Orotic acid reduction

The aerobic degradation of several azaarenes involves reduction of the rings at some stage, and are discussed in Chapter 10, Part 1. Illustrative examples include the degradation of pyridines (3-alkyl-pyridine, pyridoxal) and pyrimidines (catalyzed by dihydropyrimidine dehydrogenases). Reductions are involved in both the aerobic and the anaerobic degradation of uracil and orotic acid. 

Reduction of the pyrimidine ring has been shown to be the first step in the degradation of orotic acid by Clostridium (Zymobacterium) oroticum (Lieberman and Komberg 1953, 1954, 1955) (Figure 10.28a), and of nracil by Cl. uracilicum (Campbell 1957a-c, 1960) (Figure 10.28b), which closely follows the pathways for aerobic degradation. 

Treatment of HCN-polymer with 6.0NHC1 afforded adenine 1, AICN, 3,4-dihydroxypyrimidine 9 and 5-hydroxyuracil 10, while 1, AICN and orotic acid 11 were recovered after reaction with sodium hydroxide (Scheme 5). A reaction mechanism involving the formation of different aminopyridines as intermediates and reduction steps was proposed to explain the distribution of the obtained products. In accordance with the chemomimetic concept, orotic acid is a key intermediate in the current biosynthesis of pyrimidine nucleotides [62],... 

Classical orotic aciduria is a rare autosomal recessive disorder which is characterized by retarded growth and excretion of large quantities of orotic acid in the urine [221,222]. The disease was described in 1959 as an inborn error of pyrimidine biosynthesis in patients with crystals of orotic acid in the urine [223]. The urinary excretion of orotic acid by these patients was 1.34 g per day in contrast to approximately 0.014 g per day excreted by normal individuals [222,224]. When the diet of patients was supplemented with uridine, clinical remission and a remarkable reduction in orotic acid excretion took place [221,225,226]. 

The reduction in urinary excretion of both compounds following uridine therapy reflects the utilization of uridine for the formation of UMP by the salvage pathway. A similar phenomenon was observed in hereditary orotic aciduria following uridine replacement therapy which bypasses the congenital enzyme defect (Chapter 5). The reversal of 6-azauridine-induced orotic aciduria by hydroxyurea, methotrexate and cyclophosphamide [251] (i.e. by the drugs affecting the synthesis of DNA without any effect on orotic acid synthesis) suggests that the control of pyrimidine synthesis de novo is linked to DNA synthesis. 

The administration of a purified diet supplemented with 1% orotic acid induces in rats a rapid accumulation of lipids in the liver [290]. Such an effect is species specific and does not seem to occur in humans. The deposition of triglycerides in the liver, accompanied by a decrease in the concentration of plasma lipids, is a common and characteristic feature of fatty liver induced by various drugs. The earliest biochemical change [291,292] detected in rats given orotic acid is an increase in the pool of uridine nucleotides paralleled by a concomitant reduction of the level of adenine nucleotides and the oxidized and reduced forms of NAD. 

K39 Kobori, S. and Kawakami, S. Polarographic studies on food additives. I. Polarographic reduction wave of orotic acid. Utsunomiya Daigaku Kyoikugakubu Kiyo, Dai 2 bu, 26, 27-35 (1976) (Japan)... 

Table 3. Reduction of urinary excretion of orotic acid and orotidine by dietary purines.

The process of substitution undertaken on carboxylic acids and the derivatives of carboxylic acids (anhydrides, acid halides, esters, amides, and nitriles) generally involves a series of replacement processes. Thus, individually, substitution may involve replacement of (a) the proton attached to oxygen of the -OH group (i.e., ionization of the acid) (b) the hydroxyl (-OH) portion of the carboxylic acid (or derivative) (e.g., esterification) (c) the carbonyl oxygen and the hydroxyl (-OH) (e.g., orthoester formation, vide infra) (d) the entire carboxylic acid functionality (e.g., the Hunsdiecker reaction, already discussed Scheme 9.101) and the decarboxylation of orotic acid (as orotidine monophosphate) to uracil (as uridine monophosphate)—catalyzed by the enzyme orotidine monophosphate decarboxylase (Scheme 9.115) or (e) the protons (if any) on the carbon to which the carboxylic acid functional group is attached (e.g., the Dieckman cycUzation, already discussed earlier, c Equation 9.91). Indeed, processes already discussed (i.e., reduction and oxidation) have also accomplished some of these ends. Some additional substitutions for the carboxylic acid group itself are presented in Table 9.6, while other substitutions for derivatives of carboxylic acids are shown in Tables 9.7-9.10 and discussed subsequently. 

It is not clear why uracil was poorly utiUzed for nucleic acid synthesis in many tissues, e.g. rat liver, while it was utihzed efficiently by the mouse. Nucleoside phosphoiylase has been found in rat tissues as well as the necessary kinase to transform the nucleoside into a nucleotide 312). It has been suggested that the enzymic reduction of uracil to dihydrouracil in rat Uver proceeded so rapidly that very little uracil was avmlable for synthetic reactions 41S). More recently, it was shown that uracil was utilized more efficiently by rat liver in vitro by increaang its concentration in the incubation medium in fact, uracil became comparable to orotic acid in labeling RNA under these conditions 456). The availability of ribose 1-phosphate and the concentration of nucleoside kinase in different tissues might also have been important factors in determining uracil utilization. 

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