Pyrimidine deoxyribonucleotides phosphorylation

Metabolism of the pyrimidine deoxyribonucleotides is more complex because, in addition to transfer of phosphoryl groups, deamination and methylation reactions occur at this level. Specifically, the thymidine phosphates are derived by methylation of deoxyuridylate, and the latter may be derived from the deoxycytidine phosphates by way of deoxycytidylate deaminase. The deoxycytidine phosphates are not formed by amination of deoxyuridine phosphates, but are derived entirely from the cytidine phosphates by enzymatic reduction (Chapter 16). 

The biosynthetic pathways for the pyrimidine nucleotides (2) are more complicated. The first product, UMP, is phosphorylated first to the diphosphate and then to the triphosphate, UTP. CTP synthase then converts UTP into CTP. Since pyrimidine nucleotides are also reduced to deoxyribonucleotides at the diphosphate level, CTP first has to be hydrolyzed by a phosphatase to yield CDP before dCDP and dCTP can be produced. 

So far as is known, pyrimidine ribo- and deoxyribonucleotides are de-phosphorylated by the nucleotidases and phosphatases described in Chapter 10 as acting on purine nucleotides. Although a number of potential de-phosphorylating enzymes may be avaUable in most cells, the relative quantitative importance of each is not known. 

Although cells derive their deoxyribonucleotides primarily by reduction of ribonucleotides, the deoxyribonucleosides can be utilized to some extent by way of kinase reactions. Phosphorylation of deoxyribonucleosides represents the only known point of entry into the sequences of deoxyribonucleotide metabolism other than the main entry point, ribonucleotide reduction. Pyrimidine deoxyribonucleosides may be incorporated into DNA in animal cells by this route. The conversion of deoxyadenosine and deoxyguanosine into deoxyribonucleotides and thence into DNA would also appear possible by a kinase-initiated sequence, because the enzymatic phosphorylation of these compounds has been demonstrated. However, this route has not been well studied in animal cells and its assessment is complicated by very active deamination and phosphorolytic cleavage reactions which compete with the reactions leading to DNA. E. coli cells appear to possess only one kinase capable of phosphorylating deoxyribonucleosides, thymidine kinase. 

Both the pyrimidines and the purines are built up from small precursor molecules which are readily available in the metabolic pool (page 185). The free bases are not synthesized as such but, while being assembled, the partially constructed ring structure reacts with a special phosphorylated pentose known as PRPP (5-phosphoribosyl-l-pyrophosphate) and forms a ribonucleotide. The deoxyribonucleotides, with the exception of TMP which is formed by methylation of deoxyuridylate, are formed by reduction of the corresponding ribonucleoside diphosphate. The conversion is precisely controlled by allosteric effects which ensure that all four deoxyribonucleotides are available in amounts appropriate for nucleic acid synthesis. 

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