Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science. 2010 Dec 17;330(6011):1689-92. doi: 10.1126/science.1196154. Epub 2010 Nov 18.
Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser(3), an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.
胃饥饿素是一种胃肽激素，能刺激脊椎动物体重增加。胃饥饿素的生物活性需要肽上丝氨酸（Ser(3)）的辛酰化，这是一种不寻常的翻译后修饰，由胃饥饿素 O-酰基转移酶（GOAT）催化。在这里，我们描述了 GO-CoA-Tat 的设计、合成和表征，GO-CoA-Tat 是一种基于肽的双底物类似物，能拮抗 GOAT。GO-CoA-Tat 在体外、培养细胞和小鼠中均能强烈抑制 GOAT。GO-CoA-Tat 的腹腔给药可改善野生型小鼠的葡萄糖耐量并降低体重增加，但对胃饥饿素缺乏型小鼠无效，这支持了其有益的代谢作用是由于特异性抑制 GOAT 的概念。除了作为研究工具用于映射胃饥饿素的作用外，GO-CoA-Tat 还可能有助于为代谢疾病中 GOAT 的临床靶向治疗铺平道路。
