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Microbes & Immunity Identifying hydrogenase orthologs in the human proteome

Further along the sequences (at positions significant redox functionality, with the potential to influence
180 – 185 in humans; Figure 4), there is a well- mitochondrial oxidative stress responses. Therefore, one of the
conserved - IPGCPP- motif rich in redox-active proline initial steps should involve determining the crystal structures
residues, along with a cysteine thiol residue at position 183. of the identified human hydrogenases NDUFS2 and NDUFS7
The abundance of conserved residues associated with redox using in silico modeling and X-ray crystallography, followed
chemistry suggests an important conserved function in this by probing their functional analyses with techniques such as
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region. Notably, the -IPGCPP- motif in D. carbinolicus is cryo-electron microscopy and redox-sensitive fluorescent
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fully conserved, raising further questions about whether this probes. These investigations could clarify whether the
region is integral to the function of hydrogenase remaining NDUFS2 and NDUFS7 subunits directly interact with H
2
and potentially linking it to the electron transfer function and how this interaction affects mitochondrial electron flow
of NDUFS7. In addition, the -IPGCPP- site is significant and ROS production in human cells.
due to N-myristoylation, a post-translational modification As evidence increasingly highlights the gut microbiota’s
crucial for regulating innate immune responses, including role in shaping systemic immune responses, it is essential to
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toll-like receptor-dependent inflammatory reactions. investigate the broader immunological effects of microbial
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Consequently, H might modulate N-myristoylation and H production within the gastrointestinal system. Given
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2
thereby influence the innate immune response, although the significant H output from commensal bacteria and its
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further research is needed to validate this hypothesis. potential impact on mitochondrial redox states, research
Figure 4 also illustrates that the PKC phosphorylation should determine whether microbial-derived H directly
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site -RASPRQS-, as identified by Yoga et al., is influences immune cells or operates through the gut-liver
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relatively well conserved. Notably, the phosphorylation or gut-brain axes. Longitudinal studies using germ-free
target, serine residue 113 in humans, is represented by and hydrogen-supplemented animal models, such as those
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threonine in Ca. Heimdallarchaeota, suggesting a retained demonstrated by Yang et al., alongside human clinical
function, as threonine can also be phosphorylated. trials, could elucidate the immunomodulatory effects of H
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2
There is no correlation between the phosphorylation in both health and disease contexts.
target -RASPRQS- in R. sphaeroides, indicating divergence Another key avenue for research lies in exploring
in form and function within this region. The correlation the therapeutic potential of H in managing immune-
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between the smaller subunit of the [NiFe] hydrogenase related conditions. While studies have demonstrated
(Hyd258) and NDUFS7 also reveals the retention of the its anti-inflammatory and antioxidant effects, 10-17 the
serine residue -RASPRQS- motif. This suggests that precise mechanisms remain unclear. For instance,
in δ-proteobacteria, this segment may be significant investigating how H modulates the phosphorylation
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for understanding the influence of H on protein and N-myristoylation of mitochondrial proteins, such
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phosphorylation and cell signaling events. Understanding as NDUFS7, could provide valuable insights into its
whether H has any influence on the molecular activity of role in reducing electron leakage and mitigating ROS
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this conserved region could be crucial for advancing our production. Further clinical studies in autoimmune
knowledge of its biological effects. diseases, inflammatory disorders, and age-related
immunosenescence could offer practical applications for
5. Future perspectives harnessing these benefits.
The interplay between hydrogenase enzymes, microbial H Finally, extending research into microbial hydrogenases
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metabolism, and immune function represents a promising beyond the intestinal microbiome – specifically in the skin,
area of research, particularly regarding the role of H in oral, and respiratory microbiomes – may uncover additional
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modulating oxidative stress and inflammation. Future pathways through which H influences immune function.
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studies should explore several key areas to enhance our Understanding the interplay between hydrogenase
understanding of the evolutionary links between microbial activity, microbial H metabolism, and immune regulation
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hydrogenases and human immune regulation. offers a promising frontier for therapeutic exploration.
One significant avenue for future research is to further Such investigations could unlock novel strategies to
investigate the potential redox activity of human complex leverage microbial interactions for maintaining immune
I subunits, particularly NDUFS2 and NDUFS7, and their homeostasis and mitigating inflammation.
interactions with microbial-derived H . In accordance with
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Lu, who posits that complex I may exhibit hydrogenase- 6. Conclusion
like activity, our findings suggest that while classical [NiFe] This report provides evidence that the closest human
hydrogenase activity has been lost, NDUFS7 may retain homologs of [NiFe] hydrogenases are unlikely to possess

Volume 1 Issue 2 (2024) 88 doi: 10.36922/mi.4544