A molecular understanding of the proteins involved in fructose metabolism is essential for controlling the current spread of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism starts with the phosphorylation of d-fructose to fructose 1-phosphate by ketohexokinase (KHK). KHK exists in two alternatively spliced isoforms: the hepatic and intestinal isoform KHK-C and the peripheral isoform KHK-A. Here, the structure of apo murine KHK (mKHK), which differs from structures of human KHK in overall conformation, is reported. An isoform-selective ligand, which offers a 50-fold higher potency on mKHK and human KHK-A compared with KHK-C, is further characterized. In mKHK, large-scale conformational changes are observed upon ligand binding. The structures suggest a combined strategy for the design of species- and isoform-selective KHK inhibitors.

中文翻译：

---

人和小鼠酮己糖激酶的晶体结构为物种和亚型选择性抑制剂设计提供结构基础

对参与果糖代谢的蛋白质的分子了解对于控制当前西方人群中与果糖相关的肥胖、糖尿病和相关不良代谢状态的蔓延至关重要。果糖分解代谢始于酮己糖激酶 (KHK) 将d-果糖磷酸化为果糖 1-磷酸。KHK 存在两种选择性剪接异构体：肝和肠异构体 KHK-C 和外周异构体 KHK-A。在此，报道了载脂蛋白鼠 KHK (mKHK) 的结构，其总体构象与人类 KHK 的结构不同。进一步表征了异构体选择性配体，其对 mKHK 和人 KHK-A 的效力比 KHK-C 高 50 倍。在 mKHK 中，配体结合后观察到大规模的构象变化。这些结构提出了设计物种和亚型选择性 KHK 抑制剂的组合策略。