Tricarboxylate carrier

Toxicity assessment. Ethanol extract of the leaf, administered intraperitoneally to mice, was active, LDjf, 0.75 g/kg"" " . Ethanol extract of the fresh leaf and stem, administered intraperitoneally to mice at the minimum toxic dose of 1 mL/animal, was active. Water extract of the fresh leaf and stem, administered intraperitoneally to mice at the minimum toxic dose of 1 mL/ animal, was active " . Aqueous extract of the husk fiber, administered orally to mice, was active, LDjf, 2.30 g/kgf" " . Tricarboxylate carrier influence. Oil, administered to rats at a dose of 15% of the diet for 3 weeks, produced a differential mitochondrial fatty acid composition and no appreciable change in phospholipids composition and cholesterol level. Compared with coconut oil-fed rats, the mitochondrial tricarboxylate carrier activity was markedly decreased in liver mitochondria from fish oil-fed rats. No difference in the Arrhenius plot between the two groups was observed "". 

CN138 Giudetti, A. M., S. Sabetta, R. di Summa, et al. Differential effects of coconut oil- and fish oil-enriched diets on tricarboxylate carrier in rat liver mitochondria. J Lipid Res 2003 44(11) 2135-2141. 

The tricarboxylate carrier also has a rather limited distribution. It is most active... 

Citrate provides the precursors (acetyl-CoA, NADPH) for fatty acid synthesis and is a positive allosteric modulator of acetyl-CoA carboxylase, which is involved in the initiation of long-chain fatty acid synthesis (Chapter 18). It regulates glycolysis by negative modulation of 6-phosphofructokinase activity (see above). All of the above reactions occur in the cytoplasm, and citrate exits from mitochondria via the tricarboxylate carrier. 

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. 

The 4-phosphopantetheine group of CoA is also utilized (for essentially the same purposes) in acyl carrier proteins (ACPs) involved in fatty acid biosynthesis (see Chapter 25). In acyl carrier proteins, the 4-phosphopantetheine is covalently linked to a serine hydroxyl group. Pantothenic acid is an essential factor for the metabolism of fat, protein, and carbohydrates in the tricarboxylic acid cycle and other pathways. In view of its universal importance in metabolism, it is surprising that pantothenic acid deficiencies are not a more serious problem in humans, but this vitamin is abundant in almost all foods, so that deficiencies are rarely observed. 

The ionization state of a drag may be affected by factors other than pH. When citrate, a tricarboxylic acid, chelates metals such as aluminum, the tetravalent citrate-aluminum complex leaves a free non-complexed monocarboxylic acid which is a substrate for the monocarboxylic acid or lactate carrier in the brain endothelium. When citrate is not chelated, it has no affinity for these carriers and, as there is no di- or tricarboxylic acid carrier within the BBB, citrate is not significantly transported through the BBB via carrier-mediated transport. 

Inside the inner membrane of a mitochondrion is a viscous region known as the matrix (Fig. 1-9). Enzymes of the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle and the Krebs cycle), as well as others, are located there. For substrates to be catabolized by the TCA cycle, they must cross two membranes to pass from the cytosol to the inside of a mitochondrion. Often the slowest or rate-limiting step in the oxidation of such substrates is their entry into the mitochondrial matrix. Because the inner mitochondrial membrane is highly impermeable to most molecules, transport across the membrane using a carrier or transporter (Chapter 3, Section 3.4A) is generally invoked to explain how various substances get into the matrix. These carriers, situated in the inner membrane, might shuttle important substrates from the lumen between the outer and the inner mitochondrial membranes to the matrix. Because of the inner membrane, important ions and substrates in the mitochondrial matrix do not leak out. Such permeability barriers between various subcellular compartments improve the overall efficiency of a cell. 

In the third stage, ATP is producedfrom the complete oxidation of the acetyl unit of acetyl CoA. The third stage consists of the citric acid cycle and oxidative phosphorylation, which are the final common pathways in the oxidation offuel molecules. Acetyl CoA brings acetyl units into the citric acid cycle [also called the tricarboxylic acid (TCA) cycle or Krebs cycle], where they are completely oxidized to CO2. Four pairs of electrons are transferred (three to NAD+ and one to FAD) for each acetyl group that is oxidized. Then, a proton gradient is generated as electrons flow from the reduced forms of these carriers to O2, and this gradient is used to synthesize ATP. 

In humans, oxaloacetate must be transported out of the mitochondrion to supply the cytosolic PEPCK. Because there is no mitochondrial carrier for oxaloacetate and its diffusion across the mitochondrial membrane is slow, it is transported as malate or asparate (Figure 15-2). The malate shuttle carries oxaloacetate and reducing equivalents, whereas the aspartate shuttle, which does not require a preliminary reduction step, depends on the availability of glutamate and a-ketoglutarate in excess of tricarboxylic acid (TCA) cycle requirements. 

Cytosolic generation of acetyl-CoA ( citrate shuttle ) This pathway is shown in Figure 18-13. Citrate synthesized from oxaloacetate and acetyl-CoA is transported to the cytosol via the tricarboxylate anion carrier system and cleaved to yield acetyl-CoA and oxaloacetate. 

The urea cycle converts NH4 to urea, a less toxic molecule. The sources of the atoms in urea are shown in color. Cit-rulline is transported across the inner membrane by a carrier for neutral amino acids. Ornithine is transported in exchange for H+ or citrulline. Fumarate is transported back into the mitochondrial matrix (for reconversion to malate) by carriers for a-ketoglutarate or tricarboxylic acids. 

The Krebs cycle, also known as the tricarboxylic acid or citric acid cycle, operates within the mitochondria it fuUy oxidizes the two carbon atoms in acetyl-CoA to COj. During the oxidation process, acetate groups are carried on a 4-carbon molecule, oxaloacetate. The fact that oxaloacetate is regenerated at the end of the process makes this pathway a cycle. Availability of the carrier is important in regulating the carbon flux aroimd the cyclic pathway. 

The oxidation reactions involved are catalyzed by a series of nicotinamide adenine dinucleotide (NAD+) or flavin adenine dinucleotide (FAD) dependent dehydrogenases in the highly conserved metabolic pathways of glycolysis, fatty acid oxidation and the tricarboxylic acid cycle, the latter two of which are localized to the mitochondrion, as is the bulk of coupled ATP synthesis. Reoxidation of the reduced cofactors (NADH and FADH2) requires molecular oxygen and is carried out by protein complexes integral to the inner mitochondrial membrane, collectively known as the respiratory, electron transport, or cytochrome, chain. Ubiquinone (UQ), and the small soluble protein cytochrome c, act as carriers of electrons between the complexes (Fig. 13.1.1). 

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