Ornithine Orotic acid

Mercaptoacetic Add 2-Mercaptobenzoic Acid Methane Methanol Methionine Methotrexate Methylene Blue A-Methyl Glycine 5-Methylindole Methyl Isocyanate Methylmalonic Add Methyl Methacrylate Methylmethane Sulfonate Methyl Thiocyanate A-Methyl Thiourea Methyl Urea Naphthalene Nicotinic Acid Ornithine Orotic Acid Oxalic Acid Oxindole Palmitic Acid Paraldehyde Pentobarbital Phenol... 

The underlying biochemical defect is a failure of mitochondrial uptake of ornithine. This results in a failure of citrulline synthesis and a consequent hyperammonemia. Urinary orotic acid is high, presumably because of underutilization of carbamyl phosphate. In contrast, excretion of creatine is low, reflecting the inhibition of glycine trans-amidinase by excessive levels of ornithine. 

The two conditions can be distinguished by an increase in orotic add and uracil, which occurs in ornithine transcarbamoylase deficiency, but not in the defldency of carbamoyl phosphate synthetase. Orotic acid and uracil are intermediates in pyrimidine synthrais (see Chapter 18). This pathway is stimulated by the accumulation of carbamoyl phosphate, the substrate for ornithine transcarbamoylase in the urea cycle and for aspartate transcarbamoylase in pyrimidine synthesis. 

Ornithine transcarbamoyiase (increase in uracil and orotic acid)... 

ORNITHINE TRANSCARBAMOYLASE Ornithine ketoacid aminotransferase, ORNITHINE AMINOTRANSFERASE Ornithine oxo-acid aminotransferase, ORNITHINE AMINOTRANSFERASE ORNITHINE TRANSCARBAMOYLASE Orotate,... 

About half of the NPN of milk is accounted for by urea. Orotic acid is a particular hallmark of the milks of ruminants milks of other species contain little if any of it (Larson and Hegarty 1977). The free amino acids constituting the a-amino N fraction in Table 1.6 include those that are also found in proteins, as well as ornithine, citrulline, and cx-amino butyric acid. Quantitative analyses of the mixture of free amino acids have been published (Deutsch and Samuelsson 1958 Armstrong and Yates 1963 Rassin et al. 1978). 

An adolescent went into delirium after eating a high-protein meal. He had an extremely high blood ammonia level and excreted orotic acid and uracil in the urine. His blood also contained increased glutamine and lysine levels. Despite heroic symptomatic treatment, the patient expired after 2 weeks. His liver tissue showed normal urea cycle enzyme levels, except that for ornithine transcar-bamylase (OTC), whose activity was only 10% that of normal liver. The Km of OTC was normal. Liver carabmylphosphate levels were about 10 times normal. Theoretical computer simulations indicated that urea can be produced at normal rates when liver OTC levels are higher than 0.3% of normal. 

Ornithine transcarbamoylase OTC deficiency OTC Xp21.1 Liver Citrulline i Orotic acid TT... 

Ornithine transporter HHH disease ORNT1 13ql4 Liver, skin Citrulline T Orotic acid T... 

Diagnosis is based upon hyperammonaemia, which is detectable either spontaneously or after the oral intake of proteins - or, most obviously, following intravenous infusion of amino acids. The respective amino acids are increased in the serum prior to the disturbed metabolic reaction. Argininosuccinate is only detectable in the urine. A striking feature in these patients is their thin, brittle hair. With defective ornithine transcarbamylase, there is an increase in orotic acid, uridine and uric acid in the urine, while the respective citrulline concentration is decreased. The determination of OTC activity in liver tissue verifies the diagnosis and facilitates a genomic analysis. (172) The allopurinol test can be applied for the identification of heterozygosity (or the mild form of OTC deficiency). The liver shows steatosis, portal inflammation and portal fibrosis. 

The unaccounted N includes some phospholipids, amino sugars, nucleotides, hippuric acid and orotic acid. The a-amino N includes free amino acids and small peptides almost a complete range of amino acids, including ornithine, has been identified in milk, but glutamic acid predominates. 

When ornithine transcarbamoylase (OTC) is deficient, the carbamoyl phosphate that normally would enter the urea cycle accumulates and floods the pathway for pyrimidine biosynthesis. Under these conditions, excess orotic acid (orotate), an intermediate in pyrimidine biosynthesis, is excreted in the urine. It produces no ill effects but is indicative of a problem in the urea cycle. 

The metabolic team was consulted and obtained STAT biochemical labs including plasma acylcamitine profile, plasma amino acids, urine organic acids, and urine orotic acid. Labs showed elevated orotic acid as well as a plasma amino-acid pattern consistent with ornithine transcarbamylase (OTC) deficiency. The newborn screen was normal. The infant was placed on a protein-restricted diet, supplemented with arginine, and started on nitrogen-scavenging medications. 

In children, deficient levels of ornithine carbamoyitransferase (an enzyme involved in the urea cycle, and which converts ornithine and carbamoyl phosphate to citrulline) [218,220] present as orotic aciduria, a secondary effect resulting indirectly from the accumulation of carbamoyl phosphate. The deficiency of ornithine carbamoyitransferase leads to overall stimulation of pyrimidine synthesis de novo which is reflected by an increased production and excretion of orotic acid. 

Orius insidiosus, 4098 Orixa, 722 Ornithine, 365,417 L-Omithine, 344 Ornithine decarboxylase, 182 Ornithonyssus sylviarum, 4072 Orobanchaceae, 3585 Orobanche, 3585 Orobanche minor, 3591 Orobanchol, 3585 Orobanchol series, 3589 Orobol, 1667 Oroidin alkaloids, 265 Orotic acid, 1664 Orsaponin, 3235 OrtAo-chloranil, 1063 Orthologous/homologous, 698 Orthostatic hypotension, 697, 1373 Orawacin, 3027... 

Elevated concentrations of orotic acid and uracil may be found in the urine of heterozygote carriers for urea cycle disorders, most commonly ornithine carbamoyltransferase (OCT) deficiency. This is due to the increased flux through the pyrimidine pathway which occurs, especially where the relevant enzymes are expressed only in liver tissue, as is the case when urea cycle enzymes are defective. A protein load was used previously to stress this route and the elevation in orotic acid excretion used as a diagnostic marker. However, the test frequently failed to detect known carriers. The al-lopurinol loading test (measurement of the increment in urinary orotic acid and orotidine in three separate 8 hour urine collections over the 24 hours following a 300 mg allopurinol tablet) is the most reliable test so far for carrier detection for such disorders [17]. 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

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