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Nucleosides, Nucleotides & Nucleic Acids Dec 2016Orotate (OA) is well-known as a precursor in biosynthesis of pyrimidines; in mammals it is released from the mitochondrial dihydroorotate dehydrogenase (DHODH) for... (Review)
Review
Orotate (OA) is well-known as a precursor in biosynthesis of pyrimidines; in mammals it is released from the mitochondrial dihydroorotate dehydrogenase (DHODH) for conversion to UMP by the cytoplasmic UMP synthase enzyme. OA is also a normal part of the diet, being found in milk and dairy products, and it is converted to uridine for use in the pyrimidine salvage pathway predominantly in liver, kidney and erythrocytes. Early research into nutrition identified orotate as "vitamin B13," and its use as a complex with organic cations or metal ions was promulgated in body-building, and in assisting therapies of metabolic syndromes. It has recently been established that the amelioration of gout by dairy products arises from the competition of orotate and urate at the hURAT1 transporter. The orotic aciduria that arises in children with defective UMP synthase can be rescued by oral uridine therapy, since UMP is the end-product and also a feedback inhibitor of the de novo pathway. In contrast, Miller (dysmorphology) syndrome is connected with defects in DHODH, and hence in the supply of OA, and cannot be helped by uridine. Other models of dysmorphisms are connected with enzymes early in the pyrimidine de novo pathway. We conclude that the OA molecule is itself required for the regulation of genes that are important in the development of cells, tissues and organisms.
Topics: Animals; Anticholesteremic Agents; Diet; Humans; Orotic Acid
PubMed: 27906623
DOI: 10.1080/15257770.2016.1147580 -
Neuropediatrics Dec 2016Orotic aciduria and deficiency of uridine monophosphate synthetase have been observed in a patient, studied over 10 years, who had no megaloblastic anemia. Excretion...
Orotic aciduria and deficiency of uridine monophosphate synthetase have been observed in a patient, studied over 10 years, who had no megaloblastic anemia. Excretion of orotic acid and orotidine were 8.24 and 0.52 mmol/mol of creatinine. The ratio of 15.85 differed appreciably from that of 6 patients reported with no megaloblastic anemia. The analysis of orotidine by gas chromotography mass spectrometry was conducted. Patients with orotic aciduria with and without megaloblastic anemia cannot be distinguished by ratio of orotic acid to orotidine.
Topics: Child; Female; Humans; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Purine-Pyrimidine Metabolism, Inborn Errors; Uridine; Young Adult
PubMed: 27574833
DOI: 10.1055/s-0036-1587594 -
The Medical Letter on Drugs and... Mar 2016
Topics: Acetates; Administration, Oral; Biomarkers; Drug Costs; Humans; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Purine-Pyrimidine Metabolism, Inborn Errors; Treatment Outcome; Uridine
PubMed: 27027693
DOI: No ID Found -
Journal of Genetics and Genomics = Yi... May 2015It is timely to consider the many facets of the small molecule orotic acid (OA), which is well-known as an essential intermediate of pyrimidine de novo synthesis. In... (Review)
Review
It is timely to consider the many facets of the small molecule orotic acid (OA), which is well-known as an essential intermediate of pyrimidine de novo synthesis. In addition, it can be taken up by erythrocytes and hepatocytes for conversion into uridine and for use in the pyrimidine recycling pathway. We discuss the link between dietary orotate and fatty liver in rats, and the potential for the alleviation of neonatal hyperbilirubinaemia. We address the development of orotate derivatives for application as anti-pyrimidine drugs, and of complexes with metal ions and organic cations to assist therapies of metabolic syndromes. Recent genetic data link human Miller syndrome to defects in the dihydroorotate dehydrogenase (DHODH) gene, hence to depleted orotate production. Another defect in pyrimidine biosynthesis, the orotic aciduria arising in humans and cattle with a deficiency of UMP synthase (UMPS), has different symptoms. More recent work leads us to conclude that OA may have a role in regulating gene transcription.
Topics: Animals; Central Nervous System; Enzymes; Humans; Milk; Orotic Acid; Pyrimidines
PubMed: 26059769
DOI: 10.1016/j.jgg.2015.04.001 -
Journal of Fluorescence Jul 2015Orotic acid is an intermediate in the synthesis pathway of uridine-5'-monophosphate, and increases in body fluids of patients suffering from hereditary disorders such as...
Orotic acid is an intermediate in the synthesis pathway of uridine-5'-monophosphate, and increases in body fluids of patients suffering from hereditary disorders such as orotic aciduria and hyperammonemia. In this study, we developed a spectrofluorometric method with or without high-performance liquid chromatography for the selective and sensitive quantification of orotic acid in human biological specimens, using 4-trifluoromethylbenzamidoxime (4-TFMBAO) as a fluorogenic reagent. This reagent provided intensive fluorescence for only orotic acid amongst 62 compounds including structurally related bio-substances such as nucleic acid bases, nucleosides, nucleotides, amino acids, vitamins, bilirubin, uric acid, urea, creatine, creatinine and sugars. Under optimized reaction conditions, orotic acid was reacted with 4-TFMBAO, K3[Fe(CN)6] and K2CO3 in an aqueous solution. The fluorescence produced from the orotic acid derivative was measured at an excitation of 340 nm and an emission of 460 nm. A concentration of 1.2 μM orotic acid per 1.0 mM creatinine in normal urine and 0.64 nmol orotic acid per 5.0 × 10(5) HeLa cells were determined by this method. The present method permitted the facile quantification of orotic acid in healthy human urine and cultured HeLa cells by spectrofluorometry and/or high-performance liquid chromatography.
Topics: Adult; Benzamidines; Chromatography, High Pressure Liquid; HeLa Cells; Humans; Hydrocarbons, Fluorinated; Indicators and Reagents; Male; Orotic Acid; Spectrometry, Fluorescence; Urinalysis
PubMed: 26026930
DOI: 10.1007/s10895-015-1584-3 -
Journal of Human Genetics Sep 2015Ornithine transcarbamylase (OTC) deficiency is an X-linked inborn error of the urea cycle that leads to the accumulation of ammonia, resulting in neurological deficits....
Ornithine transcarbamylase (OTC) deficiency is an X-linked inborn error of the urea cycle that leads to the accumulation of ammonia, resulting in neurological deficits. This study was performed to describe the clinical outcomes, biochemical features and molecular spectra of patients with OTC deficiency. A total of 49 patients from 47 unrelated Korean pedigrees were included who were diagnosed with OTC deficiency based on biochemical findings and molecular analyses. Patient clinical features,biochemical findings and molecular data were analyzed retrospectively. Males with neonatal-onset phenotype presented with seizure or altered mentality (n=20). Biochemical findings showed high blood ammonia (1132.5±851.6 μmol l (− 1)) and urineorotic acid (1840.7±1731.3 mmol mol(− 1) Cr) levels. There were also five males with late-onset disease who presented with vomiting, irritability and seizure at age 8.2±9.4 years old (range, 0.6–20 years). Symptomatic females presented with vomiting,seizure, and altered mentality at age 3.5±3.5 years (range, 0.2–12.8 years; n=24). More males with the late-onset form and symptomatic females displayed mild hyperammonemia and orotic aciduria compared with those showing a neonatal phenotype (P<0.05). Molecular analysis identified 37 different mutations (22 missense, 5 large deletions, 4 small deletions, 1 insertion,3 nonsense and 2 splice sites) from all 49 patients; the mutations were dispersed throughout all coding exons. In Korean patients with OTC deficiency, mutations in OTC are genetically heterogeneous. Male patients with the neonatal-onset phenotype showed poor outcomes because of severe hyperammonemia. Early diagnosis and interventions for hyperammonemia can provide more favorable prognosis.
Topics: Adolescent; Adult; Child; Child, Preschool; DNA Mutational Analysis; Female; Humans; Infant; Infant, Newborn; Male; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Prognosis; Republic of Korea; Retrospective Studies; Young Adult
PubMed: 25994866
DOI: 10.1038/jhg.2015.54 -
World Journal of Hepatology May 2015The clinical manifestations of hyperammonemia are usually easily identifiable to the clinician when associated with liver disease and lead to prompt diagnosis and...
The clinical manifestations of hyperammonemia are usually easily identifiable to the clinician when associated with liver disease and lead to prompt diagnosis and treatment. However, hyperammonemia-induced encephalopathy is rare in adults in the absence of overt liver disease, thus diagnosis is often delayed or missed leading to potentially life threatening complications. Without proper treatment, such patients can decompensate rapidly with poor outcomes including seizures, coma, and death. Early assessment of plasma ammonia levels in patients with normal hepatic function and characteristic symptoms of encephalopathy can lead to early intervention while investigating the underlying etiology. We describe a patient who presented with a 2-year progression of waxing and waning acute mental status changes after a Roux-en-Y gastric bypass surgery. He was found to have elevated ammonia level as well as orotic aciduria; results consistent with a urea cycle disorder. After consulting neurology as well as toxicology, he ultimately improved after dietary protein restriction, sodium benzoate and lactulose therapy. While rare, clinicians should have a high index of suspicion for late onset urea cycle disorders in symptomatic patients presenting with encephalopathy secondary to hyperammonemia.
PubMed: 25954483
DOI: 10.4254/wjh.v7.i7.1007 -
Neuropediatrics Apr 2015Hereditary orotic aciduria is a rare metabolic disease that results from a defect of uridine-5-monophosphate synthase (UMPS). In affected patients, main clinical...
Hereditary orotic aciduria is a rare metabolic disease that results from a defect of uridine-5-monophosphate synthase (UMPS). In affected patients, main clinical symptoms are a markedly increased urinary excretion of orotic acid combined with megaloblastic anemia. This report describes a new case of UMPS deficiency without megaloblastic anemia but with epilepsy.
Topics: Anemia, Megaloblastic; Child, Preschool; Epilepsy; Humans; Male; Metabolic Diseases; Multienzyme Complexes; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase
PubMed: 25757096
DOI: 10.1055/s-0035-1547341 -
American Journal of Medical Genetics.... Mar 2015Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the...
Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders.
Topics: Acyl-CoA Dehydrogenase, Long-Chain; Amino Acids; Biopsy; Blood Chemical Analysis; Congenital Bone Marrow Failure Syndromes; Female; Humans; Infant; Lipid Metabolism, Inborn Errors; Liver; Male; Mitochondrial Diseases; Muscular Diseases; Pancreas; Phenotype
PubMed: 25691415
DOI: 10.1002/ajmg.a.36939 -
PloS One 2015Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In...
Ornithine transcarbamylase deficiency (OTCD, OMIM# 311250) is an inherited X-linked urea cycle disorder that is characterized by hyperammonemia and orotic aciduria. In this report, we describe a new animal model of OTCD caused by a spontaneous mutation in the mouse Otc gene (c.240T>A, p.K80N). This transversion in exon 3 of ornithine transcarbamylase leads to normal levels of mRNA with low levels of mature protein and is homologous to a mutation that has also been described in a single patient affected with late-onset OTCD. With higher residual enzyme activity, spf-J were found to have normal plasma ammonia and orotate. Baseline plasma amino acid profiles were consistent with mild OTCD: elevated glutamine, and lower citrulline and arginine. In contrast to WT, spf-J displayed baseline elevations in cerebral amino acids with depletion following immune challenge with polyinosinic:polycytidylic acid. Our results indicate that the mild spf-J mutation constitutes a new mouse model that is suitable for mechanistic studies of mild OTCD and the exploration of cerebral pathophysiology during acute decompensation that characterizes proximal urea cycle dysfunction in humans.
Topics: Amino Acid Sequence; Amino Acids; Animals; Biological Transport; Body Weight; Brain; Disease Models, Animal; Humans; Mice; Molecular Sequence Data; Mutation, Missense; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Phenotype; Poly I-C; Protein Structure, Tertiary; Rats; Survival Analysis
PubMed: 25647322
DOI: 10.1371/journal.pone.0116594