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 What is Orotic aciduria ?

“Deficiency of a Urea Cycle enzyme results in Orotic aciduria”, Justify the statement and elaborate on all the possible causes of Orotic aciduria.

Orotic aciduria refers to an excessive excretion of Orotic acid in urine. This is a disorder of pathway of pyrimidine biosynthesis.

Hereditary Orotic aciduria

Biochemical Defect– Orotic aciduria is a rare Autosomal recessive disorder. The usual form of hereditary Orotic aciduria is the buildup of Orotic acid due to the deficiency in one or both of enzymes that convert it to UMP. Either orotate phosphoribosyl transferase and orotidylate decarboxylase both are defective, or the decarboxylase alone is defective.

Type I orotic aciduria reflects a deficiency of both orotate phosphoribosyltransferase and orotidylate decarboxylase (reactions  5 and 6, Figure-1); the rarer type II orotic aciduria is due to a deficiency only of orotidylate decarboxylase (reaction 6)

Pathway of Pyrimidine Biosynthesis

 steps of pyrimidine biosynthesis

Figure-1-showing the steps of de novo pyrimidine nucleotide biosynthesis

The first step in de novo pyrimidine biosynthesis (Figure-1) is the synthesis of Carbamoyl phosphate from bicarbonate and glutamine in a multistep process, requiring the cleavage of two molecules of ATP. This reaction is catalyzed by Carbamoyl phosphate synthetase -II (CPS-II). Carbamoyl phosphate synthetase-II  primarily uses glutamine as a source of ammonia. A different enzyme mitochondrial carbamoyl phosphate synthase I catalyzes the first step of urea synthesis (Figure-2). Compartmentation thus provides two independent pools of carbamoyl phosphate.

Carbamoyl phosphate reacts with aspartate to form Carbamoyl aspartate in a reaction catalyzed by Aspartate Transcarbamoylase (Figure-1).Carbamoyl aspartate cyclizes to form Dihydro orotate, which then gets oxidized by Dihydro orotate dehydrogenase in the presence of NADto form orotate. At this stage, orotate couples to ribose, in the form of 5-phosphoribosyl-1-pyrophosphate (PRPP), a form of ribose activated to accept nucleotide bases. Orotate reacts with PRPP to form orotidylate (Orotate mono phosphate), a pyrimidine nucleotide. This reaction is driven by the hydrolysis of pyrophosphate. The enzyme that catalyzes this addition, pyrimidine phosphoribosyl transferase, is homologous to a number of other phosphoribosyl transferases that add different groups to PRPP to form the other nucleotides. 

Orotidylate is then decarboxylated to form uridylate (UMP), a major pyrimidine nucleotide that is a precursor to RNA. This reaction is catalyzed by orotidylate decarboxylase. UMP is the parent nucleotide; the other pyrimidine nucleotides are formed from UMP (Figure-1)

Clinical manifestations

This disorder usually appears in the first year of life and is characterized by growth failure, developmental retardation, megaloblastic anemia, and increased urinary excretion of Orotic acid.

UMP, The end product of this pathway, 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. Specially, the lack of CTP inhibition allows Aspartate Transcarbamoylase to remain highly active. This results in more and more production of Orotic acid which gets accumulated and is excreted in urine excessively.

Lack of CTP, TMP, and UTP leads to a decreased nucleic acid synthesis and decreased erythrocyte formation resulting in Megaloblastic anemia. 

Physical and mental retardation are frequently present. The anemia is refractory to vitamin B12 or folic acid.

Laboratory Diagnosis

The diagnosis of this disorder is suggested by the presence of severe Megaloblastic anemia with normal serum B12 and Folate levels and no evidence of TC-II deficiency (Transcobalamine- II). A presumptive diagnosis is made by finding increased urinary orotic acid. Confirmation of the diagnosis, however, requires assay of the Transferase and decarboxylase enzymes in the patient’s erythrocytes .


Uridine treatment is effective because Uridine can easily be converted into UMP by omnipresent tissue kinase, thus allowing UTP, CTP, and TMP to be synthesized and feedback inhibit further Orotic acid production.

Deficiency of Ornithine trans carbamoylase (Urea cycle disorder)

Increased excretion of orotic acid, uracil, and uridine accompanies a deficiency in liver mitochondrial ornithine transcarbamoylase (reaction 2, Figure 2). Excess carbamoyl phosphate exits to the cytosol, where it stimulates pyrimidine nucleotide biosynthesis. The resulting mild orotic aciduria is increased by high-nitrogen foods.

OTC deficiency

Figure-2- Showing the  block at the level of Ornithine transcarbamoylase that results in diffusion of carbamoyl phosphate to cytoplasm to be utilized in the pathway of pyrimidine bio synthesis causing Orotic aciduria.

Reye Syndrome

The orotic aciduria that accompanies Reye syndrome probably is a consequence of the inability of severely damaged mitochondria to utilize carbamoyl phosphate, which then becomes available for cytosolic overproduction of orotic acid.

Drug induced Orotic aciduria

1) Allopurinol  is an alternative substrate for orotate phosphoribosyltransferase (reaction 5, Figure-1), competes with orotic acid. Orotate phosphoribosyltransferase (reaction 5, Figure 1) converts the drug allopurinol  to a nucleotide (Oxypurinol ribonucleotide). The resulting nucleotide product also inhibits orotidylate decarboxylase (reaction 6, figure-1), resulting in orotic aciduria and orotidinuria (Figure-3)

Allopurinol induced orotic aciduria

Figure-3- showing Allopurinol induced Orotic aciduria

2) 6-Azauridine, following conversion to 6-azauridylate, also competitively inhibits orotidylate decarboxylase (reaction 6, Figure-1), enhancing excretion of orotic acid and orotidine.

3) The anticancer drug 5-fluorouracil is also phosphoribosylated by orotate phosphoribosyl transferase.

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