Purines (adenine and guanine) and pyrimidines (cytosine, thymine, uracil) serve fundamental roles in the replication of genetic material, gene transcription, protein synthesis, and cellular metabolism. Disorders that involve abnormalities of nucleotide metabolism range from relatively common diseases such as hyperuricemia and gout, in which there is increased production or impaired excretion of a metabolic end product of purine metabolism (uric acid), to rare enzyme deficiencies that affect purine and pyrimidine synthesis or degradation. Understanding these biochemical pathways has led, in some instances, to the development of specific forms of treatment, such as the use of allopurinol and febuxostat to reduce uric acid production.
Uric acid is the final breakdown product of purine degradation in humans. It is a weak diprotic acid with pKa values of 5.75 and 10.3. Urates, the ionized forms of uric acid, predominate in plasma, extracellular fluid, and synovial fluid, with ~98% existing as monosodium urate at pH 7.4.
Plasma is saturated with monosodium urate at a concentration of 405 μmol/L (6.8 mg/dL) at 37°C. At higher concentrations, plasma is therefore supersaturated—a situation that creates the potential for urate crystal precipitation. However, plasma urate concentrations can reach 4800 μmol/L (80 mg/dL) without precipitation, perhaps because of the presence of solubilizing substances.
The pH of urine greatly influences the solubility of uric acid. At pH 5.0, urine is saturated with uric acid at concentrations ranging from 360 to 900 μmol/L (6–15 mg/dL). At pH 7, saturation is reached at concentrations from 9840 to 12,000 μmol/L (158–200 mg/dL). Ionized forms of uric acid in urine include monosodium, disodium, potassium, ammonium, and calcium urates.
Although purine nucleotides are synthesized and degraded in all tissues, urate is produced only in tissues that contain xanthine oxidase, primarily the liver and small intestine. Urate production varies with the purine content of the diet and with rates of purine biosynthesis, degradation, and salvage (Fig. 431e-1). Normally, two-thirds to three-fourths of urate is excreted by the kidneys, and most of the remainder is eliminated through the intestines.
The total-body urate pool is the net result between urate production and excretion. Urate production is influenced by dietary intake of purines and the rates of de novo biosynthesis of purines from nonpurine precursors, nucleic acid turnover, and salvage by phosphoribosyltransferase activities. The formed urate is normally excreted by urinary and intestinal routes. Hyperuricemia can result from increased production, decreased excretion, or a combination of both mechanisms. When hyperuricemia exists, urate can precipitate and deposit in tissues as tophi.
The kidneys clear urate from the plasma and maintain physiologic balance by utilizing specific organic anion transporters (OATs), including urate transporter 1 (URAT1, SLC22A12) (Fig. 431e-2). In humans, OAT1 (SLC22A6), OAT2 (SLC22A7), ...