A summary of the steps in the production of uric acid and the genetic diseases associated with deficiencies of specific degradative enzymes are shown in Figure 22.15. [Note: The bracketed numbers refer to specific reactions in the figure.] some of the genetic diseases associated with this pathway. [Note: The numbers in brackets refer to the corresponding numbered citations in the text.] BMT = bone marrow transplantation; ERT = enzyme replacement therapy; Pi = inorganic phosphate; H2O2 = hydrogen peroxide; NH3 = ammonia.
[1] An amino group is removed from AMP to produce IMP by AMP (adenylate) deaminase or from adenosine to produce inosine (hypoxanthine-ribose) by adenosine deaminase.
[2] IMP and GMP are converted into their respective nucleoside forms, inosine and guanosine, by the action of 5′-nucleotidase.
[3] Purine nucleoside phosphorylase converts inosine and guanosine into their respective purine bases, hypoxanthine and guanine. [Note: A mutase interconverts ribose 1-and ribose 5-phosphate.] [4] Guanine is deaminated to form xanthine.
[5] Hypoxanthine is oxidized by molybdenum-containing xanthine oxidase (XO) to xanthine, which is further oxidized by XO to uric acid, the final product of human purine degradation. Uric acid is excreted primarily in the urine.
C. Diseases associated with purine degradation 1. Gout: Gout is a disorder initiated by high levels of uric acid (the end product of purine catabolism) in blood (hyperuricemia), as a result of either the overproduction or underexcretion of uric acid. The hyperuricemia can lead to the deposition of monosodium urate (MSU) crystals in the joints and an inflammatory response to the crystals, causing first acute and then progressing to chronic gouty arthritis. Nodular masses of MSU crystals (tophi) may be deposited in the soft tissues, resulting in chronic tophaceous gout (Fig. 22.16). Formation of uric acid stones in the kidney (urolithiasis) may also be seen. [Note: Hyperuricemia is not sufficient to cause gout, but gout is always preceded by hyperuricemia. Hyperuricemia is typically asymptomatic but may be indicative of comorbid conditions such as hypertension.] The definitive diagnosis of gout requires aspiration and examination of synovial fluid (Fig. 22.17) from an affected joint (or material from a tophus) using polarized light microscopy to confirm the presence of needle-shaped MSU crystals (Fig. 22.18).
a.
Uric acid underexcretion: In >90% of individuals with hyperuricemia, the cause is underexcretion of uric acid. Underexcretion can be primary, because of as-yet-unidentified inherent excretory defects, or secondary to known disease processes that affect how the kidney handles urate (for example, in lactic acidosis, lactate increases renal urate reabsorption, thereby decreasing its excretion) and to environmental factors such as the use of drugs (for example, thiazide diuretics) or exposure to lead (saturnine gout).
b.