Dihydro-orotate dehydrogenase

Lieberman 1, A Komberg (1953) Enzymatic synthesis and breakdown of a pyrimidine, orotic acid I. Dihydro-orotic dehydrogenase. Biochim Biophys Acta 12 223-234. 

HMR 1726, Terifluno-mide Dihydro-orotate dehydrogenase inhibitor Reduced number of active lesions Multiple Sclerosis... 

The phenoxyquinolines are a recent addition to crop fungicides and only one compound has been described. LY214352, an experimental fungicide, inhibits a novel target, dihydro-orotate dehydrogenase (DHO-DH) in the pyrimidine biosynthesis pathway that catalyses the conversion of dihydro-orotate into orotic acid9 (Figure 4.13). 

In vivo, Leflunomide is rapidly converted into its pharmacologically active metabolite A77 1726 (Herrmann et al., 2000). Although the precise mode of action of Leflunomide in vivo remains elusive, A77 1726 has been shown in vitro to inhibit reversibly dihydro-orotate dehydrogenase (DHODH), which catalyzes a rate-limiting step in the de novo synthesis of pyrimidines (Cherwinski et al., 1995 Williamson et al., 1996). The inhibition of DHODH activity by A77 1726 might explain part of its mechanism of action in suppressing inflammation. 

Brequinar (DUP 785, NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis by inhibiting dihydro-orotate dehydrogenase. It was originally developed as an anticancer drug, but has also been investigated for its immunosuppressant activity after transplantation. Some data suggest that that the immunosuppressant activity of brequinar may be partly due to inhibition of tyrosine phosphorylation in lymphocytes (1). 

Spirobarbiturates are of interest as inhibitors of dihydro-orotate dehydrogenase enzyme system (DHODase) <90JCS(P1)3137>. 

Leflunomide is an antirheumatic agent. It is an isoxazole immunomodulatory agent that inhibits dihydro-orotate dehydrogenase and has antiproliferative and antiinflammatory activity. It is indicated in the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms and to retard structural damage. 

Leflunomide (Arava) is a pyrimidine-synthesis inhibitor indicated for the treatment of adults with rheumatoid arthritis. This drug has found utility in the treatment of polyo-mavirus nephropathy seen in immunosuppressed renal transplant recipients and is increasingly being used for that purpose. There are no studies showing efficacy, however, compared with control patients treated with withdrawal or reduction of immune-suppression alone in BK virus nephropathy. The drug inhibits dihydro-orotate dehydrogenase in the de novo pathway of pyrimidine synthesis. It is hepa-totoxic and can cause fetal injury when administered to pregnant women. 

Orotate is an intermediate in de novo synthesis of pyrimidines. It is made by dehydrogenation of dihydroo rotate in a reaction catalyzed by dihydro orotate dehydrogenase (Figure 22.10). 

Dihydro-orotate-oxidizing activity in rat liver homogenates can be recovered completely in the mitochondrial fraction [103,104].With the exception of this system all the other enzymes of the orotate pathway appear to be present in the soluble cytosolic fraction. Dihydro-orotate dehydrogenase from rat liver was found to be located on the outer surface of the inner membrane of mitochondria [105]. Dihydro-orotate can diffuse freely from the cytosol into the mitochondria and orotate can diffuse freely from the mitochondria into the cytosol. Therefore no active transport of either dihydro-orotate or orotate is required in pyrimidine synthesis [105]. In addition to inhibiting dihydro-orotase, orotic acid strongly blocks [103] dihydro-orotate oxidation. 

B25 Blattmann, P. and Retey, J. Stereospecificity of the dihydro-orotate-dehydrogenase reaction. Eur. J. Biochem., 30,130-137 (1972)... 

Leflunomide Inhibits dihydro-orotic acid dehydrogenase (DHOD) —4 ump —4 ribonucleotides -> arrests lymphocytes in Gj Alopecia, rash, diarrhea, hepatotoxicity... 

B. leflunomide inhibition of dihydro-orotic acid dehydrogenase... 

Answer B. Leflunomide, used in rheumatoid arthritis, inhibits dihydro-orotic acid dehydrogenase >4 formation of UMP ->4- de novo synthesis of ribonucleotides — arrest of lymphocytes in the GI phase. Glucocorticoids do not decrease expression of lipoxygenase, but by preventing arachidonate formation they decrease activity of the pathway. Misoprostol, used in NSAID-induced GI ulcers, activates receptors colchicine decreases microtubular polymerization ketorolac is a potent NSAID but a nonselective inhibitor of cyclooxygenases. 

L-4,5-Dihydro-orotate oxygen oxidoreductase Dihydroorotate dehydrogenase... 

LEF inhibits the mitochondrial enzyme dihydro-orotic acid dehydrogenase, which plays a key role in pyrimidine synthesis (129,130). Because it is complimentary to the purine antagonism seen with MTX, these two drugs can be complimentary in action (131). LEF has no reported effect on adenosine. 

The first step of the biosynthesis of pyrimidine nucleotides is the irreversible carbamylation of L-aspartate by carbamyl-phosphate to form carbamylaspartate (catalyzed by the enzyme aspartate transcarbamylase). Next, carbamylaspartate is converted, by ring closure, to dihydro-orotic acid which, in turn, is reduced to orotic acid, catalyzed by the enzyme orotic acid dehydrogenase (OAD). Orotic acid (6-carboxyuracil) reacts with 5 -phosphoribosyl--1-pyrophosphate (PRPP) to form orotidine monophosphate (OMP). 

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