Protein-Noble Gas Interactions Investigated by Crystallography on Three Enzymes - Implication on Anesthesia and Neuroprotection Mechanisms

Crystallographic Studies with Xenon and Nitrous Oxide Provide Evidence for Protein-dependent Processes in the Mechanisms of General Anesthesia

“…We recently showed that the ability of xenon and nitrous oxide to bind to urate oxidase disturbs the enzymatic activity of this globular protein. 18,72 Likewise, we further showed that xenon inhibited the catalytic activity of elastase by binding to its active site 51 and demonstrated that xenon and nitrous oxide disrupt in a concentration-dependent manner both the catalytic and thrombolytic activities of tissue-type plasminogen activator, 15,17 a serine protease whose human recombinant form is the only approved therapy for acute ischemic stroke. This agrees with studies that have shown that anesthetic binding to proteins leads to an increase in…”

“…All experiments were performed at 10, 20, and 30 bar of gas pressure, which are pressures at least 10-fold that required to obtain in vivo narcotic/anesthetic effects 2 and in vitro inhibitory effects of enzyme activity. 15,17,18,51 The relevance of such pressures to the pressure (concentration) used in clinical anesthesia could therefore be questioned. It is a wellknown condition, due to slow gas penetration in crystalline systems, that the gas pressure to be used in crystallography studies must be at least 10 times higher the gas physiological concentration to allow approximating gas binding saturation in a reasonable time period.…”

Structural Basis for Xenon Inhibition in a Cationic Pentameric Ligand-Gated Ion Channel

“…In urate oxidase for example, xenon inhibited enzymatic activity though an indirect and non-competitive mechanism by binding to an allosteric internal cavity located close to the active site. Xenon induced an expansion of the volume of this hydrophobic cavity, which increased with the applied gas pressure, leading to an increase of the rigidity of the cavity and of the flexibility to the neighboring active site [ 36 , 37 , 66 ]. On the other hand, in elastase and tissue-type plasminogen activator (t-PA), xenon inhibited enzymatic activity through a direct and competitive mechanism by binding directly in the active site of the two enzymes [ 36 , 67 ].…”

Xenon–Protein Interactions: Characterization by X-Ray Crystallography and Hyper-CEST NMR

“…This approach is preferred for quantitative structural studies in which Xe occupancies, B-factors, etc. are calculated as a function of Xe pressure (Abraini et al, 2014; Colloc’h, Marassio & Prangé, 2008). There are several papers detailing the methodology of this Xe derivatization technique (Stowell et al, 1996; Schiltz, Prangé & Fourme, 1994; Schiltz, Prangé & Fourme, 2003).…”