Department of Biochemistry, University of Illinois, Urbana, IL 61801.
Department of Microbiology, University of Illinois, Urbana, IL 61801.
Proc Natl Acad Sci U S A. 2018 Jul 24;115(30):E7063-E7072. doi: 10.1073/pnas.1805862115. Epub 2018 Jul 9.
The lack of attachment of lipoic acid to its cognate enzyme proteins results in devastating human metabolic disorders. These mitochondrial disorders are evident soon after birth and generally result in early death. The mutations causing specific defects in lipoyl assembly map in three genes, , , and Although physiological roles have been proposed for the encoded proteins, only the LIPT1 protein had been studied at the enzyme level. LIPT1 was reported to catalyze only the second partial reaction of the classical lipoate ligase mechanism. We report that the physiologically relevant LIPT1 enzyme activity is transfer of lipoyl moieties from the H protein of the glycine cleavage system to the E2 subunits of the 2-oxoacid dehydrogenases required for respiration (e.g., pyruvate dehydrogenase) and amino acid degradation. We also report that LIPT2 encodes an octanoyl transferase that initiates lipoyl group assembly. The human pathway is now biochemically defined.
由于硫辛酸与其同源酶蛋白结合缺失，导致严重的人类代谢紊乱。这些线粒体疾病在出生后不久就显现出来，通常导致早期死亡。导致脂酰基组装特定缺陷的突变位于三个基因中，即 、 和 。尽管已经提出了编码蛋白的生理作用，但只有 LIPT1 蛋白在酶水平上进行了研究。据报道，LIPT1 仅催化经典脂酰基辅酶 A 连接酶机制的第二个部分反应。我们报告称，生理相关的 LIPT1 酶活性是将脂酰基部分从甘氨酸分解系统的 H 蛋白转移到呼吸（例如丙酮酸脱氢酶）和氨基酸降解所需的 2-氧代酸脱氢酶的 E2 亚基。我们还报告称，LIPT2 编码一种八酰基转移酶，它起始脂酰基组装。人类途径现在已在生化上定义。
