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High-Yield Terms

  • 5-phosphoribosyl-1-pyrophosphate (PRPP): activated form of ribose used in de novo synthesis of purine and pyrimidine nucleotides

  • Gout: a disorder that is related to excess production and deposition of uric acid crystals; does not occur in the absence of hyperuricemia

  • Severe-combined immunodeficiency (SCID): a disorder related to defects in the activity of the purine nucleotide catabolism enzyme, adenosine deaminase (ADA)

  • Tumor lysis syndrome (TLS): potentially fatal condition characterized by acute urate nephropathy, resulting from significant increases in purine nucleotide degradation from dying cancer cells

Nucleotide Metabolism

The metabolic requirements for the nucleotides and their cognate bases can be met by either dietary intake or synthesis de novo from low-molecular weight precursors. Indeed, the ability to salvage nucleotides from sources within the body essentially alleviates any nutritional requirement for nucleotides. Thus the purine and pyrimidine bases are not required in the diet. The hydrolysis and uptake of dietary nucleic acids is covered in Chapter 43. The salvage pathways are a major source of nucleotides for synthesis of DNA, RNA, and enzyme cofactors.

Both the de novo synthesis and salvage pathways of purine and pyrimidine nucleotide biosynthesis utilize an activated sugar intermediate: 5-phosphoribosyl-1-pyrophosphate (PRPP), which is generated by the action of PRPP synthetase (Figure 32-1).

FIGURE 32-1:

PRPP synthetase reaction. Reproduced with permission of the medical biochemistry page, LLC.

Purine Nucleotide Biosynthesis

The major site of purine synthesis is in the liver. Synthesis of the purine nucleotides begins with PRPP and leads to the first fully formed nucleotide, inosine 5′-monophosphate (IMP) (Figure 32-2). In purine nucleotide biosynthesis, the base is constructed upon the ribose by several amidotransferase and transformylation reactions. The synthesis of IMP requires 5 moles of ATP, 2 moles of glutamine, 1 mole of glycine, 1 mole of CO2, 1 mole of aspartate, and 2 moles of formate. The formyl moieties are carried on tetrahydrofolate (THF) in the form of N5,N10-methenyl-THF and N10-formyl-THF.

FIGURE 32-2:

Purine biosynthesis from ribose 5-phosphate and ATP. (P, PO32-_ or PO2.) Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil PA. Harper's Illustrated Biochemistry, 29th ed. New York, NY: McGraw-Hill; 2012.

IMP represents a branch point for purine biosynthesis because it can be converted into either AMP or GMP through 2 distinct reaction pathways (Figure 32-3). The pathway leading to AMP requires energy in the form of GTP; that leading to GMP requires energy in the form of ATP. The utilization of GTP in the pathway to AMP synthesis allows the cell to control the proportions of AMP and GMP to near equivalence. ...

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