Dicarboxylate translocator

Transport of phosphate, pyruvate and glutamate via their respective translocators is electroneutral and H -coupled. Although in Fig. 1 their transport has been written as cotransport of the anion with H (symport), it is also possible that the actual transport mechanism involves an exchange of the anion with OH (antiport). Experimentally, these two mechanisms cannot be distinguished. The translocators for a-oxoglutarate and malate (the latter is also called the dicarboxylate translocator) also mediate electroneutral exchanges. 

It must be realised that the kinetic properties of the translocators may vary from species to species and even from tissue to tissue in the same species. One example is the relatively high capacity of the tricarboxylate translocator in liver compared to that in heart [1,19], which is related to the absence of extramitochondrial fatty, acid synthesis in heart. Another example is the high activity of the dicarboxylate translocator in liver compared to that in heart [19] which is related to the absence of gluconeogenesis in heart. 

Most studies with isolated hepatocytes or perfused liver indicate the existence of a ApH across the mitochondrial membrane, ranging from 0-0.6 [33,34,37-39], but under some conditions the calculated ApH depends on the metabolite chosen. This indicates disequilibrium in one or more of the transport steps. Under most conditions it is unlikely that the phosphate translocator is out of equilibrium because of its very high (Table 1). Problems do arise, however, when the dicarboxylate translocator is out of equilibrium because it connects the movement of citrate, malate and a-oxoglutarate with that of H. In that case the above equation cannot... 

A direct K+ requirement for translocation has, however, been reported for glutamic acid transport in brain (Kanner and Schuldiner, 1987 Carlson et al., 1989). The dicarboxylic amino acids appear to be transported largely by specific transporters which do not participate in neutral amino acid transport. Recent studies, both in reconstituted systems and the expression of the cloned transporter, have confirmed the K+ requirement (see below). 

Translocation systems of the inner mitochondrial membrane are listed in Table 14-5. Anion translocators are responsible for electroneutral movement of dicarboxylates, tricarboxylates, a-ketoglutarate, glutamate, pyruvate, and inorganic phosphate. Specific electrogenic translocator systems exchange ATP for ADP, and glutamate for aspartate, across the membrane. The metabolic function of the translocators is to provide appropriate substrates (e.g., pyruvate and fatty acids) for mitochondrial oxidation that is coupled to ATP synthesis from ADP and Pj. 

The present discussion was intended to analyze molecular recognition in substrate binding. Of course molecular recognition also plays a major role in molecular catalysis and transport processes where transformation or translocation of the bound substrates is brought about by a suitably functionalized receptor molecule. These most important aspects are however beyond the scope of this presentation. One may just note, for the sake of illustration, that for instance cysteinyl derivatives of receptor (12 b) display marked chiral recognition in transacylation reactions with optically active substrates [26] and that dicarboxylate-dicarboxamide analogs of (12 b) allow pH regulation of the Ca /K selectivity in competitive transport of calcium and potassium ions [27]. Further information about the results obtained in the areas of molecular catalysis and transport may be found respectively in the references [28] and [29] and in the references cited therein. 

Some plants, such as corn and sugar cane, have evolved an auxiliary C4-dicarboxylic acid cycle< > that cooperates with the reductive pentose cycle in the photosynthetic assimilation of CO2. In plants with this cycle (sometimes referred to as the Hatch and Slack cycle), chloroplasts in the mesophyll cells near the surface on the leaf contain three C4-pathway specific enzymes pyruvate, phosphate-dikinase that directly converts pyruvate into phosphoenolpyruvate (PEP) with ATP, PEP carboxylase that catalyzes the carboxyla-tion of PEP to oxaloacetate, and malate dehydrogenase that finally reduces oxaloacetate to malate with NADPH. The purpose of these steps is apparently to incorporate CO2 and NADPH into malate in order to translocate them to the vascular bundle sheath cells, where they are again released by the action of a NADP-dependent malic enzyme. The malic enzyme is located in the bundle sheath chloroplasts together with the en mes of the Calvin cycle. CO2 is then reduced to carbohydrates while pyruvate is presumably transported back to the mesophyll cells. Besides the malate-type C4-plants, there is a second and larger group of species (aspartate type) that contains little malic enzyme and utilizes aspartate as the COj carrier. 

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. 

Heldt HW and Rapley L (1970) Specific transport of inorganic phosphate, 3-phosphoglycerate and dihydroxyacetone phosphate and of dicarboxylates across the inner membrane of spinach chloroplasts, FEES Lett. 10, 1 3-V+8. Werdan K and Heldt HW (1971) The phosphate translocator of spinach chloroplasts. In Proc. 2nd Int. Cong. Photosynth., Stresa, vol 2, pp 1339-13 Rutter JC and Cobb AH (1984) Translocation of orthophosphate and glucose-6-phosphate in Codium fragile chloroplasts. New Phytol, (in press). 

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