Birchall, K. | Search bioRxiv

bioRxiv2023

Natural mutations of human XDH promote the nitrite (NO2-)-reductase capacity of xanthine oxidoreductase: a novel mechanism to promote redox health?

Several rare genetic variations of human XDH have been shown to alter xanthine oxidoreductase (XOR) activity leading to impaired purine catabolism. However, XOR is a multi-functional enzyme that depending upon the environmental conditions also expresses oxidase activity leading to both O {middle dot}- and H O and nitrite ({middle dot}NO -) reductase activity leading to NO. Since these products express important, and often diametrically opposite, biological activity consideration of the impact of XOR mutations in the context of each aspect of the biochemical activity of the enzyme is needed to determine the potential full impact of these variants. Herein, we show that known naturally occurring hXDH mutations do not have a uniform impact upon the biochemical activity of the enzyme in terms of uric acid (UA), reactive oxygen species (ROS) and nitric oxide ({middle dot}NO) formation. We show that the His1221Arg mutant, in the presence of xanthine, increases UA, O2{middle dot}- and NO generation compared to the WT, whilst the Ile703Val increases UA and {middle dot}NO formation, but not O2{middle dot}-. We speculate that this change in the balance of activity of the enzyme is likely to endow those carrying these mutations with a harmful or protective influence over health that may explain the current equipoise underlying the perceived importance of XDH mutations. We also suggest that targeting enzyme activity to enhance the NO2--reductase profile in those carrying such mutations may provide novel therapeutic options, particularly in cardiovascular disease. HighlightsO_LIMutations of xanthine oxidoreductase modulate both its expression and activity C_LIO_LIThe His1221Arg natural mutation increases xanthine oxidoreductase activity C_LIO_LIRaised xanthine oxidoreductase activity coupled with increased availability of nitrite substrate leads to increased NO provision C_LI

biochemistry↗

bioRxiv2021

Incorporating Target-Specific Pharmacophoric Information Into Deep Generative Models For Fragment Elaboration

Despite recent interest in deep generative models for scaffold elaboration, their applicability to fragment-to-lead campaigns has so far been limited. This is primarily due to their inability to account for local protein structure or a users design hypothesis. We propose a novel method for fragment elaboration, STRIFE that overcomes these issues. STRIFE takes as input Fragment Hotspot Maps (FHMs) extracted from a protein target, and processes them to provide meaningful and interpretable structural information to its generative model, which in turn is able to rapidly generate elaborations with complementary pharmacophores to the protein. In a large-scale evaluation, STRIFE outperforms existing, structure-unaware, fragment elaboration methods in proposing highly ligand efficient elaborations. In addition to automatically extracting pharmacophoric information from a protein targets FHM, STRIFE optionally allows the user to specify their own design hypotheses.

systems biology↗