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Purines (adenine and guanine) and pyrimidines (thymine, cytosine, and uracil) are nitrogenous bases that are essential components of nucleotides. The addition of pentose monosaccharide (ribose or deoxyribose) to a base results in a nucleoside, which can be a ribonucleoside (adenosine, guanosine, cytidine, and uridine) or a deoxyribonucleoside (deoxyadenosine, deoxyguanosine, deoxycytidine, and thymidine). Nucleotides result from the binding of nucleosides to phosphate. The binding of a nucleoside to 1, 2, or 3 phosphate groups produces nucleoside mono-, di-, or triphosphate, respectively. Nucleotides are essential for all cells. In addition to their vital role as building blocks for DNA and RNA, they serve as carriers of activated intermediates in the synthesis of a variety of complex molecules, structural components of several essential coenzymes, messengers in signal transduction pathways, regulatory components for many of the metabolic pathways, and currency for energy transfer in cells.

Purine and pyrimidine bases are synthesized de novo or can be obtained through salvage pathways that allow the reuse of bases provided by food or normal cell turnover. The degradation of purine and pyrimidine occurs through catabolic pathways (Figs. 163-1 and 163-2). Disorders of purine and pyrimidine metabolism result from defects in any of the 3 metabolic processes: de novo synthesis, salvage pathways, and catabolism.

Figure 163-1

Purine metabolic pathways.

Figure 163-2

Pyrimidine metabolic pathways.


The de novo biosynthetic pathway of purines starts with ribose phosphate that is first converted to phosphoribosylpyrophosphate (PRPP) by the action of phosphoribosylpyrophosphate synthetase (PRPS), which is necessary for both the de novo and salvage pathways of purine and pyrimidine biosynthesis. PRPP then passes through a number of enzymatic reactions to synthesize inosine monophosphate (IMP), which is then converted to adenosine monophosphate (AMP) or guanosine monophosphate (GMP). There are 10 enzymatic steps in de novo purine synthesis to generate IMP carried out by 6 distinct enzymes, and these assemble into a multiprotein complex termed the purinosome in response to a need for purines. Because the metabolite intermediates in the biosynthetic process have significant biologic properties, there is tight regulation of purine synthesis. Adenylosuccinate lyase deficiency (Mendelian Inheritance in Man [MIM] no. 103050) and AICA-ribosiduria (MIM no. 608688) are severe neurologic defects in this pathway, with the latter due to AICAR transformylase/IMP cyclohydrolase (ATIC) deficiency.

The purine salvage pathway utilizes the purine bases adenine, guanine, and hypoxanthine and reconverts them to AMP, GMP, and IMP, respectively. Defects in this pathway include hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency (Lesch-Nyhan syndrome), adenine phosphoribosyl transferase (APRT) deficiency, and deoxyguanosine kinase (DGK) deficiency.

The catabolic pathway allows the breakdown of AMP, GMP, and IMP to uric acid. Disorders of purine catabolism include muscle adenosine monophosphate deaminase (AMPD) deficiency, adenosine deaminase (ADA) deficiency, ...

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