Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

Abstract

Almost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases' binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X-ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes.

Natural compounds with xanthine oxidase inhibitory activity: A review

“…Schematic presentation of uric acid production. (Adopted from Kumar et al, with permission copy right 2017 Wiley) [Colour figure can be viewed at wileyonlinelibrary.com]…”

Antihyperuricemic effect of dietary polyphenol sinapic acid commonly present in various edible food plants

“…It has been reported that XOD inhibitors act as antioxidants to decrease ROS and prevent oxidative stress (Kumar et al, 2018;Lin et al, 2015;Nile et al, 2018). Herein, SA was shown to inhibit the XOD enzyme and to have moderate O −• 2 scavenging activity and a strong DPPH radical scavenging activity.…”

“…LXOD plays an important role in the pathophysiology of HUA and gout (Kumar et al, 2018). The XOD enzyme catalyzes hypoxanthine to xanthine and subsequently xanthine to UA.…”

“…Thus, overproduction or under excretion of UA results in elevated body UA levels, leading to hyperuricemia (HUA), gout, chronic kidney diseases, and cardiovascular diseases as well as other life-threatening disorders (Kumar et al, 2018;Mehmood, Ishaq, Zhao, Safdar, et al, 2019a;Mehmood, Ishaq, Zhao, Yaqoob, et al, 2019b;. HUA can be reversed by preventing the reabsorption and synthesis of UA and promoting its excretion.…”

“…Natural products, enriched with numerous bioactive compounds which further decrease the risk of the onset of many diseases including hyperuricemia (Gawlik-Dziki, Dziki, Swieca, & Nowak, 2017;Hou, Lee, Hung, Fu, & Jeng, 2012;Jhang et al, 2016;Kumar et al, 2018;Lin, Yang, Zhao, & Zhao, 2018;Lin, Zhang, Liao, Pan, & Gong, 2015;Mehmood et al, 2018;Mehmood, Ishaq, Zhao, Safdar, et al, 2019a;Mehmood, Ishaq, Zhao, Yaqoob, et al, 2019b;Mehmood, Zhao, Chengtao, et al, 2019;Mehmood, Zhao, Wang, Hossen, Nadeem, 2019;Nile & Park, 2014;Zhang et al, 2015;Zhao, Chen, & Wu, 2017). Sinapic acid (SA; 3,5-dimethoxy-4-hydroxycinnamic acid) is a phenolic acid commonly present in edible plants (e.g., lemon, orange, mango, apple, strawberries, raspberries, onion, broccoli, garlic, rice, and oats, etc.)…”