Metabolic Inhibitors of O‐GlcNAc Transferase That Act In Vivo Implicate Decreased O‐GlcNAc Levels in Leptin‐Mediated Nutrient Sensing,Angewandte Chemie International Edition

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Metabolic Inhibitors of O‐GlcNAc Transferase That Act In Vivo Implicate Decreased O‐GlcNAc Levels in Leptin‐Mediated Nutrient Sensing
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2018-05-24 , DOI: 10.1002/anie.201803254
Tai-Wei Liu ₁ , Wesley F Zandberg _{1,

2} , Tracey M Gloster _{1,

3} , Lehua Deng ₁ , Kelsey D Murray ₁ , Xiaoyang Shan ₁ , David J Vocadlo ₁

Affiliation

O‐Linked glycosylation of serine and threonine residues of nucleocytoplasmic proteins with N‐acetylglucosamine (O‐GlcNAc) residues is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAc is conserved within mammals and is implicated in a wide range of physiological processes. Herein, we describe metabolic precursor inhibitors of OGT suitable for use both in cells and in vivo in mice. These 5‐thiosugar analogues of N‐acetylglucosamine are assimilated through a convergent metabolic pathway, most likely involving N‐acetylglucosamine‐6‐phosphate de‐N‐acetylase (NAGA), to generate a common OGT inhibitor within cells. We show that of these inhibitors, 2‐deoxy‐2‐N‐hexanamide‐5‐thio‐d‐glucopyranoside (5SGlcNHex) acts in vivo to induce dose‐ and time‐dependent decreases in O‐GlcNAc levels in various tissues. Decreased O‐GlcNAc correlates, both in vitro within adipocytes and in vivo within mice, with lower levels of the transcription factor Sp1 and the satiety‐inducing hormone leptin, thus revealing a link between decreased O‐GlcNAc levels and nutrient sensing in peripheral tissues of mammals.

中文翻译：

体内作用的 O-GlcNAc 转移酶代谢抑制剂表明瘦素介导的营养感应中 O-GlcNAc 水平降低

核细胞质蛋白的丝氨酸和苏氨酸残基与 N-乙酰葡糖胺 (O-GlcNAc) 残基的 O-连接糖基化由 O-GlcNAc 转移酶 (OGT) 催化。 O-GlcNAc 在哺乳动物中是保守的，并且与多种生理过程有关。在此，我们描述了适用于细胞和小鼠体内的 OGT 代谢前体抑制剂。这些 N-乙酰氨基葡萄糖的 5-硫代糖类似物通过汇聚代谢途径被同化，很可能涉及 N-乙酰氨基葡萄糖-6-磷酸脱 N-乙酰酶 (NAGA)，在细胞内产生常见的 OGT 抑制剂。我们发现，在这些抑制剂中，2-脱氧-2-N-己酰胺-5-硫代-吡喃葡萄糖苷（5SGlcNHex）在体内发挥作用，诱导各种组织中O-GlcNAc水平呈剂量和时间依赖性降低。无论是在体外脂肪细胞内还是在小鼠体内，O-GlcNAc 的减少都与转录因子 Sp1 和饱腹感激素瘦素水平的降低相关，从而揭示了 O-GlcNAc 水平下降与外周组织营养感知之间的联系。哺乳动物。

更新日期：2018-05-24

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