Gas Sensing by Bacterial H-NOX Proteins: An MD Study

Rozza, Ahmed M.; Menyhárd, Dóra K.; Oláh, Julianna

doi:10.3390/molecules25122882

Cited by 6 publications

(10 citation statements)

References 47 publications

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“…This tunnel has been observed as the shortest route in two other bacterial H‐NOX proteins from Nostoc sp. and Caldanaerobacter subterraneus, making it highly selective and typical molecular tunnel in H‐NOX proteins [53,55] . In addition, we found another longer access tunnel (between helices αA and αD) that gas molecules only rarely used to migrate to the distal pocket.…”

Section: Resultsmentioning

confidence: 80%

“…[a] The average amount of time that NO gas molecules spent inside a given pocket before exiting again. [b] The number of in‐and‐out diffusion events made by NO gas molecules, where “protein core→geminate pair” represents the in‐event path, and the reversible direction of this route represents the out‐event path [45,53] . [c] Occupancy of the pockets with at least one NO molecule during the simulation time.…”

Section: Resultsmentioning

confidence: 99%

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The Mechanism of Biochemical NO‐Sensing: Insights from Computational Chemistry

Rozza

Papp

McFarlane

et al. 2022

Chemistry A European J

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The binding of small gas molecules such as NO and CO plays a major role in the signaling routes of the human body. The sole NO-receptor in humans is soluble guanylyl cyclase (sGC) -a histidine-ligated heme protein, which, upon NO binding, activates a downstream signaling cascade. Impairment of NO-signaling is linked, among others, to cardiovascular and inflammatory diseases. In the present work, we use a combination of theoretical tools such as MD simulations, high-level quantum chemical calculations and hybrid QM/MM methods to address various aspects of NO binding and to elucidate the most likely reaction paths and the potential intermediates of the reaction. As a model system, the H-NOX protein from Shewanella oneidensis (So H-NOX) homologous to the NO-binding domain of sGC is used. The signaling route is predicted to involve NO binding to form a six-coordinate intermediate heme-NO complex, followed by relatively facile His decoordination yielding a fivecoordinate adduct with NO on the distal side with possible isomerization to the proximal side through binding of a second NO and release of the first one. MD simulations show that the His sidechain can quite easily rotate outward into solvent, with this motion being accompanied in our simulations by shifts in helix positions that are consistent with this decoordination leading to significant conformational change in the protein.

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

The Mechanism of Biochemical NO‐Sensing: Insights from Computational Chemistry

Rozza

Papp

McFarlane

et al. 2022

Chemistry A European J

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“…Epithelial-mesenchymal transition↑ MIP-1α & TNFα↓ Cxcl1 & IL-6↑, TLR↑ [27] Nrf-2/HO-1↑/SOD//glutathione/catalase↑ [28] Activating PI3K/Akt/mTOR pathway [29] (Continued) Bax↓, Bcl-2↑, Caspase-3↓; HMOX1↑, Irf1↓ [30] NMDA-receptor inhibition [31] ; activation of PI3K/Akt↑ and MAPK↑ [32] Activating mTOR/HIF1α [33] Opening of mitoKATP channel [34] Argon Ar gas and Ar solution Brain, retina kidneys, and heart…”

Section: Inflammatory Response↓ Oxidative Stress↓mentioning

confidence: 99%

“…The heme-based sensor proteins such as HO and NPAS2 thereupon play important roles in regulating cellular responses to gaseous environment changes (e.g., O 2 , CO, NO, and H 2 S) through coupling a "regulatory" heme binding site to a "functional" signal-transmitter site. [32] Distinctly, CO, NO, and H 2 S are members of the growing family of molecules termed "gasotransmitters" that influence functional, metabolic, and genetic events. [33,34] The human body's average rate of CO generation is ≈20 μmol h −1 , resulting in the normal baseline human carboxyhemoglobin level of 0.4-1%.…”

Section: Carbon Monoxide (Co)mentioning

confidence: 99%

Medical Gas Therapy for Tissue, Organ, and CNS Protection: A Systematic Review of Effects, Mechanisms, and Challenges

et al. 2022

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Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable "biological gas" (CO, H 2 , H 2 S, NO, O 2 , O 3 , and N 2 O) or "noble gas" (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO-CO, HIF-1𝜶/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF-1𝜶/ERK activation. Primary findings also reveal that the need to utilize cutting-edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad-spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma.

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“…The active-site-containing protein is represented as a green cartoon, and additional binding proteins are shown as a wheat-colored cartoon. The enzymes along with the PDB identifiers and references to the methods used to identify the tunnels in the respective panels are (A) sMMO, ,, (B) toluene 4-monooxygenase, , (C) [NiFe]-hydrogenase, − (D) nitrogenase, − (E) nitric oxide reductase, , (F) cytochrome ba3 oxidase, , (G) lipoxygenase, − (H) cytochrome P450 BM-3, , (I) H-NOX protein, , (J) α-ketoglutarate dependent-dioxygenase AlkB, , and (K) carbon monoxide dehydrogenase/acetyl-CoA synthase. − Tunnel identification methods are designated by numbers: (1) geometric methods, (2) molecular dynamics simulations, (3) xenon pressurization, and (4) mutation of tunnel-lining residues (Supporting Information). P = polar, NP = nonpolar.…”

Section: Tunnels For Substrate and Product Transport In Soluble Metha...mentioning

confidence: 99%

Small-Molecule Tunnels in Metalloenzymes Viewed as Extensions of the Active Site

Banerjee

Lipscomb

2021

Acc. Chem. Res.

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Conspectus Rigorous substrate selectivity is a hallmark of enzyme catalysis. This selectivity is generally ascribed to a thermodynamically favorable process of substrate binding to the enzyme active site based upon complementary physiochemical characteristics, which allows both acquisition and orientation. However, this chemical selectivity is more difficult to rationalize for diminutive molecules that possess too narrow a range of physical characteristics to allow either precise positioning or discrimination between a substrate and an inhibitor. Foremost among these small molecules are dissolved gases such as H2, N2, O2, CO, CO2, NO, N2O, NH3, and CH4 so often encountered in metalloenzyme catalysis. Nevertheless, metalloenzymes have evolved to metabolize these small-molecule substrates with high selectivity and efficiency. The soluble methane monooxygenase enzyme (sMMO) acts upon two of these small molecules, O2 and CH4, to generate methanol as part of the C1 metabolic pathway of methanotrophic organisms. sMMO is capable of oxidizing many alternative hydrocarbon substrates. Remarkably, however, it will preferentially oxidize methane, the substrate with the fewest discriminating physical characteristics and the strongest C–H bond. Early studies led us to broadly attribute this specificity to the formation of a “molecular sieve” in which a methane- and oxygen-sized tunnel provides a size-selective route from bulk solvent to the completely buried sMMO active site. Indeed, recent cryogenic and serial femtosecond ambient temperature crystallographic studies have revealed such a route in sMMO. A detailed study of the sMMO tunnel considered here in the context of small-molecule tunnels identified in other metalloenzymes reveals three discrete characteristics that contribute to substrate selectivity and positioning beyond that which can be provided by the active site itself. Moreover, the dynamic nature of many tunnels allows an exquisite coordination of substrate binding and reaction phases of the catalytic cycle. Here we differentiate between the highly selective molecular tunnel, which allows only the one-dimensional transit of small molecules, and the larger, less-selective channels found in typical enzymes. Methods are described to identify and characterize tunnels as well as to differentiate them from channels. In metalloenzymes which metabolize dissolved gases, we posit that the contribution of tunnels is so great that they should be considered to be extensions of the active site itself. A full understanding of catalysis by these enzymes requires an appreciation of the roles played by tunnels. Such an understanding will also facilitate the use of the enzymes or their synthetic mimics in industrial or pharmaceutical applications.

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Gas Sensing by Bacterial H-NOX Proteins: An MD Study

Cited by 6 publications

References 47 publications

The Mechanism of Biochemical NO‐Sensing: Insights from Computational Chemistry

The Mechanism of Biochemical NO‐Sensing: Insights from Computational Chemistry

Medical Gas Therapy for Tissue, Organ, and CNS Protection: A Systematic Review of Effects, Mechanisms, and Challenges

Small-Molecule Tunnels in Metalloenzymes Viewed as Extensions of the Active Site

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