Urate oxidase, also known as uricase, is an enzyme that breaks down uric acid. It transforms uric acid into a more soluble substance, aiding the body in waste management. Understanding urate oxidase offers insight into fundamental biological processes related to purine breakdown.
What is Urate Oxidase and Its Function?
Urate oxidase is an enzyme that acts within the purine degradation pathway. Purines are natural compounds found in the body and in many foods, forming components of DNA and RNA. The breakdown of purines eventually leads to the formation of uric acid.
The primary function of urate oxidase is to catalyze the oxidation of uric acid, converting it into allantoin. This conversion involves urate oxidase initiating the oxidation of uric acid to 5-hydroxyisourate, which then transforms into allantoin. Allantoin is significantly more soluble in water than uric acid, allowing for its efficient excretion from the body, primarily through the kidneys. The enzyme is a homotetramer, made of four identical subunits, and its activity comes from properly orienting its substrates.
Urate Oxidase Across Species
Urate oxidase is widely present across the animal kingdom, with most mammals possessing this enzyme. This allows them to effectively convert uric acid into allantoin, maintaining low levels of uric acid in their bloodstream, typically below 0.5-1 mg/dl. However, humans and certain other primates, such as chimpanzees and gorillas, do not produce functional urate oxidase.
The absence of a functional urate oxidase gene in humans is due to evolutionary mutations, including a significant nonsense mutation in exon 2 of the gene, estimated to have occurred about 15 million years ago. This evolutionary loss means that uric acid remains the final product of purine metabolism in humans. While the exact reasons for this loss are still debated, it has led to distinct differences in uric acid metabolism between humans and most other mammals.
Impact of Urate Oxidase Absence in Humans
The lack of functional urate oxidase in humans has significant physiological consequences, primarily leading to higher levels of uric acid in the blood, a condition known as hyperuricemia. Human serum uric acid concentrations are much higher than in other mammals, often exceeding 50 times the levels found in animals with active urate oxidase. This elevated uric acid is a metabolic dead end for humans, as it cannot be further broken down through enzymatic action.
Higher uric acid levels can contribute to several health issues. One notable condition is gout, a painful inflammatory arthritis caused by the crystallization of uric acid in joints, often in the big toe. The absence of urate oxidase makes humans susceptible to developing gout, especially when combined with genetic predispositions and lifestyle factors like a purine-rich diet, obesity, or increased alcohol consumption.
Beyond gout, elevated uric acid can also lead to the formation of uric acid kidney stones, a type of nephrolithiasis. These stones form when uric acid crystals accumulate in the kidneys, often due to low urine pH, which reduces uric acid solubility. Hyperuricemia has also been linked to other conditions, including chronic kidney disease, hypertension, and cardiovascular disease, as it can promote oxidative stress and inflammation. While uric acid does act as an antioxidant in human blood, its overaccumulation can have serious negative consequences.
Medical Uses of Urate Oxidase
Despite its absence in humans, recombinant forms of urate oxidase have found important applications in medicine to manage dangerously high uric acid levels. These therapeutic enzymes work by mimicking the natural function of urate oxidase from other species, converting uric acid into the more easily excretable allantoin. Two notable recombinant forms are rasburicase and pegloticase.
Rasburicase, a recombinant urate oxidase, is approved for preventing and treating acute hyperuricemia, especially in patients undergoing chemotherapy for hematologic malignancies. Chemotherapy can cause rapid breakdown of tumor cells, leading to a sudden release of purines and a sharp increase in uric acid, a condition known as tumor lysis syndrome. Rasburicase rapidly lowers uric acid levels, helping to prevent acute kidney failure and other complications.
Pegloticase is a modified, PEGylated form of porcine (pig) uricase, designed to reduce its antigenicity and extend its half-life in the body. It received approval for treating chronic gout in adult patients who have not responded to conventional therapies. Pegloticase is administered intravenously, typically every two weeks, and effectively reduces serum uric acid concentrations, promoting the dissolution of tophi—uric acid crystal deposits that can form in tissues in severe gout. While effective, the use of these enzymes can be limited by factors such as cost and the potential for the patient’s immune system to develop antibodies against the foreign enzyme, which can reduce its effectiveness or cause infusion reactions.