Catabolism of Purines
Catabolism of the purine nucleotides leads ultimately to the production of uric acid which is insoluble and is excreted in the urine as sodium urate crystals. This pathway is diagrammed below.
The synthesis of nucleotides from the purine bases and purine nucleosides takes place in a series of steps known as the salvage pathways. The free purine bases—adenine, guanine, and hypoxanthine—can be reconverted to their corresponding nucleotides by phosphoribosylation. Two key transferase enzymes are involved in the salvage of purines: adenosine phosphoribosyltransferase (APRT), which catalyzes the following reaction:
adenine + PRPP <—–> AMP + PPi
and hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which catalyzes the following reactions:
hypoxanthine + PRPP <——> IMP + PPi
guannine + PRPP <——–> GMP + PPi
Purine nucleotide phosphorylases can also contribute to the salvage of the bases through a reversal of the catabolism pathways. However, this pathway is less significant than those catalyzed by the phosphoribosyltransferases.
The synthesis of AMP from IMP and the salvage of IMP via AMP catabolism have the net effect of deaminating aspartate to fumarate. This process has been termed the purine nucleotide cycle (see diagram below). This cycle is very important in muscle cells. Increases in muscle activity create a demand for an increase in the TCA cycle, in order to generate more NADH for the production of ATP. However, muscle lacks most of the enzymes of the major anaplerotic reactions. Muscle replenishes TCA-cycle intermediates in the form of fumarate generated by the purine nucleotide cycle.
The purine nucleotide cycle serves an important function within exercising muscle. The generation of fumarate provides skeletal muscle with its’ only source of anaplerotic substrate for the TCA cycle. In order for continued operation of the cycle during exercise, muscle protein must be utilized to supply the amino nitrogen for the generation of aspartate. The generation of asparate occurs by the standard transamination reactions that interconvert amino acids with a-ketoglutarate to form glutamate and glutamate with oxaloacetate to form aspartate. 1
Difference between Primary and Secondary Hyperuricemia
The plasma concentration of uric acid is maintained at a relatively constant level in humans because of a balance between production and excretion. Uric acid derives from exogenous and endogenous sources: it is the end product of the metabolism of dietary purines and occurs as a result of the breakdown of purines from nucleic acids during cell turnover. A very small amount of uric acid is passively eliminated through the gastrointestinal tract. Almost all plasma uric acid is filtered at the glomerulus, and 80% is reabsorbed in the proximal tubule. Some of this plasma uric acid is subsequently secreted back into the lumen; a small amount undergoes distal reabsorption.
Hyperuricemia can result from decreased renal excretion or increased production of uric acid. In 80% to 90% of patients with primary gout, hyperuricemia is caused by renal underexcretion of uric acid, even though renal function is otherwise normal. The defect in renal excretion of uric acid in patients with primary gout may be attributed to reduced filtration, enhanced reabsorption, or decreased secretion, but it is unclear which of these mechanisms is most important. Even patients with high levels of urate excretion (overproducers) demonstrate a relative decrease in urate clearance compared to patients with normal levels of uric acid production.
Hyperuricemia may develop secondary to numerous conditions (e.g., renal insufficiency, myeloproliferative diseases, obesity, alcohol consumption, and drug intake). Patients with secondary gout related to renal disease are hyperuricemic because of a decreased filtered load of uric acid, although decreased tubular secretion may play a role in some patients. Patients with lead nephropathy seem to be particularly prone to the development of gout, and recent studies have suggested that subclinical exposure to environmental lead may contribute to some of the hyperuricemia and gout seen in the general population. The hyperuricemia associated with diuretic therapy results from volume depletion, which leads to a decreased filtered load, and from enhanced tubular reabsorption. A renal mechanism is the cause of most other cases of drug-associated hyperuricemia. Low-dose aspirin can cause significant changes in renal handling of urate within a week after therapy is started, particularly in elderly patients. Hyperuricemia and gout may be associated with cyclosporine therapy in renal and cardiac transplantation patients, and it appears to be the result of a combined effect of cyclosporine on renal blood flow and tubular function.
Overproduction of uric acid, caused by increased purine synthesis, is seen in about 10% to 20% of patients with primary gout. In addition, four specific heritable defects of purine synthesis have been identified: phosphoribosylpyrophosphate synthetase overactivity, glucose-6-phosphatase deficiency, fructose-1-phosphate aldolase deficiency, and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency. Of these heritable defects, the best-known is HGPRT deficiency. Complete deficiency of this enzyme is associated with the Lesch-Nyhan syndrome in children, and a partial deficiency has been associated with early-onset gout and nephrolithiasis.
Most diseases that cause secondary hyperuricemia characterized by overproduction of uric acid are associated with increased nucleic acid turnover. These diseases include multiple myeloma, polycythemia, pernicious anemia, hemoglobino pathies, thalassemia, other hemolytic anemias, other myeloproliferative and lymphoproliferative disorders, and other neoplasms. In addition, some critically ill patients may experience hyperuricemia resulting from accelerated breakdown of adenosine triphosphate (ATP).2
Acute gouty arthritis is usually characterized by a sudden and dramatic onset of pain and swelling, usually in a single joint. This condition occurs most often in lower extremity joints and evolves within hours to marked swelling, warmth, and tenderness. The process often extends beyond the confines of the joint and may mimic cellulitis. The pain of gout is often severe enough to make even the light pressure of bedclothes intolerable, and weight bearing is usually very difficult. Even without treatment, attacks of gout usually subside within a few days, although some attacks may last a few weeks. Early in the course of gout, affected joints usually return to normal after attacks.
The initial attack of gout is monoarticular in 85% to 90% of patients. At least half of initial attacks occur in the first metatarsophalangeal joints (a condition known as podagra), but other joints of the foot may be involved simultaneously or in subsequent attacks. Other lower extremity joints, including the ankles and knees, are often affected; in more advanced gout, attacks may occur in upper extremity joints, such as the elbow, wrist, and small joints of the fingers. In older women in particular, involvement of the small joints of the fingers (previously affected by osteoarthritis) is more commonly seen earlier in the course of the disease. Acute episodes may also involve the bursae, particularly in the olecranon or prepatellar areas. Polyarticular gout occurs as the initial manifestation in about 10% to 15% of patients and may be associated with fever.
Almost all synovial fluid aspirated early in an acute attack contains typical needlelike crystals, which are negatively birefringent and may be extracellular or may occur within polymorphonuclear leukocytes. The leukocyte count in most gouty synovial fluid rises to a range of 10,000 to 60,000/mm, but it may be much higher in some patients.
Persistent hyperuricemia with increasingly frequent attacks of gout eventually leads to joint involvement of wider distribution and chronic joint destruction resulting from deposition of massive amounts of urate in and around joints. Without therapy to lower serum uric acid levels, the average interval from the first gouty attack to the development of chronic arthritis or tophi is about 12 years.28 After 20 years, 75% of patients have tophi; patients with the highest urate levels are at highest risk. In elderly patients, particularly women, tophi may appear earlier in the course of the disease, sometimes in patients without a history of gouty attacks.
Subcutaneous tophi begin to appear in periarticular and bursal tissues, especially around the knees and elbows, along tendons of the hands and feet, and around the interphalangeal and metacarpophalangeal joints of the hands. Tophaceous deposits are usually firm and movable, and the overlying skin may be normal or thin and reddened. When close to the surface, deposits exhibit a characteristic chalky appearance and may be cream-colored or yellowish. Tophi have also been described in areas not associated with joints, such as the pinna of the ear , and in unusual visceral locations, such as the myocardium, pericardium, aortic valves, and extradural spinal regions.
Destruction of the articular cartilage and subchondral bone eventually occurs in patients with chronic articular involvement. Erosive bony lesions may be seen on x-rays as well-defined punched-out lesions in periarticular bone, often associated with overhanging edges of bone. These erosions are usually 5 mm or more in diameter and are larger than those seen in rheumatoid arthritis. Bone mineralization appears to be generally normal in chronic tophaceous gout, and periarticular osteopenia, which is seen in rheumatoid arthritis, is usually not present. The distribution of destructive joint disease in gout is often asymmetrical and patchy.2
Lesch-Nyhan syndrome (LNS), also known as Nyhan’s syndrome, is a rare, inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). LNS is an X-linked recessive disease: the gene is carried by the mother and passed on to her son. LNS is present at birth in baby boys. Patients have severe mental and physical problems throughout life. The lack of HPRT causes a build-up of uric acid in all body fluids, and leads to problems such as severe gout, poor muscle control, and moderate mental retardation, which appear in the first year of life. A striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting, that begin in the second year of life. Abnormally high uric acid levels can cause sodium urate crystals to form in the joints, kidneys, central nervous system and other tissues of the body, leading to gout-like swelling in the joints and severe kidney problems. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington’s disease. The direct cause of the neurological abnormalities remains unknown. Because a lack of HPRT causes the body to poorly utilize vitamin B12, some boys may develop a rare disorder called megaloblastic anemia.3
The symptoms caused by the buildup of uric acid (arthritis and renal symptoms) respond well to treatment with drugs such as allopurinol that reduce the levels of uric acid in the blood. The mental deficits and self-mutilating behavior do not respond to treatment. There is no cure, but many patients live to adulthood. LNS is rare, affecting about one in 380,000 live births.4
LNS is characterized by three major hallmarks: neurologic dysfunction, cognitive and behavioral disturbances, as well as uric acid overproduction (hyperuricemia). Some may also be afflicted with anemia (macrocytic). Virtually all patients are male, and male victims suffer delayed growth and puberty, and most develop shrunken testicles or testicular atrophy. Female carriers are at an increased risk for gouty arthritis, but are usually otherwise unaffected.
Treatment for LNS is symptomatic. Gout can be treated with allopurinol to control excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no standard treatment for the neurological symptoms of LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol.3
It is essential that the overproduction of uric acid be controlled in order to reduce the risk of nephropathy, nephrolithiasis, and gouty arthritis. The drug allopurinol is utilized to stop the conversion of oxypurines into uric acid, and prevent the development of subsequent arthritic tophi (produced after having chronic gout), renal stones (also known as kidney stones), and nephropathy, the resulting kidney disease. Allopurinol is taken orally, at a typical dose of 3–20 mg/kg per day. The dose is then adjusted to bring the uric acid level down into the normal range (<3 mg/dL).
Most affected individuals can be treated medication is effective in controlling the extrapyramidal motor features of the disease. Spasticity however can be reduced by the administration of baclofen or benzodiazepines.with allopurinol all through life.
Role of uric acid as an endogenous antioxidant in the body
Uric acid is considered a major antioxidant in human blood that may protect against aging and oxidative stress. Despite its proposed protective properties, elevated levels of uric acid are commonly associated with increased risk for cardiovascular disease and mortality. Furthermore, recent experimental studies suggest that uric acid may have a causal role in hypertension and metabolic syndrome. All these conditions are thought to be mediated by oxidative stress. In this study we demonstrate that differentiation of cultured mouse adipocytes is associated with increased production of reactive oxygen species (ROS) and uptake of uric acid. Soluble uric acid stimulated an increase in NADPH oxidase activity and ROS production in mature adipocytes but not in preadipocytes. The stimulation of NADPH oxidase-dependent ROS by uric acid resulted in activation of MAP kinases p38 and ERK1/2, a decrease in nitric oxide bioavailability, and an increase in protein nitrosylation and lipid oxidation. Collectively, our results suggest that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. Since oxidative stress in the adipose tissue has recently been recognized as a major cause of insulin resistance and cardiovascular disease, hyperuricemia-induced alterations in oxidative homeostasis in the adipose tissue might play an important role in these derangements.5
2) Christopher Wise, M.D., W. Robert Irby Associate Professor of Internal Medicine, Division of Rheumatology, Allergy and Immunology, Medical College of Virginia at Virginia Commonwealth University
3) NIH/NINDS Lesch-Nyhan Information Page. NIH/NINDS (February 13, 2007). Retrieved on 2007-04-12
4) Lesch-Nyhan syndrome. Genetics Home Reference. Retrieved on 2007-05-24.
5) Yuri Y. Sautin, Takahiko Nakagawa, Sergey Zharikov, and Richard J. JohnsonDivision of Nephrology, Hypertension, and Transplantation, Department of Medicine, University of Florida, Gainesville, Florida