Orotic acids structure

A rigorous structural proof of the insecticidal exotoxin (34) from Bacillus thurin-giensis has now been published,107 confirming the a-configuration of the glucosidic bond. The total synthesis of (34) is further confirmation of the correctness of the structural assignment.108 The exotoxin inhibits RNA synthesis in insects and animals and affects the incorporation of orotic acid into nuclear RNA.109... 

Consequently, the early investigators did not recognize the relationship of their synthetic product [16—18] to the natural material. This delayed the true structural assignment for orotic acid until 1930 [19—22]. A number of different or improved synthetic procedures for this important compound have appeared in the literature [21—38] since this date. 

These three compounds exert many similar effects in nucleotide metabolism of chicks and rats [167]. They cause an increase of the liver RNA content and of the nucleotide content of the acid-soluble fraction in chicks [168], as well as an increase in rate of turnover of these polynucleotide structures [169,170]. Further experiments in chicks indicate that orotic acid, vitamin B12 and methionine exert a certain action on the activity of liver deoxyribonuclease, but have no effect on ribonuclease. Their effect is believed to be on the biosynthetic process rather than on catabolism [171]. Both orotic acid and vitamin Bu increase the levels of dihydrofolate reductase (EC 1.5.1.4), formyltetrahydrofolate synthetase and serine hydroxymethyl transferase in the chicken liver when added in diet. It is believed that orotic acid may act directly on the enzymes involved in the synthesis and interconversion of one-carbon folic acid derivatives [172]. The protein incorporation of serine, but not of leucine or methionine, is increased in the presence of either orotic acid or vitamin B12 [173]. In addition, these two compounds also exert a similar effect on the increased formate incorporation into the RNA of liver cell fractions in chicks [174—176]. It is therefore postulated that there may be a common role of orotic acid and vitamin Bj2 at the level of the transcription process in m-RNA biosynthesis [174—176]. 

The structure of orotic acid. Loss of proton leads to orotate. Deposits of sodium orotate cause a painful condition. 

More definitive information on the structure of orotidine came from metabolic studies.162 These experiments showed that orotic acid and 5-0-... 

Although it is reasonable to assume from the enzymic studies cited162 that orotidine possesses the /3 configuration at the anomeric center, unequivocal determination of this feature is to be desired. Of interest is the fact that 1,3-dimethylorotic acid,119 3-methylorotic acid,119 163 and orotic acid itself are decarboxylated to the corresponding uracil derivatives at elevated temperatures. If orotidine could be decarboxylated in some similar fashion to uridine, the complete structure of XXXII would be established. 

The major bases found in nucleic acids are adenine and guanine (purines) and uracil, cytosine, and thymine (pyrimidines). Thymine is found primarily in DNA, uracil in RNA, and the others in both DNA and RNA. Their structures, along with their chemical parent compounds, purine and pyrimidine, are shown in Figure 10.1, which also indicates other biologically important purines that are not components of nucleic acids. Hypoxanthine, orotic acid, and xanthine are biosynthetic and/or degradation intermediates of purine and pyrimidine bases, whereas xanthine derivatives—caffeine, theophylline, and theobromine—are alkaloids from plant sources. Caffeine is a component of coffee beans and tea, and its effects on metabolism are mentioned in Chapter 16. Theophylline is found in tea and is used therapeutically in asthma, because it is a smooth muscle relaxant. Theobromine is found in chocolate. It is a diuretic, heart stimulant, and vasodilator. 

K4 Kaneti, J. and Golovinsky, E. Quantitative relations between the electronic structure and biological activity of some analogs of orotic acid. Chem. Biol. Interactions, 3, 421-428 (1971)... 

R3 Rajalakshmi, S., Adams, W. R. and Handschuhmacher, R. E. Isolation and characterization of low density structures from orotic acid-induced fatty livers. J. Cell Biol., 41, 625-636 (1969)... 

Showdomydn 2-P-D-ribofuranosylmaleinimide, a C-substituted Nucleoside antibiotic (see) from Strep-tomyces showdoensis, structurally relat to uridine and pseudouridine. M.p. 153 °C, [aj + 50° (c = 1, water). It selectively inhibits enzymes of uridine and orotic acid metabolism the maleinimide moiety reacts with sulfhydryl groups of the affected enzymes. S. is especially active against Streptococcus haemolyticus. 

CHEMISTRY. Vitamin B-13 is a compound of unknown structure which appears either to contain orotic acid or to yield it on decomposition (see Fig. V-36). 

Phillips and Lee calculated the 15N isotope effect for the decarboxylation of 1-methyl orotate (lb) via 2-protonation (4b) and via 4-protonation (6b). They found that in both cases, the calculated isotope effect is normal 1.0043 for 2-protonation, and 1.0054 for 4-protonation. An examination of the optimized structures showed clearly that very little bond order change occurs at Nl, regardless of which oxygen is protonated. Phillips and Lee also benchmarked their calculations by computing the IEs for protonation of pyridine and for decarboxylation of picolinic acid (17) and A-methyl picolinic acid (18) the results of these calculations are in agreement with the experimental values mentioned above. Therefore, Philips and Lee asserted that... 

Lee and Houk calculated gas phase proton affinities of orotate and depro-tonated uracil, which suggest that 0-4 rather than 0-2 is the favorable site of protonation for substrate OMP [24]. On the basis of these findings, Lee and Houk proposed a carbene-based mechanism that involves protonation at 0-4 by either an active-site acidic residue or a site-bound water molecule (Fig. 3c) [24, 25]. In this mechanism, the formation of a neutral carbene at C-6 is stabilized by an active site environment that displays a low dielectric constant. The recent determination of the crystal structures of ODCase (see below) questions the plausibility of this mechanism. These structures reveal a highly charged active site, one that might be poorly suited for stabilization of an uncharged carbene. The structures also demonstrate the lack of an acidic residue near the 0-4 atoms of bound ligands. 

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