Pyrimidine, enzymatic synthesis

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

Aim of this research was to increase efficiency of producing T. thermophilus PyrNPase in cells of genetically engineered E. coli strain by optimizing the structure of the respective translated mRNA and to investigate enzymatic synthesis of purine 3 -fluoro-3 -deoxy- and 3 -fluoro-2, 3 -dideoxynucleosides possessing antiviral and cytostatic activities from the available pyrimidine nucleosides engaging tandem reactions in the presence of recombinant nucleoside phosphorylases [8],... 

The first chemical synthesis of these substances, using a procedure which yields 1-ribofuranosyl derivatives by pyrimidine bases, was described by Hall. By using the mercuric salt of 6-azathymine and tribenzoate of D-ribofuranosyl chloride, he obtained a mixture of two monoribosyl derivatives and a diribosyl derivative. He determined the structure of the 3-substituted derivative by the similarity of spectra and other properties to those of 3-methyl-6-razauracil. The structure of the 1-ribosyl derivative was then determined from the similarity of the spectra with 6-azathymine deoxyriboside obtained enzymatically. 

Schnell B, Strauss UT, Verdino P, Faber K, Kappe CO (2000) Synthesis of enantiomerically pure 4-aryl-3,4-dihydro-pyrimidin-2(lH)-ones via enzymatic resolution preparation of the antihypertensive agent (R)-SQ 32926. Tetrahedron Asymmetry 11 1449-1453... 

It is of course surprising that amino acids can be obtained via the Strecker synthesis, purines from the condensation of HCN, pyrimidines from the reaction of cyanoacetilene with urea, and sugars from the autocatalytic condensation of formaldehyde. The synthesis of chemical constiments of contemporary organisms by non-enzymatic processes under laboratory conditions does not necessarily imply that they were either essential for the origin of life or available in the primitive environment. However, the significance of prebiotic simulation experiments is... 

In agreement with the chemomimetic concept as defined by Eschen-moser, the panel of enzymatic transformations for the biosynthesis of purines that we currently observe in the cell can be hypothesized to have evolved from primitive chemical processes [48-50]. 2-Carbonitrile and 2-carboxamide AICA and AICN derivatives, respectively, were also used as intermediates for the synthesis of adenine 1 and 8-substituted adenines 7 and 8 [51]. In principle, purine derivatives 7 and 8 may pair with pyrimidine bases by formation of Watson-Crick or Hoogsteen hydrogen bond interactions. 

The active form of folate is the tetrahydro-derivative that is formed through reduction by dihydrofolate reductase. This enzymatic reaction (Figure 29.5) is inhibited by trimethoprim, leading to a decrease in the folate coenzymes for purine, pyrimidine, and amino acid synthesis. Bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme, which accounts for the drug s selective toxicity. [Note Examples of other folate reductase inhibitors include pyrimethamine, which is used with sulfonamides in parasitic infections (see p. 353), and methotrexate, which is used in cancer chemotherapy (see p. 378).]... 

While the thiazole and pyrimidine heterocycles of thiamin can be readily synthesized chemically, the thiazole/ pyrimidine coupling and the final pyrophosphorylation are difficult reactions. In contrast, the enzymatic syntheses of the thiazole and the pyrimidine are complex, but the coupling and phosphorylation chemistry is straightforward. This synthetic/biosynthetic complementarity has been utilized in the development of an efficient chemoenzymatic synthesis of thiamin pyrophosphate (Figure 13). This route has been used for the preparation of isotopically labeled thiamin pyrophosphate to characterize the thiamin radical found in pyruvateferredoxin oxidoreductase and is the preferred method to synthesize isotopically labeled forms of thiamin pyrophosphate. 

Capecitabine is a pyrimidine analog. It is an oral systemic prodrug that is enzymatically converted to 5-fluorouracil (5-FU). Healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-flu-orouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, they inhibit the formation of thymidine triphosphate, which is essential for the synthesis of DNA. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. Capecitabine is indicated in the treatment of resistant metastatic breast cancer alone or in combination with docetaxel, and colorectal cancer. 

Purine deoxyribonucleotides are derived primarily from the respective ribonucleotide (Fig. 6.2). Intracellular concentrations of deoxyribonucleotides are very low compared to ribonucleotides usually about 1% that of ribonucleotides. Synthesis of deoxyribonucleotides is by enzymatic reduction of ribonucleotide-diphosphates by ribonucleotide reductase. One enzyme catalyzes the conversion of both purine and pyrimidine ribonucleotides and is subject to a complex control mechanism in which an excess of one deoxyribonucleotide compound inhibits the reduction of other ribonucleotides. Whereas the levels of the other enzymes involved with purine and pyrimidine metabolism remain relatively constant through the cell cycle, ribonucleotide reductase level changes with the cell cycle. The concentration of ribonucleotide reductase is very low in the cell except during S-phase when DNA is synthesized. While enzymatic pathways, such as kinases, exist for the salvage of pre-existing deoxyribosyl compounds, nearly all cells depend on the reduction of ribonucleotides for their deoxyribonucleotide... 

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