3/29/2023 0 Comments The unwalkable disease![]() ![]() B: uric acid-related diseases caused by hyperuricemia and hypouricemia. A: evolutional purine metabolism in animals. 1.Evolutional purine metabolism and urate-related diseases. Normally, ∼90% of hypoxanthine is reutilized and converted to inosine monophosphate (IMP) through the salvage pathway ( 62).įig. In fact, it has been reported that plasma XOR activity is much lower in humans than in animals ( 59). This evolutional adaptation may lead to reduction in XOR activity and activation of the salvage pathway in purine metabolism in humans. The lack of ascorbic acid, also known as vitamin C, in hominoids has been thought to cause a compensatory increase in uric acid as an antioxidant by unfunctional gene mutation of uricase to a pseudogene ( 29, 37). In higher primates, including humans, uric acid is the end product of purine metabolism and has a powerful antioxidant effect ( 27). Depending on the animal, uric acid can be further degraded to allantoin by uricase, to allantoic acid by allantoinase, to urea by allantoicase, and to ammonia by urease ( 21 Fig. XOR is transcribed and translated as xanthine dehydrogenase (XDH) and can be posttranslationally converted to xanthine oxidase (XO) ( 54). Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that catalyzes the oxidative hydroxylation of hypoxanthine to xanthine and xanthine to uric acid ( 54). ATP depletion induced by ischemia and intake of fructose and alcohol and degradation of RNA and DNA induced by cell turnover and intake of a purine-rich diet can activate the purine metabolism pathway ( Fig. Purine metabolism consists of de novo synthesis, catabolism, and salvage pathways ( 54). New insights into purine metabolism, including the role of XOR activity in the past 5 yr, are mainly discussed in this review. It has recently been suggested that discontinuation of an XOR inhibitor causes adverse cardiovascular outcomes as XOR inhibitor withdrawal syndrome, possibly due to cardiac disturbance of conduction and contraction by reduced ATP production. Treatment with an XOR inhibitor can decrease uric acid for preventing gout, reduce production of XO-related ROS, and promote reutilization of hypoxanthine and ATP production through the salvage pathway. ![]() The concentration of hypoxanthine, but not xanthine, is independently associated with obesity in a general population, indicating differential regulation of hypoxanthine and xanthine. However, XOR activity in adipose tissue is low in humans unlike in rodents, and hypoxanthine is secreted from human adipose tissue. Plasma XOR activity is associated with obesity, smoking, liver dysfunction, hyperuricemia, dyslipidemia, insulin resistance, and adipokines, indicating a novel biomarker of metabolic disorders. Because XO is involved in an increase in reactive oxygen species (ROS) by generating superoxide and hydrogen peroxide, inadequate activation of XOR promotes oxidative stress-related tissue injury. The lack of ascorbic acid, known as vitamin C, in hominoids has been thought to cause a compensatory increase in uric acid as an antioxidant by unfunctional gene mutation of uricase to a pseudogene. Uric acid is the end product of purine metabolism in humans and has a powerful antioxidant effect. Xanthine oxidoreductase (XOR) consists of two different forms, xanthine dehydrogenase and xanthine oxidase (XO), and is a rate-limiting enzyme of uric acid production from hypoxanthine and xanthine. ![]()
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