Orotic aciduria

In hereditary orotic aciduria, orotic acid is excreted in the urine because the enzymes that convert it to uridine monophosphate, orotate phosphoribosyl transferase and orotidine 5 -phosphate decarboxylase, are defective (see Figure 7-20). Pyrimidines cannot be synthesized, and therefore, normal growth does not occur. Oral administration of uridine bypasses the metabolic block and provides the body with a source of pyrimidines. 

M53 Murphey, W. H., Patchen, L. and Guthrie, R. Screening tests for argininosuccinic aciduria, orotic aciduria and other inherited enzyme deficiencies using dried blood specimens. Biochem. Genet., 6, 51-59 (1972)... 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

The orotic aciduria that accompanies Reye s syndrome probably is a consequence of the inabifity of severely damaged mitochondria to utifize carbamoyl phosphate, which then becomes available for cytosofic overproduction of orotic acid. Type I orotic aciduria reflects a deficiency of both orotate phosphoribosyltransferase and orotidylate decarboxylase (reactions 5 and 6, Figure 34—7) the rarer type II orotic aciduria is due to a deficiency only of orotidylate decarboxylase (reaction 6, Figure 34-7). 

Excess carbamoyl phosphate exits to the cytosol, where it stimulates pyrimidine nucleotide biosynthesis. The resulting mild orotic aciduria is increased by high-nitrogen foods. 

Urinary orotic acid generally is very elevated in babies with OTC deficiency and normal or even low in the infant with CPS deficiency. Patients with OTC deficiency have orotic aciduria because carbamyl phosphate spills into the cytoplasm, where it enters the pathway of pyrimidine synthesis. 

Diagnosis of CPS or OTC deficiency may not be apparent from the blood aminogram. Ornithine levels typically are normal. The presence of hyperammonemia, hyperglu-taminemia, hyperalaninemia and orotic aciduria in a critically ill infant affords presumptive evidence for OTC deficiency. The presence of this blood aminogram without orotic aciduria suggests carbamyl phosphate synthetase deficiency. 

Animal models for OTC deficiency include the sparse fur (spf) mouse (15% control enzyme activity) and the sparse fur-abnormal skin and hair (spf-ash) mouse (5% of control). Both kinds of mutant mouse manifest hyperammonemia, orotic aciduria, growth failure and sparse fur. 

Mutation of one of the two enzyme activities of UMP synthase leads to orotic aciduria, characterized by accumulation of its first substrate orotic acid and insufficient levels of the product UMP, which reduces availability of uridine triphosphate (UTP) and cytidine triphosphate (CTP) for use in nucleic acid synthesis. 

Patients with orotic aciduria excrete large amounts of orotic acid in their urine, and they exhibit lethargy, weakness, severe anemia, and growth retardation. 

The end-product of pyrimidine base synthesis is orotic acid, which is converted to the nucleotide OMP by the addition of ribose 6-phosphate (donated by PRPP). OMP is then converted to UMP, which is phosphorylated to UTP. UTP is then aminated to form CTP. A deficiency of the enzyme complex (UMP synthase) that converts orotic acid to UMP causes orotic aciduria. 

Orotidine 5 -phosphate undergoes an unusual decarboxylation (Fig. 25-14, step/), which apparently is not assisted by any coenzyme or metal ion but is enhanced over the spontaneous decarboxylation rate 1017-fold. No covalent bond formation with the enzyme has been detected.268 It has been suggested that the enzyme stabilizes a dipolar ionic tautomer of the substrate. Decarboxylation to form an intermediate ylid would be assisted by the adjacent positive charge.269,270 Alternatively, a concerted mechanism may be assisted by a nearby lysine side chain.270a d Hereditary absence of this decarboxylase is one cause of orotic aciduria. Treatment with uridine is of some value.271... 

In an inborn error of metabolism called orotic aciduria, UMP synthase is defective and the urine contains large amounts of orotate. This disorder may be treated by feeding cytidine and uridine. Large amounts of orotate may also be excreted in the urine in the various hyperammonemia syndromes. Carbamoyl phosphate, formed in the mitochondria by the action of carbamoyl phosphate synthetase I, is present in such large amounts that it spills over into the cytosol. There, the carbamoyl phosphate is rapidly converted to orotic acid and the latter is cleared by the kidneys. 

Patients with orotic aciduria can be successfully treated with UMP but not with uradl. Explain why. 

Arginino succinate aciduria AL 7cen-qll.2 Liver, skin, RBC Citrulline T Orotic acid T... 

Orotic acid is an intermediate in pyrimidine synthesis. It is synthesized from the transcar-bamylation of aspartic acid and subsequent intramolecular condensation. Any defect in ureagenesis causing accumulation of intracellular carbamoyl phosphate provides substrate for orotic acid synthesis. Therefore, a defect of OTC, or any defect distal to this step, can cause orotic aciduria. The detection of elevated orotic acid in the urine is most useful in differentiating between patients with OTC deficiency and either CPSI- or NAGS-deficient patients in whom orotic aciduria is not present. 

A second, cytosolic CPS activity (CPSII) occurs in mammals as part of the CAD trifunctional protein that catalyzes the first three steps of pyrimidine synthesis (CPSII, asparate tran-scarbamoylase, and dihydroorotase). The activities of these three enzymes—CPSII, aspartate transcarbamoylase, and dihydroorotase—result in the production of orotic acid from ammonium, bicarbonate, and ATP. CPSII has no role in ureagenesis, but orotic aciduria results from hepatocellular accumulation of carbamyl phosphate and helps distinguish CPSI deficiency from other UCDs. Defects in CPSI classically present with neonatal acute hyperammonemic encephalopathy. The plasma citrulline and urine orotic acid concentrations are both low. A definitive diagnosis can be established by enzyme assay of biopsied liver tissue or by mutation analysis. 

B-8) Orotic aciduria. Blocks in steps leading to pyrimidine synthesis may result in deficient production of pyrimidine nucleotides. There may be anemia and immune deficiency (from decreased red and while cell production) and excess orotic acid which may precipitate in the urine. Treatment with uridine may not only help supply the missing pyrimidine, but can decrease the level of orotate by uridine s negative feedback on steps that lead to orotate production. 

Carey, G. R, Kime, Z., Rogers, Q. R., Morris, J. G., Hargrove, D., Buffington, C. A., and Brusilow, S. W. (1987). An arginine-deficient diet in humans does not evoke hjqreram-monemia or orotic aciduria. /. Nutr. 117,1734-1739. 

Figure 7-20. De novo synthesis of purines and pyrimidines. Ribonucleotide reductase (R.R.) catalyzes the reduction of the ribose moiety in ADP, GDP, and CDP to deoxyribose. The source of each of the atoms is indicated in the boxes at the bottom of the figure. In hereditary orotic aciduria, the enzymes converting orotate to UMP are defective ( ).

Hereditary orotic aciduria is a rare autosomal recessive trait. In this disorder, both orotate phosphoribosyltrans-ferase and orotidine-5 -phosphate decarboxylase activities (reactions 5 and 6 in Figure 27-26) are markedly deficient. Recall that these activities occur on the polypeptide Pyr 5,6. 

Orotic aciduria is characterized by failure of normal growth and by the presence of hypochromic erythrocytes and megaloblastic bone marrow, none of which are improved by the usual hematinic agents (e.g., iron, pyridoxine, vitamin B 2, and folate). Leukopenia is also present. Treatment with uridine 2-A g/d) results in marked improvement in the hematological abnormalities, in growth and development, and in decreased excretion of orotic acid. These patients are pyrimidine auxotrophs and require an exogenous source of... 

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. 

A 4-year-old girl presents in the clinic with megaloblastic anemia and failure to thrive. Blood chemistries reveal orotic aciduria. Enzyme measurements of white blood cells reveal a deficiency of the pyrimidine biosynthesis enzyme orotate phosphoribosyltransferase and abnormally high activity of the enzyme aspartate transcarbamoylase. Which one of the following treatments will reverse all symptoms if carried out chronically ... 

The answer is e. (Murray, pp 375-401. Scriver, pp 2663-2704. Sack, pp 121-138. Wilson, pp 287—320.) Orotic aciduria is the buildup of orotic acid due to a deficiency in one or both of the enzymes that convert it to UMP Either orotate phosphoribosyltransferase and orotidylate decarboxylase are both defective, or the decarboxylase alone is defective. UMP is the precursor of UTP, CTP, and TMP All of these end products normally act in some way to feedback-inhibit the initial reactions of pyrimidine synthesis. Specifically, the lack of CTP inhibition allows aspartate transcarbamoylase to remain highly active and ultimately results in a buildup of orotic acid and the resultant orotic aciduria. The lack of CTP, TMP, and UTP leads to a decreased erythrocyte formation and megaloblastic anemia. Uridine treatment is effective because uridine can easily be converted to UMP by omnipresent tissue kinases, thus allowing UTP, CTP, and TMP to be synthesized and feedback-inhibit further orotic acid production. 

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