Dicarboxylate carrier

The next reaction occurs in the cytoplasm. Malate is transported to the cytoplasm by a dicarboxylate carrier which is specific for malate, succinate, and fumarate and which requires the entry of P, or one of these dicarboxylate anions. Cytoplasmic malate is then converted to oxaloacetate by cytoplasmic malate dehydrogenase ... 

The control of the respiration process and ATP synthesis shifts as the metabolic state of the mitochondria changes. In an isolated mitochondrion, control over the respiration process in state 4 is mainly due to the proton leak through the mitochondrial inner membrane. This type of control decreases from state 4 to state 3, while the control by the adenine nucleotide and the dicarboxylate carriers, cytochrome oxidase, increases. ATP utilizing reactions and transport activities also increase. Therefore, in state 3, most of the control is due to respiratory chain and substrate transport. 

Several additional mitochondrial carrier systems have been reconstituted into active form in proteoliposomes, using as starting material a crude neutral detergent mixture of membrane proteins from submitochondrial particles. These include the citrate transporter [203], the dicarboxylate carrier [204], and the carnitine transporters [202]. These reconstitution activities could be used as a basis for further purification and structural studies, but such studies have not yet been reported. 

Other homologous carriers also are present in the inner mitochondrial membrane. The dicarboxylate carrier enables malate, succinate, and fu-marate to be exported from the mitochondrial matrix in exchange for Pj. The tricarboxylate carrier exchanges citrate and for malate. Pyruvate in the cytoplasm enters the mitochondrial membrane in exchange for OH by means of the pyruvate carrier. In all, more than 40 such carriers are encoded in the human genome. 

Cytosolic malate dehydrogenase transfers the electrons and protons from NADH to oxaloacetate forming malate. Malate enters the mitochondrion via the dicarboxylate carrier in exchange for... 

Transformations of these sulphur compoxmds in the animal cell are regulated by variable concentrations of metabolites and enzymes in appropriate compartments. Thiosulphate enters cells only slowly, and studies of Crompton et al./l97 / showed that its transport to mitochondria is catalyzed by a dicarboxylate carrier. Little is known about other substrates of sulphurtrans-ferases such as thiocystine, 3-mercaptopyruvate, glutathione or lipolc acid, but presumably their translocations between subcellular compartments require active transport. Flg.1 shows a proposed model of distribution of principal sulpfaurtransferases and related enzymes, as well as some of their natural substrates. The scheme is certainly oversimplified and not complete but it represents the background of our investigations. 

Two key enzymes in the movement of reducing equivalents from the inside to the outside of mitochondria are NAD malate dehydrogenase and aspartate aminotransferase. These enzymes in both the cytosol and the mitochondria allow the interconversion of intermediates to form a cycle (Fig. 5). In this sequence, NADH generated inside the mitochondria is used to reduce oxaloacetate to malate. Malate moves across the inner mitochondrial membrane on the dicarboxylate carrier, where it is oxidized to oxaloacetate by cytosolic NAD malate dehydrogenase. Oxaloacetate has a limited rate of flux across the inner mitochondrial membrane (Haslam and Krebs, 1968) and is converted to aspartate by aspartate aminotransferase, with the latter compound... 

Halperin, M.L., Schiller, C.M. and Fritz, LB. (1971), The inhibition by methylmalonic acid of malate transport by the dicarboxylate carrier in rat liver mitochondria. J. Clin. Invest.y 50, 2276. 

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