Nucleotide Metabolism

Nucleotides  are composed of a nitrogenous base (adenine = A, guanine = G, cytosine = C, uracil = U, and thymine = T); a pentose sugar; and one, two, or three phosphate groups (Fig. 22.24). A and G are purines, and C, U, and T are pyrimidines. If the sugar is ribose, the nucleotide is a ribonucleoside phosphate (for example, adenosine monophosphate [AMP]), and it can have several functions in the cell, including being a component of RNA. If the sugar is deoxyribose, the nucleotide is a deoxyribonucleoside phosphate (for example, deoxyAMP) and will be found almost exclusively as a component of DNA. The committed step in purine synthesis uses 5-phosphoribosyl-1-pyrophosphate ([PRPP], an activated pentose that provides the ribose 5-phosphate for de novo purine and pyrimidine synthesis and salvage) and nitrogen from glutamine to produce phosphoribosylamine.

The enzyme is glutamine:phosphoribosylpyrophosphate amidotransferase and is inhibited by AMP and guanosine monophosphate (the end products of the pathway) and activated by PRPP. Purine nucleotides can also be produced from preformed purine bases by using salvage reactions catalyzed by adenine phosphoribosyltransferase (APRT) and hypoxanthine–guanine phosphoribosyltransferase (HGPRT). A near-total deficiency of HGPRT causes Lesch-Nyhan syndrome, a severe, inherited form of hyperuricemia accompanied by compulsive self-mutilation. All deoxyribonucleotides are synthesized from ribonucleotides by the enzyme ribonucleotide reductase.
This enzyme is highly regulated (for example, it is strongly inhibited by deoxyadenosine triphosphate [dATP], a compound that is overproduced in bone marrow cells in individuals with adenosine deaminase [ADA] deficiency). ADA deficiency causes severe combined immunodeficiency disease. The end product of purine degradation is uric acid, a compound of low solubility whose overproduction or undersecretion causes hyperuricemia that, if accompanied by the deposition of monosodium urate crystals in joints and soft tissues and an inflammatory response to those crystals, results in gout. The first step in pyrimidine synthesis, the production of carbamoyl phosphate by carbamoyl phosphate synthetase II, is the regulated step in this pathway (it is inhibited by uridine triphosphate [UTP] and activated by PRPP). The UTP produced by this pathway can be converted to cytidine triphosphate. Deoxyuridine monophosphate can be converted to deoxythymidine monophosphate by thymidylate synthase, an enzyme targeted by anticancer drugs such as 5-fluorouracil.

The regeneration of tetrahydrofolate from dihydrofolate produced in the thymidylate synthase reaction requires dihydrofolate reductase, an enzyme targeted by the drug methotrexate. Pyrimidine degradation results in soluble products.

Figure 1: Key concept map for nucleotide metabolism. THF = tetrahydrofolate; GPAT = glutamine:phosphoribosylpyrophosphate amidotransferase; ADA = adenosine deaminase; XO = xanthine oxidase; TS = thymidylate synthase; RNR = ribonucleotide reductase; CPS II = carbamoyl phosphate synthetase II; AMP, GMP, CMP, TMP, and IMP = adenosine, guanosine, cytidine, thymidine, and inosine monophosphates; d = deoxy; PPi = pyrophosphate; PRPP = 5-phosphoribosyl-1-pyrophosphate.