What is Xanthine Dehydrogenase?
Xanthine dehydrogenase is a molybdenum-containing enzyme that catalyzes two sequential oxidation reactions in purine metabolism: converting hypoxanthine to xanthine, and then xanthine to uric acid, using NAD+ as the electron acceptor. 1
Biochemical Structure and Function
Xanthine dehydrogenase (XDH) is a complex molybdo/iron-sulfur/flavoprotein enzyme that exists as a homodimer with a total molecular weight of approximately 290 kDa 2
Each subunit contains four essential cofactors: one molybdenum-pterin center, two [2Fe-2S] iron-sulfur clusters, and one FAD (flavin adenine dinucleotide) 2
The enzyme's activity is directly proportional to the amount of molybdenum present in the body, making molybdenum an essential trace element for this enzymatic function 1
Role in Purine Metabolism
XDH catalyzes the final two steps of purine catabolism: first oxidizing hypoxanthine to xanthine, then further oxidizing xanthine to uric acid 1, 3
This enzymatic pathway prevents hypoxanthine-induced DNA mutations by converting these purine metabolites to uric acid for excretion 1
The enzyme preferentially uses NAD+ as its electron acceptor, distinguishing it from xanthine oxidase (which uses molecular oxygen) 3, 4
Clinical Significance in Drug Metabolism
Xanthine dehydrogenase/oxidase is the primary target of allopurinol, the anti-gout medication 1, 3
Allopurinol acts as a competitive inhibitor by being converted to oxypurinol, which blocks the enzyme's active site and prevents conversion of hypoxanthine and xanthine to uric acid 1
When allopurinol inhibits this enzyme, xanthine and hypoxanthine levels increase, which can lead to xanthine crystalluria if massive cell lysis occurs (particularly relevant in tumor lysis syndrome) 1, 5
This enzyme is critical in the metabolism of azathioprine and 6-mercaptopurine, where xanthine oxidase converts 6-MP to inactive 6-thiouric acid as one of three competing metabolic pathways 1, 6
Important Drug Interaction
Concurrent use of allopurinol with azathioprine or 6-mercaptopurine requires dose reduction of the chemotherapy agents by 50-75%, because blocking xanthine oxidase shunts more drug toward the active (and toxic) metabolic pathway 1, 5
This interaction can lead to life-threatening myelosuppression if chemotherapy doses are not appropriately reduced 1
Conversion to Xanthine Oxidase
Xanthine dehydrogenase can be proteolytically or oxidatively converted to xanthine oxidase, which uses molecular oxygen instead of NAD+ as the electron acceptor, producing superoxide radicals 2, 7
This conversion is clinically relevant in postischemic reperfusion injury, where xanthine oxidase generates reactive oxygen species that contribute to tissue damage 2, 8