Moon Dong Oh
Department of Biology Education, Daegu University, 201, Daegudae-ro, Gyeongsan-si 38453, Gyeongsangbuk-do, Republic of Korea.
Biomolecules. 2024 Dec 10;14(12):1572. doi: 10.3390/biom14121572.
Type 2 Diabetes Mellitus (T2DM) and obesity are globally prevalent metabolic disorders characterized by insulin resistance, impaired glucose metabolism, and excessive adiposity. Methionine aminopeptidase 2 (MetAP2), an intracellular metalloprotease, has emerged as a promising therapeutic target due to its critical role in regulating lipid metabolism, energy balance, and protein synthesis. This review provides a comprehensive analysis of MetAP2, including its structural characteristics, catalytic mechanism, and functional roles in the pathophysiology of T2DM and obesity. The unique architecture of MetAP2's active site and its interactions with substrates are examined to elucidate its enzymatic function. The review also explores the development of MetAP2 inhibitors, focusing on their mechanisms of action, preclinical and clinical findings, and therapeutic potential. Special emphasis is placed on docking studies to analyze the binding interactions of six key inhibitors (fumagillin, TNP-470, beloranib, ZGN-1061, indazole, and pyrazolo[4,3-b]indole) with MetAP2, revealing their structural determinants for efficacy and specificity. These findings underscore the potential of MetAP2 as a therapeutic target and provide valuable insights for the rational design of next-generation inhibitors to address obesity and T2DM.
2型糖尿病（T2DM）和肥胖是全球普遍存在的代谢紊乱疾病，其特征为胰岛素抵抗、糖代谢受损和过度肥胖。蛋氨酸氨肽酶2（MetAP2）是一种细胞内金属蛋白酶，由于其在调节脂质代谢、能量平衡和蛋白质合成中起关键作用，已成为一个有前景的治疗靶点。本综述对MetAP2进行了全面分析，包括其结构特征、催化机制以及在T2DM和肥胖病理生理学中的功能作用。研究了MetAP2活性位点的独特结构及其与底物的相互作用，以阐明其酶功能。本综述还探讨了MetAP2抑制剂的研发情况，重点关注其作用机制、临床前和临床研究结果以及治疗潜力。特别强调对接研究，以分析六种关键抑制剂（烟曲霉素、TNP - 470、贝洛尼布、ZGN - 1061、吲唑和吡唑并[4,3 - b]吲哚）与MetAP2的结合相互作用，揭示其疗效和特异性的结构决定因素。这些发现强调了MetAP2作为治疗靶点的潜力，并为合理设计下一代治疗肥胖和T2DM的抑制剂提供了有价值的见解。
