Normal uric acid metabolism
In humans, uric acid is the end product of purine base degradation. The main processes of its production occur in the tissues of the liver and intestines. In a healthy body, the concentration of this metabolite in blood serum is maintained within a strict range of 0.15–0.47 mmol/L. Elimination of excesses occurs predominantly through the kidneys (daily urine contains 400 to 600 mg/dL), and in small amounts through the gastrointestinal tract.
Biochemical synthesis of uric acid is completed in two stages. Both of these steps are catalyzed by the enzyme xanthine oxidase:
- Oxidation of hypoxanthine to form xanthine and hydrogen peroxide.
- Further oxidation of xanthine directly into uric acid (also releasing $H_2O_2$).
Pathogenesis of gouty arthritis
If the uric acid concentration exceeds the threshold of 0.42 mmol/L, hyperuricemia is diagnosed. It can occur due to excessive intake of purines from meat-based foods, as well as due to disruptions in their endogenous synthesis or renal excretion mechanisms.
The main problem with uric acid is its extremely poor solubility. When the solubility threshold is exceeded, it begins to crystallize in the form of sodium urates. These crystals deposit in the synovial fluid of articular cartilage, ligamentous apparatus, and soft tissues, forming specific gouty nodes — tophi.
The mechanism of development of the acute symptom complex is as follows:
- Urate crystals are recognized by the immune system and phagocytosed by neutrophils.
- Sharp crystals damage the lysosomal membranes inside the cells.
- There is a massive release of lysosomal enzymes into the tissues.
- Acute inflammation develops, accompanied by severe pain, marked edema, local redness, and elevated temperature.
At the same time, excess urates often lead to the formation of calculi in the kidneys (urolithiasis).
Genetic causes of the pathology
Epidemiological data show that gout affects 0.3% to 1.7% of the population. At the same time, the serum urate pool in men is initially twice as high, which is why they encounter the disease 20 times more often than women. Genetic factors play a significant role in the development of primary hyperuricemia:
- PRPP synthetase anomalies. Mutations can lead to hyperactivation of this enzyme or to the loss of its sensitivity to feedback inhibition by the end products of purine synthesis. As a result, purines are produced uncontrollably.
- Decreased hypoxanthine-guanine phosphoribosyltransferase activity. Partial loss of this enzyme's function disrupts the mechanisms of reuse (reutilization) of purine bases, shunting their excess into catabolic pathways.
Biochemical principles of treatment
Therapeutic measures for gout aim to reduce the purine load and block urate synthesis:
- Diet therapy: strict restriction of foods rich in purines (meat, offal, chocolate, coffee). Abundant alkaline drinking is indicated to shift pH and improve salt solubility.
- Pharmacological inhibition: the gold standard is the prescription of allopurinol.
Mechanism of action of allopurinol: Allopurinol is a structural analogue of hypoxanthine. It acts as a competitive and "suicide" inhibitor of xanthine oxidase. The enzyme perceives the drug as a substrate and oxidizes it to oxypurinol. The resulting oxypurinol firmly and irreversibly binds to the active center of the enzyme, blocking its work. As a result, purine catabolism stops at the stage of hypoxanthine and xanthine. These substances dissolve in the body's biological fluids 10 times better than uric acid and are easily excreted by the kidneys without forming crystals.
Briefly: answers to topical questions
What is the name of the severe genetic disease associated with the complete absence of hypoxanthine-guanine phosphoribosyltransferase?
The severe genetic disease associated with the complete absence of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) enzyme activity is called Lesch-Nyhan syndrome.
This pathology is a severe form of X-linked hyperuricemia. Due to the lack of the enzyme, the purine reutilization pathway is disrupted, leading to the following consequences:
- PRPP accumulates within the cell and activates de novo purine synthesis.
- Hypoxanthine and Guanine — cannot be reused and are oxidized by xanthine oxidase to uric acid.
The disease is accompanied by neurotoxicity, the development of gout, and the appearance of uric acid crystals in the urine (pink stains on diapers).
Class and exam questions
Men are affected 20 times more often than women
This is because the physiological serum urate pool in men is twice as high as in women, meaning the crystallization threshold is reached faster.
How do uric acid crystals cause joint pain?
Precipitated urates are engulfed by neutrophils. The crystals mechanically damage lysosomes inside the cells, leading to a massive release of enzymes into the synovial fluid and triggering an acute inflammatory process.
How does allopurinol prevent tophi formation?
The drug blocks the enzyme xanthine oxidase, stopping the breakdown of purines at the hypoxanthine stage. Hypoxanthine is soluble in body fluids 10 times better than uric acid and is safely excreted in the urine.
What else to study on this topic
- Structural formulas of hypoxanthine, xanthine, and uric acid
- PRPP synthesis reactions and regulation of purine metabolism
- Pathways of reutilization ("salvage") of purine bases
- Biochemical mechanisms of urate phagocytosis by neutrophils
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