Uracil pyrimidine synthesis from

More complex, but still feasible, is the synthesis of pyrimidine bases from simple prebiotic substrates, although the reported yields of these reactions are relatively low. In this context, two main prebiotic precursors have been identified cyanoethine and a primary product of its hydrolysis, cyanoacetaldehyde. These compounds contain a preformed C-C bond which is incorporated in the C5-C6 position of the pyrimidine ring. In 1968 Ferris and co-workers reported that the reaction of cyanoethine with cyanate at 30 °C yields cytosine and, after its hydrolysis, uracil in acceptable yield [27]. trans-Cyanovinylurea was recovered as a key intermediate for this transformation. However, this reaction requires relatively high concentrations of cyanate (>0.1 mol/1), unlikely to occur in aqueous media due to its rapid degradation to carbon dioxide and ammonia. Cyanoethine also reacts with cyanate and yields cytosine and uracil at elevated temperatures. In this reaction urea or guanidine (also considered as prebiotic organic compounds) can easily replace cyanate (Figure 8.8) [26]. 

A facile one-pot synthesis of pyrazolo[3,4-d]pyrimidines 55 from 6-hydrazino-uracils 53 with isocyanates 54 has been reported <02TL895>. 

While the PRTases salvage nucleobases within cells, nucleosides such as adenosine and uridine are present in the blood at much higher concentrations ( 1 pM) than the equivalent nucleobases, adenine and uracil. Indeed, the brain synthesizes pyrimidine nucleotides (UTP and CTP) via salvage synthesis from uridine produced by the liver and released into the circulation. Human cells may contain at least three types of nonspecific nucleoside transporters, and nucleosides are internalized more rapidly than nucleobases. 

Uracil, produced by the pyrimidine synthesis pathway, is not a component of DNA. Rather, DNA contains thymine, a methylated analog of uracil. Another step is required to generate thymidylate from uracil. Thymidylate synthase catalyzes this finishing touch deoxyuridylate (dUMP) is methylated to thymidylate (TMP). As will be discussed in Chapter 27. the methylation of this nucleotide facilitates the identification of DNA damage for repair and, hence, helps preserve the integrity of the genetic information stored in DNA. The methyl donor in this reaction is N, N methylenetetrahydrofolate rather than -S-adenosylmethionine. 

Orotic Acid. l,2,3,6.Tetrahydro-2,6-dioxo-4-py-nmidinecartroxyhc acid uracil-6-carboxylic acid whey factor animal galactose factor Oropur Orotyl. CjH.N.O, mol wt 156.10. C 38.47%. H 2.58%, N 17.95%. O 41.00%. A pyrimidine precursor in animal organisms, found in milk Bachstez. Ber. 64, 2683 (1931) Hilbert, J. Am. Chem. Soc. 54, 2082 (1932) Johnson, Schroeder, ibid. 2942. Synthesis from aspartic acid Nye. Mitchell, ibid. 69, 1382 (1947). Prepn by condensation of urea with monoethyl ester of ox -alacetic acid in methanol Scriabine, U.S. pat. 2,937,175... 

A series of other barbiturates (phenobarbital, barbital, thiopental, pentobarbital at 1 mmol l i concentration inhibit the orotate uptake system without affecting the incorporation of uracil into cellular pyrimidines [287]. While barbituric acid and hexobarbital are less active, phenylethylhydan-toin, chlorpromazine and phenethyl alcohol are extremely active. Phenobarbital also depresses the utilization of orotic acid for the synthesis of cytidine nucleotides in the liver [288]. a-Hexachlorocyclohexane, an inhibitor of the phenobarbital type, was even more effective in depressing de novo cytidine nucleotide synthesis from orotic acid [289]. 

The suggestion of a control of pyrimidine synthesis stems from the observation that pyrimidine-requiring mutants of E. coli in pyrimidine-free medium accumulated carbamylaspartic acid and, to a lesser extent, dihy-droorotic acid and orotic acid this accumulation was prevented by the addition of uracil and cytosine to the medium (443). It was shown further employing enzyme preparations that cytidine and particularly cytidine 5 -phosphate were effective inhibitors of carbamylaspartic acid synthesis, suggesting that the inhibition of this enzyme by a pyrimidine nucleotide was the mechanism for the feedback control of pyrimidine biosynthesis in bacteria. The decreased formation of dihydroorotic acid and orotic acid were probably secondary events reflecting the earlier metabolic block. 

The hitherto difficultly accessible pyrazolo[4,3-step synthesis from 6-(bromomethyl)-l,3-dimethyl-5-nitro-uracils (259) (Scheme 61). Condensation in ethyl acetate at 0"C allows isolation of the alkylamino-intermediates (261), which in boiling ethanol cyclize to the N-oxides (260). 

Partly saturated pyrazino[l,2-r-]pyrimidines were prepared by formation of the pyrazine ring. 2-Substituted-8-hydroxy-3,4-dihydro-177,277-pyrazino[l,2-r-]pyrimidin-l-ones were prepared by a [6+0] synthesis involving cyclization of 6-hydroxy-pyrimidine-4-(fV-hydroxyethyl)carboxamides <2005W02005/087766>. The 2/7-pyra-zino[l,2-c]pyrimidine-3-carboxamide 164 (Y = NH) was formed from [5+1] atom fragments via the uracil derivative 163 (Y = NH) and DMF-dimethyl acetal. Compounds 163 were prepared from 6-chloromethyluracil and glycine methyl ester 162 (Y = NH) (Scheme 20) <2004W02004/014354>. 

The synthesis of the pyrimidines involves cyanoacetylene, which is synthesised in good yield from discharge reactions of CH4 and N2. The reaction with cyanoacetylene or cyanoacetylaldehyde, in a concentrating environment, produces cytosine and uracil according to Figure 8.6. 

Pyrimidine annulated heterocycles fused at positions 5 and 6 to uracil were synthesized via a three-step sequence starting from uracil 63 [20]. Firstly, the reaction with 3-bromocyclohexene gave the AT-allyl-vinyl core system 64 in 80% yield. Upon heating 64 in EtOH in the presence of HCl, aza-Claisen rearrangement gave rise to the C-cyclohexenyl uracil 65 in 38% yield. Final bromination ( 66) and dehydrogenation steps ( 67) allowed synthesis of the desired tricyclic fused uracil systems (Scheme 15). 

Carbamoyl phosphate synthetase formation in liver taken from tadpoles treated with thyroxine is enhanced by the addition of orotic acid, uracil or uridine (cytosine and adenosine had no effect). The synthesis of this enzyme is not affected by these pyrimidines in untreated animals. This indicates that there is a relative pyrimidine deficiency during thyroxine-induced metamorphosis [140]. 

The common pyrimidine ribonucleotides are cytidine 5 -monophosphate (CMP cytidylate) and uridine 5 -monophosphate (UMP uridylate), which contain the pyrimidines cytosine and uracil. De novo pyrimidine nucleotide biosynthesis (Fig. 22-36) proceeds in a somewhat different manner from purine nucleotide synthesis the six-membered pyrimidine ring is made first and then attached to ribose 5-phosphate. Required in this process is carbamoyl phosphate, also an intermediate in the urea cycle (see Fig. 18-10). However, as we noted... 

RNA differs from DNA in three ways the sugar is D-ribose, the pyrimidine uracil replaces thymine (the other three bases are the same), and the molecules are mainly single-stranded. The three principal types of RNA are messenger RNA (involved in transcribing the genetic code), transfer RNA (which carries a specific amino acid to the site of protein synthesis), and ribosomal RNA. 

An alternative to the terrestrial synthesis of the nucleobases is to invoke interstellar chemistry. Martins has shown, using an analysis of the isotopic abundance of 13C, that a sample of the 4.6 billion year old Murchison meteorite which fell in Australia in 1969 contains traces of uracil and a pyrimidine derivative, xanthine. Samples of soil that surrounded the meteor when it was retrieved were also analyzed. They gave completely different results for uracil, consistent with its expected terrestrial origin, and xanthine was undetectable [48], The isotopic distributions of carbon clearly ruled out terrestrial contamination as a source of the organic compounds present in the meteorite. At 0°C and neutral pH cytosine slowly decomposes to uracil and guanine decomposes to xanthine so both compounds could be the decomposition products of DNA or RNA nucleobases. They must have either travelled with the meteorite from its extraterrestrial origin or been formed from components present in the meteorite and others encountered on its journey to Earth. Either way, delivery of nucleobases to a prebiotic Earth could plausibly have been undertaken by meteors. The conditions that formed the bases need not have been those of an early Earth at all but of a far more hostile environment elsewhere in the Solar System. That environment may have been conducive to the production of individual bases but they may never have been able to form stable DNA or RNA polymers this development may have required the less extreme conditions prevalent on Earth. 

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