Xanthine Oxidase and Transforming Growth Factor Beta-activated Kinase 1: Potential Targets for Gout Intervention

Abstract

Background: Gout, an inflammatory arthritis, caused by the deposition of monosodium urate crystals into affected joints and other tissues has become one of the major health problems of today's world. The main risk factor for gout is hyperuricemia, which may be caused by excessive or insufficient excretion of uric acid. The incidence is usually in the age group of 30- 50 years, commonly in males. In developed countries, the incidence of gout ranges from 1 to 4%. Despite effective treatments, there has been an increase in the number of cases over the past few decades. Objective: In recent years, the development of targeted drugs in gout has made significant achievements. The global impact of gout continues to increase, and as a result, the focus of disease-modifying therapies remains elusive. In addition, the characterization of available instrumental compounds is urgently needed to explore the use of novel selective and key protein-ligand interactions for the effective treatment of gout. Xanthine oxidase (XO) is a key target in gout to consider the use of XO inhibitors in patients with mild to moderate condition, however, the costs are high and no other direct progress has been made. Despite many XO inhibitors, a selective potent inhibitor for XO is limited. Likewise, in recent years, attention has been focused on different strategies for the discovery and development of new selectivity ligands against transforming growth factor beta-activated kinase 1 (TAK1), a potential therapeutic target for gout. Therefore the insight on human XO structure and TAK1 provides a clue into protein-ligand interactions and provides the basis for molecular modeling and structure-based drug design. Conclusion: In this review, we briefly introduce the clinical characteristics, the development of crystal, inhibitors, and crystal structure of XO and TAK1 protein.

Xanthine oxidoreductase mediates genotoxic drug‐induced autophagy and apoptosis resistance by uric acid accumulation and TGF‐β‐activated kinase 1 (TAK1) activation

“…XOR plays a critical role in activating TAK1 17 . XOR inhibitors can substitute TAK1 inhibitors and be developed as alternative novel anti‐inflammatory drugs 40 . Our present study shows that genotoxic drug‐induced activation of TAK1 and several downstream signaling pathways in HeLa cells was eliminated by allopurinol.…”

“…17 XOR inhibitors can substitute TAK1 inhibitors and be developed as alternative novel anti-inflammatory drugs. 40 Our present study shows that genotoxic druginduced activation of TAK1 and several downstream signaling pathways in HeLa cells was eliminated by allopurinol. ATM likely activates TAK1 through these ubiquitinated adaptor proteins, whereas uric acid binding to TAK1 leads to its persistent activation.…”