Showing papers on "Urea cycle published in 2007"

Neurological implications of urea cycle disorders

Abstract: The urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate–nitric oxide–cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

Enzymatic Evidence for the Key Role of Arginine in Nitrogen Translocation by Arbuscular Mycorrhizal Fungi

Abstract: Key enzymes of the urea cycle and (15)N-labeling patterns of arginine (Arg) were measured to elucidate the involvement of Arg in nitrogen translocation by arbuscular mycorrhizal (AM) fungi. Mycorrhiza was established between transformed carrot (Daucus carota) roots and Glomus intraradices in two-compartment petri dishes and three ammonium levels were supplied to the compartment containing the extraradical mycelium (ERM), but no roots. Time courses of specific enzyme activity were obtained for glutamine synthetase, argininosuccinate synthetase, arginase, and urease in the ERM and AM roots. (15)NH(4)(+) was used to follow the dynamics of nitrogen incorporation into and turnover of Arg. Both the absence of external nitrogen and the presence of L-norvaline, an inhibitor of Arg synthesis, prevented the synthesis of Arg in the ERM and resulted in decreased activity of arginase and urease in the AM root. The catabolic activity of the urea cycle in the roots therefore depends on Arg translocation from the ERM. (15)N labeling of Arg in the ERM was very fast and analysis of its time course and isotopomer pattern allowed estimation of the translocation rate of Arg along the mycelium as 0.13 microg Arg mg(-1) fresh weight h(-1). The results highlight the synchronization of the spatially separated reactions involved in the anabolic and catabolic arms of the urea cycle. This synchronization is a prerequisite for Arg to be a key component in nitrogen translocation in the AM mycelium.

Dysregulation of C/EBPα by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease

Abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD. The resultant ammonia toxicity might exacerbate the neurological deficits of HD. Suppression of C/EBPalpha, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in HD. We found that in the presence of mutant Htt, C/EBPalpha loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBPalpha into aggregates, as well as suppressed expression of the C/EBPalpha gene. Consumption of protein-restricted diets not only led to the restoration of C/EBPalpha's activity, and repair of the urea cycle deficiency and hyperammonemia, but also ameliorated the formation of Htt aggregates, the motor deterioration, the suppression of striatal brain-derived neurotrophic factor and the normalization of three protein chaperones (Hsp27, Hsp70 and Hsp90). Treatments aimed at repairing the urea cycle deficiency may provide a new strategy for dealing with HD.

Nutritional management of patients with urea cycle disorders

Abstract: The nutritional management of patients with urea cycle disorders (UCDs) involves restriction of dietary protein along with provision of adequate protein-free energy, essential amino acid supplements, and vitamins and minerals in combination with nitrogen-scavenging drugs. The present paper discusses nutrition therapy for a range of circumstances: during an acute hyperammonaemic episode and at hospital discharge; before, during, and after surgery; and for lifelong chronic management of UCDs.

Ornithine transcarbamylase deficiency presenting as encephalopathy during adulthood following bariatric surgery

Abstract: Background Neurological complications following bariatric surgery are rare. Whereas nutritional deficiencies are the most common cause of neurological symptoms, the unmasking of previously subclinical metabolic disorders can also lead to significant morbidity. Objective To characterize the clinical presentation, serum biochemical fluctuations, and functional enzymatic analysis of a case of functional ornithine transcarbamylase deficiency unmasked by a dietary change following bariatric surgery. Design Case report. Setting Tertiary referral center, hospital (inpatient) setting. Patient A 29-year-old woman who presented with intermittent encephalopathy associated with recurrent hyperammonemia. Interventions Clinical, biochemical, and mutational studies. Results The pattern of intermittent hyperammonemia and encephalopathy following oral and parenteral nutrition suggested a urea cycle abnormality. Functional enzymatic assay results showed markedly reduced ornithine transcarbamylase activity in the absence of known coding mutations. Conclusion Previously asymptomatic ornithine transcarbamylase deficiency should be suspected in adult patients who develop recurrent hyperammonemia and encephalopathy following bariatric surgery.

Differential liver protein expression during schistosomiasis.

Abstract: The arrival of eggs in the liver during Schistosoma mansoni infection initiates a protective granulomatous response; however, as the infection progresses, this response results in chronic liver fibrosis. To better understand the impact of schistosomiasis on liver function, we used a proteomic approach to identify proteins whose expression was significantly altered in schistosome-infected mice 8 weeks postinfection. Identification of differentially expressed proteins by mass fingerprinting revealed that schistosome infection markedly reduced the abundance of proteins associated with several normal liver functions (i.e., citric acid cycle, fatty acid cycle, and urea cycle), while proteins associated with stress responses, acute phase reactants, and structural components were all significantly more abundant. The expression patterns of several immunity-related proteins (peroxiredoxin 1, arginase 1, and galectin 1) suggested that different protein forms are associated with schistosome infection. These findings indicate that acute schistosomiasis has a significant impact on specific liver functions and, moreover, that the alterations in specific protein isoforms and upregulation of unique proteins may be valuable as new markers of disease.

Proteomic analysis of hepatic iron overload in mice suggests dysregulation of urea cycle, impairment of fatty acid oxidation, and changes in the methylation cycle

Abstract: Liver iron overload can be found in hereditary hemochromatosis, chronic liver diseases such as alcoholic liver disease, and chronic viral hepatitis or secondary to repeated blood transfusions. The excess iron promotes liver damage, including fibrosis, cirrhosis, and hepatocellular carcinoma. Despite significant research effort, we remain largely ignorant of the cellular consequences of liver iron overload and the cellular processes that result in the observed pathological changes. In addition, the variability in outcome and the compensatory response that likely modulates the effect of increased iron levels are not understood. To provide insight into these critical questions, we undertook a study to determine the consequences of iron overload on protein levels in liver using a proteomic approach. Using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) combined with matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS), we studied hepatic iron overload induced by carbonyl iron-rich diet in mice and identified 30 liver proteins whose quantity changes in condition of excess liver iron. Among the identified proteins were enzymes involved in several important metabolic pathways, namely the urea cycle, fatty acid oxidation, and the methylation cycle. This pattern of changes likely reflects compensatory and pathological changes associated with liver iron overload and provides a window into these processes.

Effects of barley grain processing and dietary ruminally degradable protein on urea nitrogen recycling and nitrogen metabolism in growing lambs.

Abstract: The objective of this study was to determine how interactions between dietary ruminally degradable protein (RDP) level and ruminally fermentable carbohydrate (RFC) alter urea N transfer to the gastrointestinal tract (GIT) and the utilization of this recycled urea N in rapidly growing lambs fed high-N diets. Four Suffolk ram lambs (34.8 +/- 0.5 kg of BW) were used in a 4 x 4 Latin square design with 21-d periods and a 2 x 2 factorial arrangement of dietary treatments. The dietary factors studied were 1) dry-rolled vs. pelleted barley as the principal source of RFC and 2) dietary levels of RDP of 60 vs. 70% (% of CP). All diets contained 28.8 g of N/kg of DM. Experimental diets were composed of 80% concentrate mixture and 20% barley silage (DM basis) and were fed twice daily at 0900 and 1700 as total mixed rations. Nitrogen balance was measured from d 15 to 20, and urea N kinetics were measured from d 15 to 19 using intrajugular infusions of [(15)N(15)N]-urea. Nitrogen intake (P = 0.001) and fecal (P = 0.002) and urinary (P = 0.03) N excretion increased as dietary RDP level increased, but the method of barley processing had no effect. Feeding dry-rolled compared with pelleted barley (P = 0.04) as well as feeding 60% RDP compared with 70% RDP (P = 0.04) resulted in a greater N digestibility. Whole-body N retention was unaffected (P >/= 0.74) by dietary treatment. Dietary treatment had no effect on endogenous production of urea N and its recycling to the GIT; however, across dietary treatments, endogenous production of urea N (45.8 to 50.9 g/d) exceeded N intake (42.3 to 47.9 g/d). Across dietary treatments, 30.6 to 38.5 g/d of urea N were recycled to the GIT, representing 0.67 to 0.74 of endogenous urea N production; however, 0.64 to 0.76 of urea N recycled to the GIT was returned to the ornithine cycle. In summary, although dietary treatment did not alter urea N kinetics, substantial amounts of hepatic urea N output were recycled to the GIT under the dietary conditions used in this study, and additional research is required to determine how this recycled urea N can be efficiently captured by bacteria within the GIT.

Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene.

Abstract: N-acetylglutamate synthase (NAGS) deficiency, an autosomal recessive disorder, is the last urea cycle disorder for which molecular testing became available. This is the first comprehensive report of 21 mutations that cause NAGS deficiency and of commonly found polymorphisms in the NAGS gene. Five mutations are reported here for the first time. A total of 10 disease-causing mutations are associated with acute neonatal hyperammonemia; the remaining mutations were found in patients with late onset disease. Residual enzymatic activities are included in this report and the deleterious effects of eight mutations were confirmed by expression studies. Mutations in the NAGS gene are distributed throughout its reading frame. No mutations have been found in exon 1, which encodes for the putative mitochondrial targeting signal and variable segment of NAGS. Three polymorphisms have been found. Early, accurate, and specific diagnosis of NAGS deficiency is critical since this condition can be successfully treated with N-carbamylglutamate (NCG, Carbaglu®; Orphan Europe). Treatment with NCG should be initiated as soon as a patient is suspected of having NAGS deficiency. Molecular testing represents the most reliable method of diagnosis. Hum Mutat 28(8), 754–759, 2007. Published 2007 Wiley-Liss, Inc.

Ionic, Osmotic, and Nitrogenous Waste Regulation

Abstract: Among primitive fishes, there is a diversity of strategies that have evolved to cope with ion, water, and nitrogen balance. The whole physiological spectrum is found from ionic and osmotic conformation to the regulation of body fluids distinct from the environment. The most primitive of vertebrates, the marine hagfish iono‐ and osmoconforms to its seawater environment, whereas their euryhaline relatives, the lampreys, iono‐ and osmoregulate. The gills of Agnathans contain both pavement and mitochondrial rich cells, but the arrangement of cells and structural features are unique relative to euryhaline teleosts. Coelacanths are osmoconformers but ionoregulators, maintaining high internal urea levels like the elasmobranchs. In many primitive species, ammonia is the dominant excretory product as it is in most teleost fishes. The exception is the coelacanth and estivating lungfish that synthesize urea via the urea cycle and excrete urea. Membrane transporters have been isolated in fish that regulate urea and possibly ammonia movements between tissue compartments and to the environment. Nitrogen excretion during early life stages presents a particular challenge in encapsulated embryos dependent on yolk protein catabolism. As yet, little is known about how primitive fish embryos face these challenges. Research on primitive fish species will broaden our knowledge of the evolution of osmoregulation and excretion in fish and terrestrial vertebrates.

Fatal Initial Adult-Onset Presentation of Urea Cycle Defect

Abstract: Background Ornithine transcarbamylase (OTC) deficiency presents most commonly with neonatal hyperammonemic coma. The gene is on the X chromosome, but the disease may manifest as a dominant trait. Mutations that lead to later-onset presentations may lead to life-threatening disease and may be unrecognized, particularly when the first clinical disease occurs in adulthood. Objective To document the clinical and metabolic consequences of a mutation in theOTCgene. Design Case reports. Setting A metabolic/biochemical genetic referral service. Main Outcome Measures Clinical and biochemical observations in 3 generations of a family. Results A mutation in codon 208 of exon 6 in theOTCgene was found in a family in which the proband died of hyperammonemia at 52 years of age. Conclusions Diagnosis of late-onset presentations of urea cycle defect in adults may be delayed. Heightened awareness could lead to effective treatment.

A novel bifunctional N-acetylglutamate synthase-kinase from Xanthomonas campestris that is closely related to mammalian N-acetylglutamate synthase.

Abstract: In microorganisms and plants, the first two reactions of arginine biosynthesis are catalyzed by N-acetylglutamate synthase (NAGS) and N-acetylglutamate kinase (NAGK). In mammals, NAGS produces an essential activator of carbamylphosphate synthetase I, the first enzyme of the urea cycle, and no functional NAGK homolog has been found. Unlike the other urea cycle enzymes, whose bacterial counterparts could be readily identified by their sequence conservation with arginine biosynthetic enzymes, mammalian NAGS gene was very divergent, making it the last urea cycle gene to be discovered. Limited sequence similarity between E. coli NAGS and fungal NAGK suggests that bacterial and eukaryotic NAGS, and fungal NAGK arose from the fusion of genes encoding an ancestral NAGK (argB) and an acetyltransferase. However, mammalian NAGS no longer retains any NAGK catalytic activity. We identified a novel bifunctional N-acetylglutamate synthase and kinase (NAGS-K) in the Xanthomonadales order of gamma-proteobacteria that appears to resemble this postulated primordial fusion protein. Phylogenetic analysis indicated that xanthomonad NAGS-K is more closely related to mammalian NAGS than to other bacterial NAGS. We cloned the NAGS-K gene from Xanthomonas campestis, and characterized the recombinant NAGS-K protein. Mammalian NAGS and its bacterial homolog have similar affinities for substrates acetyl coenzyme A and glutamate as well as for their allosteric regulator arginine. The close phylogenetic relationship and similar biochemical properties of xanthomonad NAGS-K and mammalian NAGS suggest that we have identified a close relative to the bacterial antecedent of mammalian NAGS and that the enzyme from X. campestris could become a good model for mammalian NAGS in structural, biochemical and biophysical studies.

In vitro demonstration of intra-locus compensation using the ornithine transcarbamylase protein as model

Abstract: Ornithine transcarbamylase deficiency (OTCD) is an X-linked inborn defect of metabolism of the urea cycle, which causes hyperamonemia. Mutations of the OTC gene have been recognized as the genetic cause underlying the OTC deficiency. The severity of the disease is associated with the type of mutation, leading either to neonatal onset of hyperammonemia or to a later appearance of the disease. The mutation Thr125Met is associated with neonatal hyperammonemia. Recently, the disease-causing Thr125Met mutation in humans was reported as wild-type neutral allele in chimpanzees. Further analysis confirmed the presence of Met125 fixed in chimpanzees together with Thr135, representing the only two divergent positions between human and chimpanzee OTCs. Thr125 and Thr135 were identified as ancestral mammalian combination, so the Thr135Ala substitution occurred as human-specific event, whereas the substitution of Thr125Met was characteristic of the chimpanzee linage. Only when Met125 emerges in a background with the human-specific Ala135, a highly deleterious effect is observed, suggesting among other hypotheses the existence of a compensatory effect in chimpanzee. To explore this hypothesis, we built an in vitro cell model system to study the effect of the three distinct genetic backgrounds (Ala135-Thr125; Ala135-Met125 and Thr135-Met125) on the OTC protein function. We observed that the human Thr125Met mutant is inactive, whereas the chimp OTC shows an enzymatic activity comparable with the wild-type human OTC. We concluded that the presence of a threonine at position 135 in chimps rescues the deleterious effect of the methionine at position 125, in a mechanism of intra-locus compensation.

Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes.

Abstract: The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia ...

Alternative-pathway therapy for hyperammonemia.

Abstract: Ammonia is a toxic compound produced in the body from the catabolism of amino acids and protein. Hyperammonemia can damage muscle and brain.1 The body converts ammonia to urea in the liver by means of the urea-cycle enzymes, and the urea so generated is subsequently eliminated in the urine as nitrogenous waste. This essential process is necessary for the maintenance of health. Metabolic disorders are associated with a defect or deficiency of each of the six enzymes in the urea cycle (Figure 1). These inborn errors of metabolism disrupt the normal processing of ammonia and result in hyperammonemia. In the . . .

C/EBPα knock-in hepatocytes exhibit increased albumin secretion and urea production

Abstract: The CCAAT/enhancer-binding protein α (C/EBPα) is essential for maintaining the differentiated state of hepatocytes in vivo. C/EBPα activates albumin transcription and coordinates the expression of multiple ornithine cycle enzymes involved in urea production. We have examined the effects of the C/EBPα knock-in gene on the mRNA and protein expression of genes involved in liver-specific functions, such as albumin and urea production. Albumin mRNA and protein levels are higher in knock-in hepatocytes compared with wild-type hepatocytes. mRNA levels for the ornithine cycle enzymes, namely arginase, carbamylphosphate synthetase 1, and ornithine transcarbamylase, also increase. Albumin secretion and urea production are sustained at higher levels in culture in knock-in hepatocytes. We have previously established that C/EBPα induces early liver glycogen storage in C/EBPα knock-in mice. Our present observations underline the importance of C/EBPα in liver metabolism and suggest that the induction of C/EBPα expression enhances hepatocyte function.

Distribution of arginase in tissues of cat (Felis catus)

Abstract: Arginase (EC 3.5.3.1), the final enzyme in the urea cycle, catalyses the hydrolysis of l-arginine to l-ornithine and urea. High activity of this enzyme in the liver indicates its primary role in ammonia detoxification. However, its wide tissue distribution suggests that this enzyme might perform other functions besides hepatic ureagenesis. Although the distribution and properties of arginase from many tissues of human, laboratory animals and some domestic animals have been studied, little is known about the pattern of distribution and physiological roles of this enzyme in the cat. The purpose of this study was to examine and compare the distribution of arginase in different tissues of the cat. A selection of tissue samples was assayed for arginase by the diacetyl monoxime method of determination of enzymatically formed urea. The protein content of tissues and enzymatic activities were calculated as units per gram tissue and units per milligram protein of the tissue. Results showed that the liver was the richest source of arginase followed by the oesophageal and tongue mucosal layers. Significant activity of this enzyme was found in the mucosa of the small intestine, kidney cortex, lung, testis and ovary. The results of this study will be discussed in terms of the involvement of arginase in several biochemical and physiological functions in this species.

Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency

Abstract: A patient with recurrent episodes of hyperammonaemia (highest ammonia level recorded 229 μmol/L, normal 9–33) leading to altered levels of consciousness was diagnosed with partial N-acetylglutamate synthase (NAGS) deficiency (9% residual activity) at age 5 years and was treated with ammonia-conjugating agents (Ucephan 250 mg/kg per day and later sodium phenylbutyrate 200–250 mg/kg per day) for 15 years. A chronically low serum carnitine level (pretreatment plasma free carnitine 4 nmol/L, normal 37 ±8 nmol/L; total carnitine 8 nmol/L, normal 46 ±10) was assumed to be secondary and was treated with supplemental carnitine (30–50 mg/kg per day). Hypoglycaemia (blood sugar 35 mg/dl, normal 70–100), cardiomegaly, and fatty liver were also noted at diagnosis. The patient died unexpectedly at age 20 years. In retrospect, it was learned that the patient had stopped his carnitine without medical consultation several weeks prior to his death. Additional molecular investigations identified two mutations (R254X and IVS3 + 1G > A) in the patient’s OCTN2 (SLC22A5) gene, consistent with a diagnosis of primary carnitine deficiency due to carnitine transporter defect. R245X is a founder mutation in Southern Chinese populations. It is unknown whether the original NAGS deficiency was primary or secondary, but molecular analysis of the NAGS gene failed to identify mutations. Urea cycle enzyme expression may be affected by fatty acid suppression of an AP-1 binding site in the promoter enhancer region of the urea cycle gene. Regardless, it is clear that the NAGS abnormality has led to delay of recognition of the OCTN2 defect, and modified the clinical course in this patient.

Acrodermatitis enteropathica-like dermatosis associated with ornithine transcarbamylase deficiency.

Abstract: The urea cycle is the major metabolic pathway for excretion of waste nitrogen. Ornithine transcarbamylase deficiency is the most frequent urea cycle disorder. It is a hereditary-X-linked disease with over 150 mutations described (1).Ornithine transcarbamylase deficiency causes vomiting, lethargy, hyperventilation, and even death, mainly in the neonatal period (2). Ammonia, an extremely toxic molecule for the organism, is generated during protein catabolism and is accumulated in patients with this deficiency. Part of the treatment consists of a low-protein diet, to avoid hyperammonemia episodes, which can even have a fatal outcome. Patients can become deficient in several amino acids, either through the low-protein diet or directly through the primary enzyme deficiency; this in turn can cause an acrodermatitis enteropathica-like dermatosis.

Urea Inhibits the In vitro Formation of Fluorescent Advanced Glycation End Products

Abstract: Advanced glycation end products are a heterogeneous group of compounds yielded from non- enzymatic glycosylation between proteins and carbohydrate, a process also known as the Maillard reaction. Advanced glycation end products are thought to be involved in chronic complications of diabetes mellitus and age-related diseases. Many advanced glycation end products are capable of forming cross-links between proteins. A large number of them are fluorophores. Studies on the inhibition of advanced glycation end product formation have received increasing recognition from both a nutritional and medical research standpoint. We tested the in vitro inhibition of fluorescent advanced glycation end products by urea on bovine serum albumin and L-lysine, comparing its inhibition capacity with a well-known advanced glycation end product inhibitor, aminoguanidine. Four different pairs of fluorescence filters were used to analyze the fluorescent intensity of glycated samples before and after they were treated with urea and aminoguanidine. We found that urea decreased the fluorescence of glycated samples more effectively than aminoguanidine, suggesting that urea formed in the urea cycle and in extrahepatic tissues by arginase from L-arginine might be a possible natural protector of advanced glycation end-products formation.

Flexibility of the hepatic zonation of carbon and nitrogen fluxes linked to lactate and pyruvate transformations in the presence of ammonia

Abstract: It has been proposed that key enzymes of ureagenesis and the alanine aminotransferase activity predominate in periportal hepatocytes. However, ureagenesis from alanine, when measured in the perfused liver, did not show periportal predominance and even the release of the direct products of alanine transformation, lactate and pyruvate, was higher in perivenous cells. An alternative way of analyzing the functional distributions of alanine aminotransferase and the urea cycle along the hepatic acini would be to measure alanine and urea production from precursors such as lactate or pyruvate plus ammonia. In the present work these aspects were investigated in the bivascularly perfused rat liver. The results of the present study confirm that gluconeogenesis and the associated oxygen uptake tend to predominate in the periportal region. Alanine synthesis from lactate and pyruvate plus ammonia, however, predominated in the perivenous region. Furthermore, no predominance of ureagenesis in the periportal region was found, except for conditions of high ammonia concentrations plus oxidizing conditions induced by pyruvate. These observations corroborate the view that data on enzyme activity or expression alone cannot be extrapolated unconditionally to the living cell. The current view of the hepatic ammonia-detoxifying system proposes that the small perivenous fraction of glutamine synthesizing perivenous cells removes a minor fraction of ammonia that escapes from ureagenesis in periportal cells. However, since urea synthesis occurs at high rates in all hepatocytes with the possible exclusion of those cells not possessing carbamoyl-phosphate synthase, it is probable that ureagenesis is equally important as an ammonia-detoxifying mechanism in the perivenous region.

Amino Acids and the Mitochondria

Abstract: This chapter describes some of the important physiological functions of amino acids in the mitochondria and the alterations caused by specific pathologies. To some extent all of the featured items are dependent upon the movement of amino acids across the highly selective permeability barrier that is the inner mitochondrial membrane. The performance of this transport by specific carriers is the subject of the first section. Once inside the mitochondrial matrix the amino acids become involved in a bewildering number of critical metabolic pathways. The second section elaborates on two of the most significant namely: the malateaspartate shuttle essential for the transfer of reducing equivalents between the cytoplasm and the mitochondria; and the urea cycle, which is responsible for maintaining sub-toxic levels of ammonia. The final section covers the changes to mitochondrial amino acid metabolism that occur under different pathological conditions. In this case three examples have been chosen comprising ischemiareperfusion in heart, myocardial hypertrophy and the special relationship that exists between glutamine and cancer cells.

Valproic Acid—Induced Hyperammonemia in a Patient With Schizoaffective Disorder:

Abstract: Valproic acid is used in psychiatry as a mood stabilizer and can be very effective in reducing symptoms of agitation. Valproic acid may cause hyperammonemia through carnitine deficiency created by ...