Using a functional enzyme model to understand the chemistry behind hydrogen sulfide induced hibernation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 52; pp. 22090 - 22095
• Main Authors: Collman, James P, Ghosh, Somdatta, Dey, Abhishek, Decréau, Richard A
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.12.2009; National Acad Sciences
• Subjects: Active sites; Animals; Biochemistry; Catalytic Domain; Cytochromes; Electric current; Electrochemistry; Electron Spin Resonance Spectroscopy; Electron Transport Complex IV - antagonists & inhibitors; Electron Transport Complex IV - chemistry; Electron Transport Complex IV - metabolism; Enzymes; Experiments; Hibernation; Hibernation - drug effects; Hibernation - physiology; Hydrogen; Hydrogen sulfide; Hydrogen Sulfide - metabolism; Hydrogen Sulfide - pharmacology; Iron - chemistry; Models, Biological; Models, Molecular; Molecules; Nuclear Magnetic Resonance, Biomolecular; Oxidases; Oxygen; Physical Sciences; Porphyrins; Respiration; Spectroscopy, Fourier Transform Infrared
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0904082106

The toxic gas H₂S is produced by enzymes in the body. At moderate concentrations, H₂S elicits physiological effects similar to hibernation. Herein, we describe experiments that imply that the phenomenon probably results from reversible inhibition of the enzyme cytochrome c oxidase (CcO), which reduces oxygen during respiration. A functional model of the oxygen-reducing site in CcO was used to explore the effects of H₂S during respiration. Spectroscopic analyses showed that the model binds two molecules of H2S. The electro-catalytic reduction of oxygen is reversibly inhibited by H₂S concentrations similar to those that induce hibernation. This phenomenon derives from a weak, reversible binding of H₂S to the FeII porphyrin, which mimics heme a₃ in CcO's active site. No inhibition of CcO is detected at lower H₂S concentrations. Nevertheless, at lower concentrations, H₂S could have other biological effects on CcO. For example, H₂S rapidly reduces FeIII and CuII in both the oxidized form of this functional model and in CcO itself. H₂S also reduces CcO's biological reductant, cytochrome c, which normally derives its reducing equivalents from food metabolism. Consequently, it is speculated that H₂S might also serve as a source of electrons during periods of hibernation when food supplies are low.