Identification of the human mitochondrial oxodicarboxylate carrier - Bacterial expression, reconstitution functional characterization, tissue distribution, and chromosomal location
Identification of the human mitochondrial oxodicarboxylate carrier - Bacterial expression, reconstitution functional characterization, tissue distribution, and chromosomal location
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DOI：
10.1074/jbc.m009607200
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发表时间：
2001-03-16
影响因子：
4.8
通讯作者：
Walker, JE
中科院分区：
文献类型：
--
作者：
Fiermonte, G;Dolce, V;Walker, JE
在酿酒酵母中，基因ODC 1和ODC 2编码氧代二羧酸载体的同种型。它们都转运C5-C7氧代二羧酸穿过线粒体的内膜，并且是线粒体载体蛋白家族的成员。直系同源物在秀丽隐杆线虫和黑腹果蝇的基因组中编码，人类表达序列标签（EST）编码密切相关蛋白质的一部分。来自EST的信息已用于完成人cDNA序列。该序列已被用于将该基因定位于染色体14q11.2，并显示该基因在所检查的所有组织中表达。通过在大肠杆菌中过表达产生人蛋白质，纯化并重组成磷脂囊泡。它具有与酵母氧代二羧酸载体蛋白（ODC）相似的转运特性。人和酵母ODC均通过反向交换机制催化氧代二羧酸2-氧代己二酸和2-氧代戊二酸的转运。己二酸、戊二酸以及较小程度的庚二酸、2-氧代庚二酸、2-氨基己二酸、草酰乙酸和柠檬酸也由人ODC转运。人ODC和酵母ODC之间的主要差异在于2-氨基己二酸由前者转运而不是由后者转运，而苹果酸由酵母ODC转运而不是由人直系同源物转运。在哺乳动物中，2-氧代己二酸是赖氨酸、色氨酸和羟赖氨酸催化剂中的常见中间体。它从细胞质转运到线粒体中，在线粒体中转化为乙酰辅酶A。人ODC缺陷可能是2-氧代己二酸酸血症的原因，这是赖氨酸、色氨酸和羟赖氨酸代谢的先天性缺陷。
In Saccharomyces cerevisiae, the genes ODC1 and ODC2 encode isoforms of the oxodicarboxylate carrier. They both transport C5-C7 oxodicarboxylates across the inner membranes of mitochondria and are members of the family of mitochondrial carrier proteins. Orthologs are encoded in the genomes of Caenorhabditis elegans and Drosophila melanogaster, and a human expressed sequence tag (EST) encodes part of a closely related protein. Information from the EST has been used to complete the human cDNA sequence. This sequence has been used to map the gene to chromosome 14q11.2 and to show that the gene is expressed in all tissues that were examined. The human protein was produced by overexpression in Escherichia coli, purified, and reconstituted into phospholipid vesicles. It has similar transport characteristics to the yeast oxodicarboxylate carrier proteins (ODCs), Both the human and yeast ODCs catalyzed the transport of the oxodicarboxylates 2-oxoadipate and 2-oxoglutarate by a counter-exchange mechanism. Adipate, glutarate, and to a lesser extent, pimelate, 2-oxopimelate, 2-aminoadipate, oxaloacetate, and citrate were also transported by the human ODC. The main differences between the human and yeast ODCs are that 2-aminoadipate is transported by the former but not by the latter, whereas malate is transported by the yeast ODCs but not by the human ortholog, In mammals, 2-oxoadipate is a common intermediate in the catabolism of lysine, tryptophan, and hydroxylysine. It is transported from the cytoplasm into mitochondria where it is converted into acetyl-CoA. Defects in human ODC are likely to be a cause of 2-oxoadipate acidemia, an inborn error of metabolism of lysine, tryptophan, and hydroxylysine.