Uricase, also known as urate oxidase, is a naturally occurring enzyme fundamental to purine metabolism. It acts as a catalyst to transform uric acid, a compound produced during purine breakdown, into a far more soluble substance. This conversion is biologically important because it makes the final product easier for an organism to excrete.
Fundamental Function and Biochemistry
Uricase catalyzes the oxidative breakdown of uric acid, the final waste product of purine metabolism. The reaction uses oxygen and water, resulting in the formation of allantoin, carbon dioxide, and hydrogen peroxide.
The biological significance of this enzymatic step lies in the dramatic difference in water solubility between the two compounds. Uric acid is poorly soluble in water, especially at the normal physiological pH of the human body. Allantoin, the product of the uricase reaction, is approximately five to ten times more soluble than uric acid.
Because allantoin is highly water-soluble, the kidneys can efficiently eliminate it without the risk of crystallization. Uricase is widely distributed across the biological world, found in most mammals, invertebrates, plants, and various microorganisms. In these organisms, the enzyme prevents uric acid accumulation by ensuring its rapid conversion into an easily excretable waste product.
The Evolutionary Loss in Humans
Unlike most mammals, humans and certain great apes possess a non-functional version of the uricase gene, meaning the enzyme is not produced. This loss of function is attributed to several independent genetic mutations that accumulated over millions of years of hominoid evolution. The inability to produce functional uricase means that uric acid remains the final, poorly soluble end product of purine metabolism in humans.
Researchers hypothesize that retaining higher uric acid levels may have conferred an evolutionary advantage to early hominids. Uric acid is a powerful antioxidant, and maintaining higher circulating levels may have offered protection against oxidative stress, particularly in the brain. Another theory suggests that elevated uric acid helped maintain blood pressure in ancestral populations that experienced periods of low-salt diets.
This evolutionary change resulted in significantly higher levels of uric acid in human blood compared to most other mammals. When the concentration of uric acid in the blood, known as hyperuricemia, exceeds its solubility threshold, it can lead to the formation of monosodium urate crystals. The deposition of these crystals in the joints is the underlying cause of gout, a painful inflammatory arthritis.
Therapeutic Applications
The absence of functional uricase in humans and the resulting risk of hyperuricemia led to the development of therapeutic uricase preparations. These medications introduce the enzyme externally to manage conditions characterized by high uric acid levels. The core principle is to rapidly reduce the body’s uric acid burden by converting it to the highly soluble allantoin.
A major clinical scenario for therapeutic uricase is the management of acute hyperuricemia associated with Tumor Lysis Syndrome (TLS). TLS is a potentially life-threatening complication that occurs after chemotherapy for certain cancers. The rapid destruction of cancer cells releases massive amounts of purines, which are metabolized into uric acid, risking acute kidney injury.
Administering uricase provides a rapid way to clear excessive uric acid from the circulation, often within hours. This rapid conversion prevents the formation of uric acid crystals in the kidneys, which could lead to acute renal failure. Therapeutic uricase is also used to treat patients with severe, chronic gout that has proven refractory to conventional oral urate-lowering therapies.
Specific Clinical Forms and Delivery
Therapeutic uricase is produced using recombinant DNA technology, typically derived from non-human sources like fungi or bacteria. Because these enzymes are foreign proteins, they carry a risk of triggering an immune response, leading to allergic reactions or the development of antibodies that reduce effectiveness. Two main pharmaceutical forms have been developed, differentiated by their structure and intended use.
One form is non-pegylated recombinant uricase, often used for the short-term treatment of acute hyperuricemia in TLS. This form acts quickly to lower uric acid levels but has a relatively short half-life, meaning it is quickly cleared from the body. It is administered via intravenous (IV) infusion, typically for a few days.
The second, longer-acting form is created through pegylation, where strands of polyethylene glycol (PEG) are chemically attached to the enzyme. Pegylation increases the enzyme’s size, masking it from the immune system, reducing immunogenicity, and extending its circulating half-life to about two weeks. This modified enzyme is indicated for the long-term management of chronic refractory gout, requiring sustained uric acid lowering. All therapeutic uricase products are administered through IV infusion, and patients must be closely monitored for infusion reactions or the development of anti-drug antibodies.