同工型的突变与糖原贮积病V型有关。迄今为止,已鉴定出导致糖原贮积病的PYGM基因突变超过65个。糖原贮积病V型的症状包括肌肉无力,肌痛和缺乏耐力,所有这些都源于肌肉组织中的低葡萄糖水平。肝糖原磷酸化酶(PYGL)的同工型的突变与赫氏病(糖原贮积病VI型)相关。赫氏病通常与轻度症状有关,通常仅限于低血糖症,有时由于残留的酶活性而难以诊断。糖原磷酸化酶的脑亚型(PYGB)已被提议作为胃癌的一个生物标志物。
Glycogen phosphorylase inhibition improves beta cell function复制标题
糖原磷酸化酶抑制改善 β 细胞功能
发表时间:2018-01-01
影响指数:6.6
作者: Lilla Nagy
期刊:Br J Pharmacol
Cellular glycogen content depends on the net synthesis and degradation of glycogen. Glycogen synthase is responsible for glycogen synthesis, while glycogen phosphorylase (GP) catalyses the breakdown of glycogen to glucose. The two enzymes are regulated in an opposing fashion; only one of them is active at any one time. GP is a heterodimeric enzyme that possesses seven allosteric binding sites. The allosteric binding sites are potential targets for allosteric modulation by pharmacological agents. GP inhibitors (GPi-s), with a few exceptions, are not selective for the liver, muscle and brain isoforms of GP. Hence, the current GPi-s are likely to block all GP activity in cells regardless of the proportions of GP isoforms. GP activation induces the production of hepatic glucose and modulates blood glucose levels. Consequently, GPi-s were investigated as possible anti-diabetic agents to reduce blood glucose levels by inducing the storing of glucose in the form of glycogen. GPi-s have been tested in human clinical studies and have reached phase II trials. In the endocrine pancreas the beta cells are responsible for the synthesis and secretion of insulin, a hormone that promotes glucose uptake in tissues like skeletal muscle or white adipose tissue. Insulin secretion is induced by glucose uptake, followed by glucose breakdown through glycolysis and mitochondrial oxidation leading to increases in ATP levels. This increased production of ATP leads to the closing of ATP-sensitive potassium channels (KATP) and to increased calcium influx. Calcium influx induces the fusion of insulin-rich granules with the cell membrane leading to insulin secretion. Since glucose is the major regulator of beta cell function, persistent hyperglycaemia combined with peripheral insulin resistance in type 2 diabetic conditions results in the beta cells being overworked to maintain normal blood glucose levels. Hence, chronic exposure to high glucose leads to the exhaustion of beta cells, progressive beta cell failure and, eventually, to the loss of beta cells.
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