Xanthine dehydrogenase

Xanthine dehydrogenase (XDH) is an enzyme that plays a crucial role in the catabolism of purines in humans and many other organisms. It catalyzes the oxidation of hypoxanthine to xanthine and then xanthine to uric acid, which is an important process in the purine degradation pathway. This enzyme is closely related to xanthine oxidase (XO), with which it shares a significant sequence homology and catalytic capabilities, differing mainly in the final electron acceptor used in the oxidative process.

Function

Xanthine dehydrogenase is a molybdenum-containing enzyme that belongs to the family of oxidoreductases. It plays a pivotal role in the oxidative metabolism of purines, converting hypoxanthine to xanthine and subsequently xanthine to uric acid, a process critical for the elimination of excess nitrogen from the body. The enzyme is widely distributed in tissues, including the liver, intestine, and muscle. Its activity is essential for maintaining the balance of purine bases and for the regulation of uric acid levels in the blood, preventing conditions such as gout and hyperuricemia.

Structure

The enzyme is a complex homodimer, each subunit of which contains a molybdenum cofactor (MoCo), a flavin adenine dinucleotide (FAD) binding domain, and two iron-sulfur ([Fe-S]) clusters. These components are crucial for the enzyme's catalytic activity, facilitating the transfer of electrons from xanthine to NAD+ (in the case of XDH) or oxygen (in the case of XO).

Genetic Regulation

The gene encoding xanthine dehydrogenase is located on the human chromosome 2p23.1. It is subject to complex regulation, including transcriptional and post-transcriptional mechanisms that control its expression and activity in response to various physiological and pathological conditions. Mutations in the gene can lead to decreased enzyme activity and contribute to disorders such as xanthinuria.

Clinical Significance

Alterations in XDH activity can have significant clinical implications. Reduced activity of the enzyme, due to genetic mutations or inhibition by drugs such as allopurinol, can lead to xanthinuria, characterized by the accumulation of xanthine in the urine and the potential for xanthine stone formation in the kidneys. Conversely, increased XDH activity can contribute to the pathogenesis of gout, hyperuricemia, and certain types of kidney stones by elevating uric acid levels in the blood and tissues.

Pharmacological Inhibition

Xanthine dehydrogenase is a target for pharmacological inhibition in the treatment of conditions associated with elevated uric acid levels, such as gout. Allopurinol and its metabolite, oxypurinol, are among the most commonly used inhibitors. These agents act by mimicking the substrate of the enzyme, thereby blocking its activity and reducing the production of uric acid.

See Also

• Purine metabolism
• Gout
• Hyperuricemia
• Xanthine oxidase
• Allopurinol