Cmp

Pyrimidine ribonucleotide de novo synthetic route

RNA X CDP lipids

Figure 2 Metabolic pathways for the synthesis of DNA and RNA from their purine and pyrimidine ribo- and deoxyribonucleotide precursors. The dotted line from dCTP indicates the route of breakdown to deoxycytidine (dC), which can be salvaged by dC kinase and incorporated into dCDP lipids or DNA. HCO3, bicarbonate; CP, carbamoyl phosphate; N-CA, carbamoyl aspartate; DHOA, dihydroorotic acid; OA, orotic acid; OMP, orotidylic acid; PP-rib-P, 5-phosphoribosyl-1-pyrophosphate; PRA, 5-phosphoribosylamine; GAR, glycinamide ribotide; FGAR, N-formyl glycinamide ribotide; FGAM, N-formylglycinamidine ribotide; AIR, 5-aminoimidazole ribotide; CAIR, 5-aminoimidazole-4-carboxy ribotide; SAICAR, N-succino-5-aminoimidazole-4-carboxamide ribotide; AICAR, 5-aminoimidazole-4-carboxamide ribotide; FAICAR, 5-formamidoimidazole-4-carboxamide ribotide.

molecules such as carbon dioxide, amino acids, and ribose sugars as precursors; and the energetically less expensive 'salvage' pathway. Purine bases and pyr-imidine nucleosides from the breakdown of nucleic acids and nucleotide cofactors are salvaged within the cells, generating nucleotides that can be incorporated into nucleic acids. In most cells in the body, salvage processes are more important than de novo synthesis, and the ribonucleotides recycled in this way exert feedback control on the de novo routes.

The ribonucleoside 5'-monophosphates generated from either pathway are rapidly phosphorylated within the cell to the triphosphate form for immediate use in the synthesis of RNA or in a variety of cellular processes. The most abundant ribonucleo-tide in the body is adenosine 5'-triphosphate (ATP), which is the universal energy carrier of all living organisms (Figure 1B). In addition, ATP molecules are part of the coenzymes (NAD, NADP, FAD, etc.), which assist in many reactions including the conversion of food into energy. Adenosine and gua-nosine nucleotides within cells have roles in the transduction of external signals into cellular responses and in the translation and synthesis of proteins. Pyrimidines, present at much lower concentrations in cells, also fulfill diverse functions. UDP-glucose and CDP-lipids are active intermediates in the synthesis of glycogen and membranes, respectively, and sugars linked to UDP or GDP are used in the glycosylation of proteins, many of which are exposed on the outer surface of cells. UDP-glucuronic acid is an essential component of the pathways in liver, gut, and kidney that convert foreign molecules and steroids into soluble forms for disposal from the body.

To make DNA, the ribonucleoside diphosphates (rNDP) are reduced to the corresponding 2'-deoxyr-ibonucleoside diphosphates (dNDP) in a reaction catalyzed by ribonucleotide reductase. This reaction produces dADP, dGDP, and dCDP, which are phos-phorylated to the triphosphate form; dUDP is converted via dUMP to dTMP, providing the four substrates essential for DNA synthesis. The DNA polymerase enzymes form double-stranded DNA by sequential addition of monomers complementary to the bases on the opposite strand. Crucially, a 'proofreading' activity in the enzyme ensures the accuracy of the process, and hence double-stranded DNA provides a stable format for genetic information.

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