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Metabolic Pathways

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Purines comprise bases, nucleosides in association with ribose or deoxyribose, and nucleotides with one or more added phosphate groups. Purine nucleotides are essential cellular constituents. They are the building blocks of the polynucleotides, DNA and RNA, and, under the form of mononucleotides or of nucleosides, also intervene in numerous cellular functions. Among these are energy transfer (eg, by adenosine triphosphate [ATP]), metabolic regulation (eg, by guanosine triphosphate [GTP]), and signaling (eg, by adenosine). Purine metabolism can be divided into three pathways (Fig. 168-1):

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Figure 168-1.
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Pathways of purine metabolism. (1) PRPP (phosphoribosylpyrophosphate) synthetase; (2) adenylosuccinate lyase (adenylosuccinase); (3) AICAR transformylase; (4) IMP cyclohydrolase (3 and 4 form ATIC); (5) adenylosuccinate synthetase; (6) AMP deaminase; (7) 5′-nucleotidase(s); (8) adenosine deaminase; (9) purine nucleoside phosphorylase; (10) hypoxanthine-guanine phosphoribosyltransferase; (11) adenine phosphoribosyltransferase; (12) adenosine kinase; (13) guanosine kinase; (14) xanthine oxidase (dehydrogenase); (15) guanine deaminase. Enzyme defects are indicated by solid bars. AICAR, aminoimidazolecarboxamide ribotide; AMP, adenosine monophosphate; ATIC, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase; FAICAR, formylaminoimidazolecarboxamide ribotide; GMP, guanosine monophosphate; IMP, inosine monophosphate; P, phosphate; PRPP, phosphoribosyl pyrophosphate; S-Ado, succinyladenosine; SAICAR, succinylaminoimidazolecarboxamide ribotide; S-AMP, adenylosuccinate; XMP, xanthosine monophosphate.

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  1. 1. The biosynthetic pathway, starts with the formation, often termed de novo, of the high-energy compound phosphoribosyl pyrophosphate (PRPP) and leads in 10 steps to the synthesis of the nucleoside monophosphate inosine monophosphate (IMP). From IMP, two reactions lead to the formation of adenosine monophosphate (AMP). Subsequently, the nucleoside di- and triphosphates ADP and ATP and their deoxy counterparts are synthesized. Two other reactions convert IMP into GMP, from which GDP, GTP, and their deoxy counterparts are formed.

    2. The purine catabolic pathway starts from the nucleoside monophosphates GMP, IMP, and AMP and produces uric acid, a poorly soluble compound that tends to crystallize once its plasma concentration increases above 6.5 to 7.0 mg/dl (0.38–0.47 mmol/l).

    3. The purine salvage pathway utilizes the purine bases guanine, hypoxanthine, and adenine, which are provided by food intake or the catabolic pathway, and reconverts them by phosphoribosylation into GMP, IMP, and AMP, respectively. It also utilizes the purine nucleosides adenosine, guanosine, and their deoxy counterparts by phosphorylation into the corresponding monophosphates, catalyzed by kinases.

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Inborn errors of purine metabolism comprise errors of purine nucleotide synthesis, of purine catabolism, and of purine salvage. They should be considered in patients with hyper- or hypouricemia, kidney stones, and a variety of muscle, neurological, and other symptoms (Table 168-1). The deficiencies of adenosine deaminase and purine nucleoside phosphorylase, two purine catabolic enzymes, cause severe combined immunodeficiency (SCID; see Chapter 188). Adenosine deaminase superactivity causes hemolytic anemia. The deficiency of deoxyguanosine kinase causes a mitochondrial disease. The deficiency of thiopurine methyltransferase is of importance in pharmacogenetics.

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Table Graphic Jump Location
Table 168-1. Main Presenting Clinical Signs and Laboratory Data in Inborn Errors ...

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