Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Japan.
Pharmacol Rev. 2009 Dec;61(4):430-81. doi: 10.1124/pr.109.001958.
A breakthrough using "reverse pharmacology" identified and characterized acyl ghrelin from the stomach as the endogenous cognate ligand for the growth hormone (GH) secretagogue receptor (GHS-R) 1a. The unique post-translational modification of O-n-octanoylation at serine 3 is the first in peptide discovery history and is essential for GH-releasing ability. Des-acyl ghrelin, lacking O-n-octanoylation at serine 3, is also produced in the stomach and remains the major molecular form secreted into the circulation. The third ghrelin gene product, obestatin, a novel 23-amino acid peptide identified from rat stomach, was found by comparative genomic analysis. Three ghrelin gene products actively participate in modulating appetite, adipogenesis, gut motility, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. Knockdown or knockout of acyl ghrelin and/or GHS-R1a, and overexpression of des-acyl ghrelin show benefits in the therapy of obesity and metabolic syndrome. By contrast, agonism of acyl ghrelin and/or GHS-R1a could combat human anorexia-cachexia, including anorexia nervosa, chronic heart failure, chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease, burn, and postsurgery recovery, as well as restore gut dysmotility, such as diabetic or neurogenic gastroparesis, and postoperative ileus. The ghrelin acyl-modifying enzyme, ghrelin O-Acyltransferase (GOAT), which attaches octanoate to serine-3 of ghrelin, has been identified and characterized also from the stomach. To date, ghrelin is the only protein to be octanylated, and inhibition of GOAT may have effects only on the stomach and is unlikely to affect the synthesis of other proteins. GOAT may provide a critical molecular target in developing novel therapeutics for obesity and type 2 diabetes.
使用“反向药理学”的突破方法，从胃中鉴定并表征了酰基 ghrelin 作为生长激素（GH）促分泌素受体（GHS-R）1a 的内源性同源配体。丝氨酸 3 上的 O-辛酰化这种独特的翻译后修饰在肽类发现史上尚属首次，对于 GH 释放能力至关重要。缺乏丝氨酸 3 上 O-辛酰化的脱酰基 ghrelin 也在胃中产生，并且仍然是分泌到循环中的主要分子形式。第三个 ghrelin 基因产物 obestatin 是通过比较基因组分析从大鼠胃中发现的一种新型 23 个氨基酸肽。三种 ghrelin 基因产物积极参与调节食欲、脂肪生成、肠道动力、葡萄糖代谢、细胞增殖、免疫、睡眠、记忆、焦虑、认知和应激。酰基 ghrelin 和/或 GHS-R1a 的敲低或敲除，以及脱酰基 ghrelin 的过表达在肥胖和代谢综合征的治疗中显示出益处。相比之下，酰基 ghrelin 和/或 GHS-R1a 的激动作用可以对抗人类厌食-恶病质，包括神经性厌食症、慢性心力衰竭、慢性阻塞性肺疾病、肝硬化、慢性肾脏病、烧伤和手术后恢复，以及恢复肠道动力障碍，如糖尿病或神经性胃轻瘫和术后肠梗阻。从胃中也鉴定并表征了将辛酰基附着到 ghrelin 丝氨酸-3 上的 ghrelin O-酰基转移酶（GOAT）。迄今为止，ghrelin 是唯一被辛酰化的蛋白质，GOAT 的抑制作用可能仅对胃有影响，不太可能影响其他蛋白质的合成。GOAT 可能为开发肥胖症和 2 型糖尿病的新型治疗药物提供关键的分子靶标。
