Uricase Enzyme: A Link Between Uric Acid Reduction and Cardiovascular Health

Figure 01: Uricase Enzymatic Reaction.

Uric Acid Metabolism

The first step in uric acid synthesis involves purine metabolism at the liver and is catalyzed by the enzyme xanthine oxidase. The following steps in this process result in the conversion of hypoxanthine into xanthine and then into uric acid. Within the human body, nearly two-thirds of uric acid is eliminated via the kidneys and the remaining one-third is expelled through the intestines. Renal redistribution of uric acid follows a cycle of filtration, absorption, secretion, and post-secretory absorption. All of the aforementioned processes rely on URAT1 and GLUT9. Malfunction in this system causes a concentration of uric acid in the blood.

Hyperuricemia: Causes and Clinical Significance

Hyperuricemia is observed and diagnosed when uric acid concentration in the blood rises up to and exceeds the saturation point at which it becomes a solute in the blood plasma. Primary hyperuricemia is attributed to genetic causes, while secondary hyperuricemia occurs due to dietary, renal, and pharmacological changes. The pathological importance of hyperuricemia is primarily observed in gout. However, hyperuricemia is also observed in various pathological states such as the metabolic syndrome, diabetes, and cardiovascular diseases. Hyperuricemia has been shown to contribute to and worsen inflammation, combine with and worsen oxidative stress, and propagate damage to the blood vessels.

Uricase Enzyme: Structure and Function

Uricase (urate oxidase) oxidizes uric acid to allantoin, hydrogen peroxide, and carbon dioxide, and is a peroxisomal enzyme. Allantoin is easily excreted due to its high-water solubility. Uricase is a homotetrameric protein that has active sites that bind uric acid and molecular oxygen. This reaction significantly decreases uric acid and thus, inhibits the formation of uric acid crystals. In the therapeutics field, recombinant forms of uricase effectively decrease uric acid concentration in the serum in a short period.

Figure 02: Mechanism of Uricase Function

Evolutionary Loss of Uricase In Humans

There were uricase gene mutations that lead to the inactivation of the gene during primate evolution. Some advantages in the early environments were decreased oxidative stress and relative hypotensive survival during low-salts. In current environments, the loss of uricase predisposes individuals to the formation of uric acid crystals in the tissues (hyperuricemia). In the presence of uricase, less than 1% of the uric acid remains in the plasma.

Figure 03: Evolutionary Loss of Uricase.

Role of Uric Acid In Cardiovascular Diseases

The chemistry Urate further contributes to cardiovascular pathology through multiple cascading interactions of different processes in the circulation. Counter to its solvent role, urate diminishes the production of nitric oxide and augments its consumption, resulting in vasodilatory and flow-mediated vasodilation endothelial dysfunction. Uric acid also aggravates the consumption of/logs the production of Reactive Oxygen Species (ROS) causing inflammation and the accompanying oxidative damage to the cell and tissues. This further promotes vascular remodeling, increased excrescence stiffness, and atherosclerosis. Hyperuricemia with up-regulation of uric acid and the components of the renin-angiotensin promotes further hypertension crisis.

Mechanistic Link Between Uric Acid and Cardiovascular Health

At the vascular cellular or tissue level, uric acid moves across cell membranes through specific transporters and activate a plethora of pro-inflammatory processes and pathways, such as NF-κB. The term a plethogenesis of mechanisms describes the ultimate vascular inflammation leading to association and exacerbation of increased muscle cell pliability and pliable media. Uric acid also aggravates oxidative stress by activating and further mounting the NADPH and torpor of oxidase activating the mitochondrial machinery. These processes, as Group of the studies state, are collectively an adduced and exacerbative injury to the Endothelial tissue impairment leading to multifarious and severe cardiovascular dysfunction.

Figure 04: Uric Acid and Cardiovascular Damage Mechanism.

Figure 05: Pathophysiological Flowchart.

Therapeutic Role of Uricase

Uricase-type therapies decompose uric acid into allantoin. Thus, recombinant uricase therapies are preferred to xanthine oxidase inhibitors when uric acid levels are extremely elevated or when patients are refractory to other therapies. Tumor lysis syndrome and refractory gout are two medical conditions in which a rapid fall in uric acid levels is a therapeutic necessity. In these conditions, multiple recombinant uricase products are very effective.

Uricase-Based Drugs and Clinical Studies

Rasburicase and pegloticase are two examples of uricase-based therapies. Rasburicase is used primarily in oncology in the prophylaxis and treatment of tumor lysis syndrome, and pegloticase is indicated for chronic refractory gout. Clinical studies for both uricase-based therapies showed a remarkable decline in serum urate concentration and an overall positive clinical response. The aforementioned studies also revealed the issues of infusion reactions and other immunogenicity-related concerns, which require close monitoring of the patients.

Benefits of Uric Acid Reduction in Cardiovascular Health

Decreasing uric acid levels has been associated with a healthy blood pressure, improved endothelial function, and decreased cardiovascular risk. There is a body of research that suggests opening uric acid to a previously casual relationship with history of hypertension and cardiovascular diseases. However, many in the field of research consider uric acid to be just a biomarker. This does remain an open research topic.

Figure 06: Clinical Impact Graph.