Urate oxidase

The enzyme urate oxidase (UO), or uricase or factor-independent urate hydroxylase, absent in humans, catalyzes the is_associated_with::oxidation of is_associated_with::uric acid to is_associated_with::5-hydroxyisourate:


 * is_associated_with::Uric acid + O2 + H2O &rarr; is_associated_with::5-hydroxyisourate + H2O2 &rarr;  is_associated_with::allantoin + CO2

Structure
Urate oxidase is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many is_associated_with::peroxisomes. The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site.

Urate oxidase is a homotetrameric enzyme containing four identical active sites situated at the interfaces between its four subunits. UO from A. flavus is made up of 301 residues and has a molecular weight of 33438 dalton. It is unique among the is_associated_with::oxidases in that it does not require a metal atom or an organic co-factor for is_associated_with::catalysis. Sequence analysis of several organisms has determined that there are 24 amino acids which are conserved, and of these, 15 are involved with the active site.

Significance of absence in humans
Humans do have a is_associated_with::gene for urate oxidase, but it is nonfunctional. Thus uric acid is the end product of is_associated_with::catabolism of is_associated_with::purines in humans. Excessive concentration of uric acid in the blood stream leads to is_associated_with::gout.

Urate oxidase is found in nearly all organisms, from is_associated_with::bacteria to is_associated_with::mammals, and plays different metabolic roles, depending on its host organism. It was lost in early is_associated_with::primate is_associated_with::evolution, and so is absent in humans and other higher apes.

It has been proposed that the loss of urate oxidase is_associated_with::protein expression has been advantageous to is_associated_with::hominids, since uric acid is a powerful is_associated_with::antioxidant and scavenger of singlet oxygen and radicals. Its presence provides the body with protection from is_associated_with::oxidative damage, thus prolonging life and decreasing age-specific cancer rates. However, this is highly unlikely as proteins are capable of being activated only when concentrations exceed a certain amount. Adequate uric acid levels could still be maintained to protect the body while preventing evolutionarily disadvantageous conditions like gout.

Urate oxidase is formulated as a protein drug (is_associated_with::rasburicase) for the treatment of acute is_associated_with::hyperuricemia in patients receiving is_associated_with::chemotherapy. A PEGylated form of urate oxidase is in clinical development for treatment of chronic hyperuricemia in patients with "treatment-failure gout".

In legumes
UO is also an essential enzyme in the ureide pathway, where is_associated_with::nitrogen fixation occurs in the root nodules of is_associated_with::legumes. The fixed nitrogen is converted to is_associated_with::metabolites that are transported from the roots throughout the plant to provide the needed nitrogen for is_associated_with::amino acid biosynthesis.

In legumes, 2 forms of uricase are found: in the roots, the tetrameric form; and, in the uninfected cells of root nodules, a monomeric form, which plays an important role in nitrogen-fixation.