Lipoic acid biosynthesis defects
Lipoic acid biosynthesis defects
复制标题
DOI：
10.1007/s10545-014-9705-8
复制
发表时间：
2014-07-01
影响因子：
4.2
通讯作者：
Sperl, Wolfgang
中科院分区：
文献类型：
--
作者：
Mayr, Johannes A.;Feichtinger, Rene G.;Sperl, Wolfgang
脂酸盐是一种共价结合的辅因子，在人类的五个氧化还原反应中是必不可少的：在四个2-氧酸脱氢酶和甘氨酸裂解系统(GCS)中。两种来自能量代谢的酶，α-酮戊二酸脱氢酶和丙酮酸脱氢酶；三种来自氨基酸代谢的酶，支链酮酸脱氢酶，2-氧己二酸脱氢酶，和GCS。所有这些酶都由多个亚基组成，具有相似的结构。线粒体的脂肪酸盐合成包括线粒体脂肪酸的合成直至辛酰-酰基载体蛋白；以及三个脂酸盐特有的步骤，包括辛酸转移酶2(LIPT2)将辛酸转移到甘氨酸裂解H蛋白(LIPT2)，硫辛酸合成酶(LIAS)合成脂酸盐，以及脂酰转移酶1(LIPT1)的脂酸盐转移(LIPT1)，这是硫辛酸脱氢酶的E2亚基硫辛化所必需的。二氢硫辛基脱氢酶(DLD)使还原形式的二氢硫辛酸重新激活。已发现LIAs突变可导致非酮症高血糖的变异型，并伴有早发性惊厥，并伴有脑病和心肌病的线粒体能量代谢缺陷。LIPT1缺乏使GCS幸免于难，并导致一名患者合并2-氧酸脱氢酶缺陷和过早死亡，以及一名受影响较轻的具有Leigh样表型的患者。由于LiAs是一种铁硫簇依赖的酶，最近发现的一些线粒体铁硫簇合成的缺陷，包括NFU1、BOLA3、IBA57、GLRX5，都表现出LiAs缺陷和LiAs样表型。与DLD缺乏症一样，根据受影响的酶中哪一种是最具限速性的，可以预期脂酸盐合成缺陷的临床谱更广。
Lipoate is a covalently bound cofactor essential for five redox reactions in humans: in four 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). Two enzymes are from the energy metabolism, alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase; and three are from the amino acid metabolism, branched-chain ketoacid dehydrogenase, 2-oxoadipate dehydrogenase, and the GCS. All these enzymes consist of multiple subunits and share a similar architecture. Lipoate synthesis in mitochondria involves mitochondrial fatty acid synthesis up to octanoyl-acyl-carrier protein; and three lipoate-specific steps, including octanoic acid transfer to glycine cleavage H protein by lipoyl(octanoyl) transferase 2 (putative) (LIPT2), lipoate synthesis by lipoic acid synthetase (LIAS), and lipoate transfer by lipoyltransferase 1 (LIPT1), which is necessary to lipoylate the E2 subunits of the 2-oxoacid dehydrogenases. The reduced form dihydrolipoate is reactivated by dihydrolipoyl dehydrogenase (DLD). Mutations in LIAS have been identified that result in a variant form of nonketotic hyperglycinemia with early-onset convulsions combined with a defect in mitochondrial energy metabolism with encephalopathy and cardiomyopathy. LIPT1 deficiency spares the GCS, and resulted in a combined 2-oxoacid dehydrogenase deficiency and early death in one patient and in a less severely affected individual with a Leigh-like phenotype. As LIAS is an iron-sulphur-cluster-dependent enzyme, a number of recently identified defects in mitochondrial iron-sulphur cluster synthesis, including NFU1, BOLA3, IBA57, GLRX5 presented with deficiency of LIAS and a LIAS-like phenotype. As in DLD deficiency, a broader clinical spectrum can be anticipated for lipoate synthesis defects depending on which of the affected enzymes is most rate limiting.