Ornithine transport, mitochondrial

The clinical syndrome of acute neonatal hyper-ammonemic encephalopathy described in the case report represents the classical presentation of a patient with a urea cycle disorder (UCD). It is important to note that this neonatal course represents only the most common and severe presentation of a UCD. This holds true for all the diseases listed in Table 18-1, with the exceptions of arginase (ARG-1) deficiency, which results in progressive spasticity of the lower limbs, and of the mitochondrial membrane transporters citrin and ornithine transporter 1 (ORNT-1). Deficiency of citrin results in adult-onset encephalopathy deficiency of... 

Figure 47-SO The major metabolic pathways for the use of ammonia by the hepatocyte. Solid bars indicate the sites of primary enzyme defects in various metabolic disorders associated with hyperammonemia /) carbamyl phosphate synthetase I, (2) ornithine transcarbamylase, (3) argininosuccinate synthetase, (4) argininosuccinate lyase, (5) arginase, (6) mitochondrial ornithine transport, (7) propionyi CoA carboxylase, (fi) methylmalonyl CoA mutase, (9) L-lysine dehydrogenase, and (10) N-acetyl glutamine synthetase. Dotted lines indicate the site of pathway activation (+) or inhibition ( ). (From Flannery OB, Hsia YE, Wolf 6. Current status of /lyperommofiemjo syndromes. Hepatology 1982 2 495-506,)...

PIHH syndrome. 238970 Mitochondrial ornithine transporter MisceUaneous Disorders of Amino Acid Metabolism <1 100,000. Mental retardation,. seizures, pyramidal signs, compromised. sense of vibration. . v ... 

Begum, L., M.A. Jalil, K. Kobayashi, M. lijima, M.X. Li, T. Yasuda, M. Horiuchi, A. Del Arco, J. Satrustegui, and T. Saheki, 2002. Expression of three mitochondrial solute carriers, citrin, aralarl and ornithine transporter, in relation to urea cycle in miee. Biochim. Biophys. Acta 1574,283-292. 

Fiermonte, G., V. Dolce, L. David, EM. Santorelli, C. Dionisi-Vici, F. Palmieri, and J.E. Walker, 2003. The mitochondrial ornithine transporter Bacterial expression, reconstitution, lunctional characterization, and tissue distribution of two human isoforms. J. Biol. Chem. 278,32778-32783. 

The cause is defective transport of dibasic amino acids by the proximal tubule and intestine. The transport defect occurs at the basolateral rather than the luminal membrane. Hyperammonemia reflects a deficiency of intra-mitochondrial ornithine. An effective treatment is oral citrulline supplementation, which corrects the hyperammonemia by allowing replenishment of the mitochondrial pool of ornithine. 

As we noted in Chapter 16, the enzymes of many metabolic pathways are clustered (p. 605), with the product of one enzyme reaction being channeled directly to the next enzyme in the pathway. In the urea cycle, the mitochondrial and cytosolic enzymes appear to be clustered in this way. The citrulline transported out of the mitochondrion is not diluted into the general pool of metabolites in the cytosol but is passed directly to the active site of argininosuccinate synthetase. This channeling between enzymes continues for argininosuccinate, arginine, and ornithine. Only urea is released into the general cytosolic pool of metabolites. 

Specific carriers in the inner mitochondrial membrane transport ornithine, citrulline, ammonium ion, and HC03 (C02) into and out of the mitochondrial matrix. 

The complete urea cycle as it occurs in the mammalian liver requires five enzymes Argininosuccinate synthase, arginase, and argininosuccinate lyase (which function in the cytosol), and ornithine transcarbamoylase, and carbamoyl phosphate synthase (which function in the mitochondria). Additional specific transport proteins are required for the mitochondrial uptake of L-ornithine, NH3, and HC03 and for the release of L-citrulline. 

Arginine and fumarate are produced from argininosuccinate by the cytosolic enzyme argininosuccinate lyase. In the final step of the cycle arginase cleaves urea from aspartate, regenerating cytosolic ornithine, which can be transported to the mitochondrial matrix for another round of urea synthesis. 

The uiea cycle may be considered to be a mitochondrial pathway, as carbamyl phosphate synthase and ornithine transcarbamylase are mitochondrial enzymes however, the enzymes catalyzing subsequent steps of the pathway arc cytosolic-The steps leading to conversion of citrulline to ornithine occur in the cytosol. Hence, the pathway is shared by the mitochondrial and cytosolic compartments. The fumarate produced by the urea cycle is converted to malate by a cytoplasmic form of fumarase. Mittxihondrial fumarase is part of the Krebs cycle. Cytoplasmic malate can enter the mitochondrion by means of a transport system, such as the malate/phosphate exchanger or the ma ate/a-ketoglutaratc exchanger. These transport systems are membrane-bound proteins. 

Ammonia is condensed with bicarbonate and ATP in the mitochondrion to form carbamoyl phosphate in a reaction catalyzed by carbamoyl phosphate synthetase I. Two molecules of ATP are used in this reaction one provides the phosphate, and the other is hydrolyzed to ADP and inorganic phosphate (P) to provide the energy that drives the reaction to products. The activated carbamoyl group is then transferred to the amino acid ornithine by the mitochondrial enzyme ornithine transcarbamoylase to form citrulline. Citrulline then is transported out of the mitochondrion to the cytosol, where the rest of the reactions... 

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 first two reactions in the biochemical pathway that converts NFL,+ to urea (i.e., the formation of carbamoyl phosphate and citrulline) occur in the mitochondrial matrix. Subsequent reactions that convert citrulline to ornithine and urea occur in the cytosol. Both citrulline and ornithine are transported across the inner membrane by specific carriers. 

Carbamoyl phosphate reacts with ornithine to form citrulline (see Fig. 38.12). The high- energy phosphate bond of carbamoyl phosphate provides the energy required for this reaction, which occurs in mitochondria and is catalyzed by ornithine transcarbamoylase. The product citrulline is transported across the mitochondrial membranes in exchange for cytoplasmic ornithine and enters the cytosol. The carrier for this transport reaction catalyzes an electroneutral exchange of the two compounds. 

Hyperornithinemia- Defect in mitochondrial hyperammonemia- transport of ornithine homocitrulhnuiia (HHH syndrome) Disorders of carbohydrate metabolism Hyperornithinemia, hyperammonemia, homocitrullinuria, hyperglutaminemia, hyperalaninemia Ataxia, lethargy, vomiting, choreoathetosis, seizures, coma, developmental delay Protein restriction arginine supplementation None... 

It has been suggested that the inability of catabolic ornithine to enter mitochondria in N. erassa is not due to impermeability of the inner mitochondrial membrane to ornithine but due to the inhibition of ornithine influx by arginine (56). If this were correct, the proposed change would simply involve the loss of this inhibitory mechanism rather than the acquisition of a new transport system. 

In the first reaction of the cycle the carbamoyl group is transferred from carbamoyl phosphate to ornithine to yield citrulline. Neither of these amino acids are known to occur in proteins. The remainder of the cycle reactions are cytoplasmic so citrulline is transported by a specific uniport carrier across the inner mitochondrial membrane. In the cytosol, argininosuccinate is formed by a condensation reaction which produces a covalent linkage between the carbonyl carbon atom of citrulline and the amino group of aspartate. This reaction, catalysed by argininosuccinate synthase, is readily reversible but is driven forward by the irreversible... 

---