Molecule of the Month: Xanthine Oxidoreductase

Xanthine Oxidoreductase (PDB entries 1fo4 and 1fiq)

Xanthine oxidoreductase is actually two enzymes in one. Early in the study of the enzyme, scientists purified a form that uses NAD and a different form that uses oxygen. Scientists originally thought they were two different enzymes and gave them two names: xanthine dehydrogenase and xanthine oxidase. However, when they finally got a look at the amino acid sequence, both enzymes turned out to be the same. The forms differ in two ways. First, there are several disulfide bridges in the enzyme: if they are formed, the enzyme acts as the oxidase, if they are broken, the enzyme acts as the dehydrogenase. Second, the enzyme may be clipped by proteases to convert it permanently to the oxidase form. Two examples are shown here: the dehydrogenase form is shown on the left from PDB entry 1fo4 and the proteolyzed oxidase form is shown on the right from PDB entry 1fiq . One of the sites of cleavage is shown in white with a star. The last step in the electron transfer chain is an FAD group, shown here in turquoise. In the dehydrogenase form, this transfers electrons to NAD, but in the oxidase form, a loop of protein, shown here in bright red, covers the FAD, excluding NAD but allowing smaller oxygen molecules to accept electrons from FAD. To explore these structures in more detail, click on the image for an interactive JSmol.

Several xanthine oxidoreductase structures in the PDB also show the details of ligand binding in the enzyme. For instance, PDB entry 1jrp shows the enzyme with a purine-like inhibitor bound to the molybdenum cofactor.