- The study uncovered the evolutionary and molecular mechanisms by which zinc-dependent macrodomains reverse ADP-ribosylation, a key modification in cellular processes
- Structural analysis showed that these macrodomains use a zinc ion to hydrolyse ADP-ribose from proteins, revealing their enzymatic reaction mechanism
- Evolutionary studies found zinc-dependent macrodomains are conserved across species, highlighting their important biological role
- The findings propose that targeting these macrodomains could lead to new therapies for diseases involving dysregulated ADP-ribosylation, like cancer and viral infections
, led by scientists from the University of ºù«Ӱҵ, as well as other British, Dutch and Chinese institutions focuses on the role of a group of enzymes known as zinc-dependent macrodomains (Zn-Macros) in reversing ADP-ribosylation, a vital cellular process. This discovery could lead to innovative treatments to combat , a growing global health threat.
is a reversible modification of proteins and DNA that regulates important cellular responses to stress. While this signalling mechanism is well-studied in higher eukaryotes, where it regulates responses to DNA damage, reactive oxygen species and infection, the importance of its role in microorganisms is also becoming increasingly evident, which include the regulation of the host immune response, microbial immune evasion and adaptation to specific hosts.
The research team used a combination of phylogenetic, biochemical, and structural approaches to investigate the function of Zn-Macros. These enzymes are found in some pathogenic microbes and are essential for removing ADP-ribosyl modifications, thereby helping the pathogens survive oxidative stress.
revealed that the catalytic activity of Zn-Macros is strictly dependent on a zinc ion within the active site of these enzymes. The researchers also identified structural features that contribute to substrate selectivity within different types of Zn-Macro enzymes, which may be exploited for the development of future therapies.
The findings have significant implications for the fight against bacterial and fungal infections that pose an increasing risk to human health, a problem that is exacerbated by the development of antimicrobial resistance and the emergence of multidrug-resistant strains. has published that pose the greatest risk, emphasising the need for new antimicrobial strategies.
Addressing antimicrobial resistance will require a multifaceted strategy, including the discovery and characterization of new antimicrobial targets, along with assessing their potential for therapeutic use in innovative (co-)treatment approaches.
The authors of the study suggest that targeting the Zn-Macro pathway could reduce the virulence of major human pathogens, including Staphylococcus aureus and Streptococcus pyogenes. These pathogens rely on the crosstalk between lipoic acid metabolism and ADP-ribosylation signalling for their defence mechanisms. Disrupting this pathway could enhance the effectiveness of existing treatments and provide new therapeutic options.
The study's findings represent a significant step forward in the fight against antimicrobial resistance and highlight the potential of Zn-Macros as therapeutic targets.
Our findings uncover the evolutionary and molecular mechanisms behind ADP-ribosylation reversal by zinc-dependent macrodomains. By understanding this regulatory process, we can explore new avenues for drug development in diseases where ADP-ribosylation plays a critical role. I believe that further investigation into the physiological role of Zn-Macros could lead to the development of new antimicrobial therapies as these enzymes are primarily found in pathogenic microorganisms and have structurally distinct features that make them suitable for drug development.
Dr Antonio Ariza
University Teaching Associate