Hydrogenase

[NiFe] hydrogenase maturation#

The maturation pathway is elaborate and requires dedicated accessory proteins. HypA: nickel metallochaperone; delivers nickel (Ni) to the active site precursor. HypB: GTPase/nickel metallochaperone; works with HypA.

HypC/HypD: scaffold complex for iron (Fe)(CO)(CN)2 assembly.

HypE/HypF: synthesize the CN- ligands from carbamoyl phosphate. Endopeptidase: cleaves the C-terminal extension after nickel insertion, locking the metal in place.

Key interconnection with urease: In Helicobacter pylori, HypA and HypB are shared between hydrogenase and urease maturation pathways. Nickel transfer from HypA to UreE demonstrates that the two enzyme systems are coordinately metalated from a common nickel pool.

This means nickel allocation between energy metabolism (hydrogenase) and acid survival (urease) is a regulated decision for the bacterium.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

Helicobacter hepaticus—Liver pathogenesis#

Single [NiFe] H2-uptake hydrogenase. Supports amino acid uptake and cell growth in the hepatobiliary niche. Linked to liver lesions in mice (hepatitis and hepatocellular carcinoma models).

H2 concentrations in mouse liver (~50 uM) exceed the enzyme Km (~2.5 uM), so the hydrogenase is always saturated in vivo—paralleling the H. pylori situation in the stomach.

Campylobacter jejuni—Chicken colonization and beyond#

Membrane-bound [NiFe] uptake-type hydrogenase. Essential for growth and chicken colonization—directly relevant to the food safety chain. hydB deletion impairs cell division and host cell interaction.

Campylobacter concisus has the highest H2-uptake activity of any pathogenic bacterium characterized to date. Campylobacter hydrogenases provide competitive advantage in the microaerobic environment of the intestinal mucus layer.

Shigella flexneri—Phagolysosomal acid combat#

H2-uptake hydrogenases Hya and Hyb combat acid stress in phagolysosomes. Hya activity is three-fold activated within minutes of acid exposure—a rapid-response acid defense mechanism. H2 oxidation provides energy for maintaining intracellular pH homeostasis during the acid assault within macrophage phagosomes.

[[escherichia-coli]]—Multiple hydrogenases, respiratory flexibility#

Contains both H2-uptake (Hyd-1, Hyd-2) and H2-evolving (Hyd-3/Hyc, Hyd-4/Hyf) hydrogenases. Hyd-3 is part of the formate hydrogenlyase (FHL) system: formate --> CO2 + H2. This is critical for mixed-acid fermentation under anaerobic conditions.

Provides respiratory flexibility in the oxygen-variable gut environment.

In pathogenic E. coli, H2 metabolism supports acid resistance and energy generation in nutrient-limited intracellular niches (for UPEC inside bladder epithelial cells).

In the preterm gut, [NiFe] hydrogenase enables NEC-associated E. coli to use H2 as an energy source in the inflamed anaerobic environment.^{[2]Nickel as a Catalytic Driver of Necrotizing Enterocolitis: Dietary Nickel, Microbial Metallomics, and the Activation of Nickel-Dependent Virulence Pathways in the Preterm GutKaren Pendergrass · 2026Open reference 2 ↓}

Bilophila wadsworthia—H2-fueled taurine metabolism#

Uses H2 as an energy source coupled to taurine/sulfite respiration. H2-powered sulfite reduction produces H2S, which may contribute to inflammatory bowel disease pathology. Links hydrogen metabolism to bile acid metabolism and gut Metal-Driven Inflammation.

The CagA-Hydrogenase-Cancer Connection#

This is one of the most consequential pathways in the wiki, linking dietary nickel to gastric cancer through a defined molecular mechanism.

Nickel availability (dietary, environmental) --> metalation of [NiFe] hydrogenase active site in H. pylori. Hydrogenase activity --> H2 oxidation --> proton motive force (PMF) generation. PMF --> powers the Type IV secretion system (T4SS).

T4SS --> translocates CagA oncoprotein into gastric epithelial cells. CagA --> activates SHP-2 phosphatase, disrupts cell polarity, promotes proliferation --> gastric adenocarcinoma.

Evidence supporting this chain. Hydrogenase deletion mutants cannot translocate CagA and do not cause cancer in animal models. Cancer-patient strains have higher hydrogenase activity than gastritis-only strains.

The nickel-free diet (Campanale 2014) that enhanced H. pylori eradication likely works partly by depleting hydrogenase.^{[3]Nickel Free-Diet Enhances the Helicobacter pylori Eradication Rate: A Pilot StudyCampanale M, Nucera E, Ojetti V et al. · 2014Open reference 3 ↓}

Implication: Nickel availability indirectly influences gastric cancer risk through hydrogenase activity. This means environmental and dietary nickel exposure has oncogenic potential not through direct metal toxicity (as with nickel compound carcinogenesis via epigenetic mechanisms) but through enabling a pathogen's carcinogenic machinery.