Dihydroorotic acid dehydrogenase

The fourth step in the de novo synthesis of pyrimidine nucleotides—the conversion of dihydroorotic acid to orotic acid—is catalyzed by dihydroorotic acid dehydrogenase. The enzyme, located on the cytosolic side of the inner membrane of mitochondria, is a target for antitumor agents. 

Leflunomide This drug inhibits dihydroorotic acid dehydrogenase, an enzyme involved in ribonucleotide synthesis. Leflunomide arrests lymphocytes in the Gj phase of the cell cycle. Leflunomide is used in rheumatoid arthritis. The drug causes alopecia, rash, and diarrhea. 

DIHYDROOROTATE OXIDASE DIMETHYLANILINE MONOOXYCENASE FERREDOXIN NADP REDUCTASE GLUTATHIONE REDUCTASE 0-2-HYDROXY ACID DEHYDROGENASE... 

Leflunomide (Arava) is an anti-proliferative drug that inhibits dihydroorotate dehydrogenase, an enzyme essential for the synthesis of pyrimidines such as uracil, via aromatisation of dihydroorotic acid. It also has some immunomodulatory effects and is useful for intractable cases of rheumatoid arthritis, despite being liable to cause a number of serious side-effects. It is actually a prodrug, being converted into the active compound, a nitrile formed by cleavage of the isoxazole ring (cf. 25.5.1). 

In the next step of pyrimidine biosynthesis, the entire aspartate molecule adds to carbamoyl phosphate in a reaction catalyzed by aspartate transcarbamoylase. The molecule subsequently closes to produce a ring (catalyzed by dihydroorotase), which is oxidized to form orotic acid (or its anion, orotate) through the actions of dihydroorotate dehydrogenase. The enzyme orotate phosphoribosyl transferase catalyzes the transfer of ribose 5-phosphate from PRPP to orotate, producing orotidine 5 -phosphate, which is decarboxylated by orotidylic acid dehydrogenase to form... 

Dihydroorotic acid is oxidized by a DPN-requiring dehydrogenase to the pyrimidine, orotic acid. Orotic acid is an efficient precursor of other pyrimidines and is required by certain microorganisms. The conversion... 

Steric effects and FMO control have been combined in an elegant way to achieve regiospecific synthesis of pyrazole inhibitors of dihydroorotate dehydrogenase <2006SL901>. When the size of the propargylic acid ester 86 is increased from ethyl to diphenylmethyl, pyrazole 87 is formed from compound 85 regiospecifically (Scheme 3 Table 4) <2006H(68)1007>. 

CYTOCHROME P-450 REDUCTASE DIHYDROOROTATE OXIDASE FMN ADENYLYLTRANSFERASE GLUTAMATE SYNTHASE GLYCOLATE OXIDASE (S)-2-HYDROXY-ACID OXIDASE l-LACTATE DEHYDROGENASE (CYTOCHROME)... 

The second step in pyrimidine synthesis is the formation of car-bamoylaspartate, catalyzed by aspartate transcarbamoylase. The pyrimidine ring is then closed hydrolytically by dihydroorotase. Thi resulting dihydroorotate is oxidized to produce orotic acid (onotate, Figure 22.21). The enzyme that produces orotate, dihydroorotate dehydrogenase, is located inside the mitochondria. All other reactions in pyrimidine biosynthesis are cytosolic. [Note The first three enzymes in this pathway (CPS II, aspartate transcarbamoylase, and dihydroorotase) are all domains of the same polypeptide chain. (See k p. 19 for a discussion of domains.) This is an example of a multifunctional or multicatalytic polypeptide that facilitates the ordered synthesis of an important compound.]... 

The third reaction is the oxidation of the ring to form a carbon-carbon bond. The reducing equivalents are transferred to a flavin cofactor of the enzyme dihydroorotate dehydrogenase. The product is orotic acid. 

FIGURE 5. (A) Interaction of atovaquone with the Fe-S center (on left) in the cytochrome bc complex via H-bonding with the coordinated His (Plate VIII). (B) The active center of a class 2 dihydroorotate dehydrogenase (PDB ID 1UUM) with a hound inhibitor atovaquone (top baU-and-stick stmcture), orotic acid (green) and riboflavin 5 -(dihydrogen phosphate) (FMN, pink) (Plate IX)... 

Polypore mushroom (Hapalopilus rutilans) has also been reported. Three German patients developed reduced vision, somnolence, weakness with decreased motor tone and activity at least 24 hours after the mushroom meal. Clinical biochemistry measurements found electrolyte imbalances and evidence of liver and kidney damage. These symptoms are probably due to polyporic acid, which inhibits the enzyme dihydroorotate dehydrogenase and is found in... 

Figure 2 shows the main stages of pyrimidine nucleotides biosynthesis. In stage 1 aspartic add and carbamyl phosplmte (formed from ammonia, CO3 and ATP) condense to form carbamyl aspartic acid. This derivative cydizes with loss of water to form dihydroorotic add which is converted by a dehydrogenase to orotic add. The nudeotide of orotic acid (orotidylic add (OI )) is dien formed in... 

---