Uricase, also known as urate oxidase, is an enzyme that catalyzes the oxidation of uric acid. Its primary function is to break down uric acid, preventing its accumulation in various organisms.
The Biological Role of Uricase
Uricase is present in most mammals, converting uric acid into allantoin, a more soluble compound. This conversion is a step in the purine degradation pathway, allowing for easier excretion of allantoin from the body, primarily through the kidneys. Unlike most mammals, humans and great apes do not possess a functional uricase enzyme due to genetic mutations.
The absence of functional uricase in humans means that uric acid remains the final product of purine metabolism. In other mammals, uric acid levels range from 1 to 2 milligrams per deciliter (mg/dL) due to uricase. However, in primates, including humans, uric acid concentrations are naturally higher, around 3-4 mg/dL in healthy individuals.
Uric Acid and Human Health
In humans, uric acid is the end-product of purine metabolism, a natural process involving the breakdown of substances found in cells and many foods. When uric acid levels in the blood become too high, a condition known as hyperuricemia occurs. This can happen if the body produces too much uric acid or if the kidneys are unable to excrete enough of it.
Sustained high levels of uric acid can lead to the formation of sharp, needle-like crystals, particularly in and around joints and in the kidneys. These crystals can trigger an inflammatory response, causing intense pain and swelling, a condition known as gout. Gout flares can affect any joint, but frequently begin in the big toe. If hyperuricemia persists for several years, these uric acid crystals can form visible lumps under the skin called tophi, which can worsen joint pain and cause damage. Elevated uric acid levels are also linked to the formation of kidney stones.
Therapeutic Applications of Uricase
Given the health issues associated with high uric acid levels in humans, recombinant forms of uricase have been developed for therapeutic use. These medications, such as rasburicase and pegloticase, function by mimicking the natural enzyme, converting uric acid into allantoin, which is more readily excreted. This rapid reduction in uric acid levels can be beneficial in certain medical conditions.
Therapeutic uricase is primarily used to treat severe, refractory gout, which is gout that has not responded adequately to other treatments. Pegloticase, for instance, is administered intravenously every two weeks for chronic gout in patients who are intolerant to or have not achieved target uric acid levels with conventional therapies. Uricase is also used to manage hyperuricemia associated with tumor lysis syndrome, a serious complication of cancer treatment where rapid breakdown of cancer cells releases large amounts of purines, leading to a sudden surge in uric acid. Rasburicase, a non-PEGylated recombinant uricase, is often used short-term for this purpose, administered intravenously for up to 7 days. While effective in rapidly lowering uric acid and dissolving tophi, the use of these therapeutic uricases requires careful monitoring for potential side effects, including infusion reactions and the development of antibodies against the enzyme.