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Microbes & Immunity Identifying hydrogenase orthologs in the human proteome

Figure 4. Short sections of the Clustal alignment between NDUFS7 and the small hydrogenase subunits
Notes: Blue highlights indicate conserved residues within the protein kinase C phosphorylation site -RASPRQS-. Yellow highlights mark
the -IPGCPP- N-myristoylation site. Asterisks “*” identify identical residues across all sequences. Colons “:” show similar residues. Full stops “.” denotes
weakly similar residues.

As previously noted, the inflammatory response is are concentrated, thus enhancing the potential for ROS
significantly influenced by the redox status of cells and their formation. In addition, incomplete reduction of ubiquinone
compartments, with ROS playing essential roles in both at the Q module can lead to the production of semiquinone,
normal cellular functions and pathological conditions. In a negatively charged intermediate capable of contributing to
healthy cells, ROS participate in signaling pathways essential oxidative stress and proinflammatory signaling. The redox
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for homeostasis and immune responses. Nevertheless, midpoint potential of the ubiquinone/semiquinone couple
during inflammation, ROS production is often elevated. (−0.163 V) is similar to that of the oxygen/superoxide
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Overproduction of ROS or deficiencies in antioxidant couple (−0.16 V), suggesting that semiquinones may also
defense mechanisms can lead to oxidative stress, damaging significantly contribute to ROS formation in this context.
cellular components such as lipids, proteins, and DNA, Notably, reports indicate that the subunits of complex I that
thus exacerbating inflammatory responses. 49,50 ROS acts form the ubiquinone docking channel may have originated
as a signaling molecule that activates transcription factors, from hydrogenase enzymes. 28,29,31
including NFκB and activating protein-1, which are Numerous empirical and pre-clinical studies have
responsible for upregulating proinflammatory cytokines identified H as an effective redox mediator and regulator
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such as TNF-α and various ILs (for instance, IL-6 and of the immune response. 58-64 In single-celled organisms,
IL-1β), thereby amplifying the inflammatory cascade. 51,52 H is metabolized by hydrogenase enzymes that catalyze
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While ROS is necessary for cell signaling and pathogen the reversible oxidation/reduction of H . Among the
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defense, their prolonged presence can lead to chronic various hydrogenase groups, [NiFe] hydrogenases are the
inflammation and tissue damage, contributing to aging most prevalent, found in diverse microbiota, fungi, and
and various health conditions. Therefore, maintaining a plants. 65-67 All characterized [NiFe] hydrogenases comprise
balance between ROS production and antioxidant defenses a large subunit containing the active H deprotonation site
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is vital for regulating inflammation and preventing disease and a smaller subunit housing up to nine iron-sulfur (FeS)
progression. clusters. Similarly, complex I of the mitochondrial electron
Due to its nearly constant redox activity and abundant transport chain also relies on a series of FeS clusters to
electron supply, complex I serves as a prominent source of transfer electrons to the terminal N2 cluster, where they
superoxide within the mitochondria. There are potentially reduce ubiquinone to ubiquinol.
two sites within complex I where O can accept electrons In the present study, initial BLASTp analysis identified
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from the nicotinamide adenine dinucleotide co-factor: NDUFS2 as the most similar to the catalytic units of
(i) the flavin mononucleotide (FMN) module and (ii) the [NiFe] hydrogenases investigated. Supporting these
the ubiquinone binding site. Duong et al. identified findings, matrix analysis (Figure 1) identified a relatively
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through in silico modeling that the FMN module is likely strong correlation between NDUFS2 and NDUFS7 with
the putative site for ROS production, concluding that the [NiFe] hydrogenases from Ca. Heimdallarchaeota
ROS generation is further stimulated by the absence of (27% and 35%, respectively) and δ-proteobacterium
ubiquinone at the ubiquinone/complex I interface. In the D. carbinolicus (23% and 35%, respectively). In contrast,
absence of ubiquinone, the intraprotein channel becomes the α-proteobacterium R. sphaeroides showed less than
accessible to O , exposing it to a region where electrons 20% homology, indicating greater evolutionary distance.
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Volume 1 Issue 2 (2024) 86 doi: 10.36922/mi.4544