Structure and Inhibition of Insect UDP-N-acetylglucosamine Pyrophosphorylase: A Key Enzyme in the Hexosamine Biosynthesis Pathway,Journal of Agricultural and Food Chemistry

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Structure and Inhibition of Insect UDP-N-acetylglucosamine Pyrophosphorylase: A Key Enzyme in the Hexosamine Biosynthesis Pathway
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-07-22 , DOI: 10.1021/acs.jafc.4c03834
Qiong Lu ₁ , Yong Zhou ₂ , Yi Ding ₁ , Yuntian Cui ₁ , Wenda Li ₁ , Tian Liu ₁

Affiliation

UDP-N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the last step in the hexosamine biosynthesis pathway to directly produce UDP-N-acetylglucosamine (UDP-GlcNAc). Because UAPs play important physiological and pathological roles in organisms, they are considered potential targets for drug and pesticide development. However, the lack of efficient and selective inhibitors is a bottleneck that must be overcome. This study reports the first crystal structure of the insect UAP from Spodoptera frugiperda (SfUAP) in complex with UDP-GlcNAc. SfUAP has two insect-specific structural characteristics in the active pocket, namely, a free Cys (Cys³³⁴) and a Mg²⁺ binding site, which differentiate it from human UAP (HsAGX1) and fungal UAP (AfUAP) in terms of substrate and inhibitor binding. N-(4-Nitrophenyl)maleimide (pNPMI) and myricetin are discovered as potent covalent and noncovalent inhibitors of SfUAP, respectively. Moreover, myricetin can significantly reduce the level of cellular O-GlcNAcylation by inhibiting both UAP and O-GlcNAc transferase. These findings provide novel insights into the development of UAP-based drugs and pesticides.

中文翻译：

昆虫 UDP-N-乙酰氨基葡萄糖焦磷酸化酶的结构与抑制：己糖胺生物合成途径中的关键酶

UDP-N-乙酰葡糖胺焦磷酸化酶（UAP）催化己糖胺生物合成途径的最后一步，直接产生 UDP-N-乙酰葡糖胺（UDP-GlcNAc）。由于 UAP 在生物体中起着重要的生理和病理作用，因此它们被认为是药物和杀虫剂开发的潜在靶标。然而，缺乏高效和选择性的抑制剂是必须克服的瓶颈。本研究报道了来自草地贪夜蛾 （SfUAP）的昆虫 UAP 与 UDP-GlcNAc 复合物的第一个晶体结构。影魔UAP 在活性口袋中具有两个昆虫特异性结构特征，即游离 Cys （Cys³³⁴）和 Mg²⁺ 结合位点，这在底物和抑制剂结合方面区别于人 UAP （HsAGX1）和真菌 UAP （AfUAP）。N-（4-硝基苯基）马来酰亚胺（pNPMI）和杨梅素分别被发现是 SfUAP 的有效共价和非共价抑制剂。此外，杨梅素可以通过抑制 UAP 和 O-GlcNAc 转移酶来显着降低细胞 O-GlcNAcylation 的水平。这些发现为基于 UAP 的药物和杀虫剂的开发提供了新的见解。

更新日期：2024-07-22

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