Definition
FAD-dependent urate hydroxylase, more commonly known as urate oxidase or uricase (EC 1.7.3.3), is an enzyme that catalyzes the hydroxylation of uric acid (urate) to 5‑hydroxyisourate. The reaction requires flavin adenine dinucleotide (FAD) as a tightly bound prosthetic group and molecular oxygen as the oxidant.
Catalyzed Reaction
$$ \text{uric acid} + O_2 + H_2O ;\xrightarrow{\text{urate hydroxylase (FAD)}}; 5\text{-hydroxyisourate} + H_2O_2 $$
The 5‑hydroxyisourate subsequently degrades non‑enzymatically (or via a dedicated isourate hydrolase) to allantoin, which is more water‑soluble and readily excreted.
Biological Occurrence
- Microorganisms: Widely present in bacteria, fungi, and many lower eukaryotes.
- Animals: Found in most mammals, amphibians, and reptiles.
- Humans and higher primates: The functional gene is a pseudogene; therefore, humans lack an active urate hydroxylase enzyme. This loss contributes to comparatively high plasma uric acid levels.
Structure and Cofactor
- The enzyme is a homotetramer (or, in some species, a homodimer) of ~30–35 kDa subunits.
- Each subunit binds one molecule of FAD, which mediates electron transfer from uric acid to molecular oxygen.
- Crystal structures (e.g., from Candida spp. and Bacillus spp.) reveal a typical flavoprotein fold with a conserved active‑site motif that orients uric acid for hydroxylation.
Physiological Role
- Purine catabolism: Completes the degradation pathway of purine nucleotides by converting uric acid to allantoin, facilitating nitrogen excretion.
- Protection against oxidative stress: By converting uric acid—a potential antioxidant and pro‑oxidant—into less reactive metabolites, the enzyme helps maintain redox balance in organisms that possess it.
Clinical and Biotechnological Relevance
- Gout and hyperuricemia: Humans lack functional urate hydroxylase, making uric acid the final purine catabolite. Elevated uric acid can precipitate gout; thus, recombinant uricase (e.g., rasburicase) is used clinically to lower serum uric acid in oncology patients undergoing chemotherapy.
- Biocatalysis: Engineered urate oxidases are explored for biotechnological applications such as biosensors for uric acid and bioremediation of nitrogen‑rich waste streams.
Genetics
- The gene is commonly designated uox (uricase) in bacterial and fungal genomes. In mammals with a functional enzyme, the gene is expressed primarily in the liver and, to a lesser extent, in the kidney.
- In humans, the UOX pseudogene contains multiple inactivating mutations, rendering it transcriptionally inactive.
Related Enzymes
- Urate transporter proteins (e.g., URAT1): Mediate uric acid reabsorption in renal tubules.
- Isourate hydrolase (EC 3.3.2.1): Catalyzes the conversion of 5‑hydroxyisourate to allantoin.
References
- Wikipedia contributors. “Uricase.” Wikipedia, The Free Encyclopedia.
- EC 1.7.3.3 – Urate oxidase entry in the IUBMB Enzyme Nomenclature database.
- J. D. Hsu et al., “Crystal structure of urate oxidase from Candida sp.” J. Biol. Chem., 2008.
- R. P. J. Wang et al., “Therapeutic applications of recombinant urate oxidase.” Clin. Pharmacol. Ther., 2015.
