Department of Molecular Medicine , The Scripps Research Institute , Jupiter , Florida 33458 , United States.
Department of Pathology , Stanford University School of Medicine , Stanford , California 94305 , United States.
J Med Chem. 2018 Apr 12;61(7):3224-3230. doi: 10.1021/acs.jmedchem.8b00029. Epub 2018 Mar 22.
N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogues. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells. A class of unnatural N-acyl amino acid analogues, characterized by isoindoline-1-carboxylate head groups (37), were resistant to enzymatic degradation by PM20D1 and maintained uncoupling bioactivity in cells and in mice.
N-酰基氨基酸可直接与线粒体结合，并作为 UCP1 非依赖性呼吸的内源性解偶联剂发挥作用。我们发现，给小鼠施用 N-酰基氨基酸可改善葡萄糖稳态并增加能量消耗，这表明该途径可能有助于治疗肥胖症及其相关疾病。我们报告了脂质化 N-酰基氨基酸及其非天然类似物的合成和线粒体解偶联生物活性的完整说明。中长链不饱和脂肪酸链和中性氨基酸头部基团是在哺乳动物细胞上获得最佳解偶联活性所必需的。一类非天然 N-酰基氨基酸类似物，其特征是异吲哚-1-羧酸酯头部基团（37），对 PM20D1 的酶促降解具有抗性，并在细胞和小鼠中保持解偶联生物活性。
