NiFe-hydrogenase (also called [nickel (Ni)-iron (Fe)] hydrogenase or nickel-iron hydrogenase) is a class of enzymes that catalyze reversible hydrogen (H₂) oxidation. The active site contains both nickel (nickel) and iron (iron) metal atoms arranged in a sophisticated bimetallic cluster. The reaction catalyzed is:
`` H₂ ↔ 2H⁺ + 2e⁻ ``
In the forward direction, H₂ is oxidized to protons and electrons, releasing energy that powers ATP synthesis (in some bacteria). In the reverse direction, protons are reduced to H₂ (used for energy storage or stress relief).
NiFe-hydrogenases are found in. H. pylori (survival in the microaerophilic gastric niche). Methanobrevibacter smithii (methane production; H₂ consumption). Sulfate-reducing bacteria (Desulfovibrio, desulfomonas)—H₂ is the preferred electron donor in sulfate reduction.
NiFe-hydrogenases are virulence factors enabling anaerobic persistence and interkingdom cooperation (H₂ produced by one organism consumed by another in the same biofilm).
Mechanism#
Active site structure:
The NiFe-hydrogenase active site is a bi-metallic cluster containing. Nickel (nickel (Ni))—the main catalytic site. Iron (iron (Fe))—coordinates the substrate and facilitates electron transfer.
Bridging ligands: cyanide (CN⁻) and carbonyl (CO) groups stabilize the iron center.
Nickel coordination: Histidine and cysteine residues.
The bimetallic arrangement is critical: neither metal alone is sufficient; both nickel and iron are required for catalysis.
Catalytic cycle:
`` H₂ binding → heterolytic cleavage of H-H → H⁺ released to solvent → 2e⁻ transferred to electron transport chain (quinone, NAD⁺, etc.) ``
This is energetically favorable under anaerobic or microaerophilic conditions (when dissolved O₂ is low).
Nickel and iron acquisition. Bacteria must acquire both nickel and iron from the environment. H. pylori: Uses NixA (nickel permease) and iron transporters; competes with host Transferrin and Lactoferrin for iron. Sulfate-reducing bacteria: Acquire metals from sediment or gut contents; highly dependent on Iron and Nickel availability.
Role in Disease#
H. pylori persistence in the microaerophilic gastric niche:
H. pylori lives in the mucus layer where O₂ is scarce but not zero (microaerophilic, ~1–5% O₂). Under these conditions.
Oxidative phosphorylation is insufficient (not enough O₂ for efficient ATP synthesis). H₂ oxidation via NiFe-hydrogenase becomes critical—provides additional ATP and electrons for reducing O₂ via cytochrome c oxidase. Without NiFe-hydrogenase: H. pylori cannot thrive in low-O₂ niches; burden is reduced.
Related conditions. Gastric Ulcer, Gastric Adenocarcinoma—H. pylori NiFe-hydrogenase enables persistent colonization. Methane-predominant SIBO (small intestinal bacterial overgrowth): M. smithii NiFe-hydrogenase consumes H₂ produced by fermentative bacteria; enables overgrowth by reducing H₂-induced inhibition.
Interkingdom cooperation in biofilms:
In polymicrobial biofilms (e.g., cystic fibrosis lung, diabetic foot ulcers). Fermentative bacteria (e.g., bacteroides) produce H₂ as a metabolic byproduct. M. smithii or sulfate-reducers (via NiFe-hydrogenase) consume H₂. This removes H₂ (which inhibits fermentation), enabling primary fermenters to proliferate.
The biofilm becomes self-sustaining; difficult to eradicate.
Metal Connections#
NiFe-hydrogenase is a paradigm for Primitive 4: Metal Dependencies as Achilles' Heels:
Dual metal requirement. Bacteria cannot substitute monometallic hydrogenases if both nickel (Ni) and iron (Fe) are depleted. Simultaneous nickel and iron starvation is more potent than either metal alone.
This is clinically relevant for H. pylori and dysbiotic methanogens.
Nickel availability in the stomach:
- H. pylori gastric infection depends on both NiFe-hydrogenase AND Nickel-Urease
- Both enzymes require nickel; nickel-limited conditions → both virulence pathways compromised
- Therapeutic target: Nickel chelation or dietary nickel restriction in H. pylori-infected patients
Iron availability and bacterial competition:
- H. pylori must compete with host Transferrin, Lactoferrin, and Lipocalin-2 for iron
- In dysbiotic states with Iron overload (e.g., Crohn's Disease, hemochromatosis), H. pylori thrives
- Iron sequestration via nutritional immunity limits H. pylori burden
Sulfate-reducer ecology:
Connections#
Related enzymes. Nickel-Urease—complementary H. pylori virulence factor; both require nickel. [FeFe]-hydrogenases—simpler hydrogenases containing only iron; less common in pathogens. Cytochrome c oxidase—uses H₂ electrons; works in tandem with NiFe-hydrogenase in H. pylori.
Related organisms. H. pylori—primary pathogen expressing NiFe-hydrogenase; microaerophilic survival. M. smithii—methane-producing archaeon; H₂ consumer in the gut. Sulfate-reducing bacteria (Desulfovibrio, )—H₂-dependent sulfate reducers in anaerobic environments.
bacteroides—H₂ producers in fermentation; work synergistically with H₂-consuming methanogens.
Related concepts. Hypoxia/—low-O₂ niches where NiFe-hydrogenase enables survival. Nutritional Immunity (Metal Sequestration)—nickel and Iron sequestration as defenses against NiFe-hydrogenase-dependent pathogens. Biofilm—interkingdom cooperation via H₂ consumption.
—H. pylori NiFe-hydrogenase enables co-persistence with other microaerophiles. metal-cofactor-dependency—dual-metal requirement is a strategic vulnerability.
Related metals and proteins. Nickel—essential cofactor; nickel depletion disables NiFe-hydrogenase. Iron—essential cofactor; iron sequestration limits H. pylori persistence.—product of sulfate-reducer NiFe-hydrogenase coupled to sulfate reduction; dysbiotic byproduct.
Disease pages. ,—H. pylori-driven diseases where NiFe-hydrogenase enables microaerophilic survival. SIBO, methane-predominant dysbiosis—conditions with elevated M. smithii and H₂-consuming activity.
References 8
Numbered by first appearance in the article, then reconciled with its declared source list.
- 1
Benoit SL, Bhatt RJ, Maier RJ (2021). The nickel-chelator dimethylglyoxime inhibits human amyloid beta peptide in vitro aggregation. Scientific Reports.
- 2
Alexander C. Razavi, Kaitlin S. Potts, Tanika N. Kelly et al. (2019). Sex, gut microbiome, and cardiovascular disease risk. Biology of Sex Differences.
- 3
★Monisha Jaishankar, Tenzin Tseten, Naresh Anbalagan et al. (2014). Toxicity, Mechanism and Health Effects of Some Heavy Metals. Interdisciplinary Toxicology.
- 4
Jhommara Bautista, Walter D. Cardona-Maya, Kelly Gancino-Guevara et al. (2025). Bautista 2025 — Reprogramming Prostate Cancer Through the Microbiome. Frontiers in Medicine.
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Shuya Lv, Jingrong Huang, Yadan Luo et al. (2024). Lv 2024 — Gut Microbiota Is Involved in Male Reproductive Function: A Review. Frontiers in Microbiology.
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Yuqi Wu, Oscar Wong, Sizhe Chen et al. (2025). Wu 2025 — Distinct Diet-Microbiome Associations in Autism Spectrum Disorder. Nature Communications.
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Swierc J, Drzymala S, Wozniak D et al. (2022). The influence of nickel on intestinal microbiota disturbances. Pomeranian Journal of Life Sciences.
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Babak Khorsand, Hamid Asadzadeh Aghdaei, Ehsan Nazemalhosseini-Mojarad et al. (2022). Khorsand 2022 — Overrepresentation of Enterobacteriaceae and Escherichia coli is the major gut microbiome signature in Crohn's and UC: comprehensive metagenomic analysis of IBDMDB datasets. Frontiers in Cellular and Infection Microbiology.
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