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Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping
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Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 13295

Special Issue Editor

Prof. Dr. Sergey Siletsky

E-Mail Website
Guest Editor
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory, Moscow 119991, Russia
Interests: biophysics; biochemistry; molecular bioenergetics; mechanisms of enzyme action; membrane proteins; terminal oxidases; cytochrome oxidase; cytochromes; retinal proteins; photosystem 2; proton pump; electrogenic mechanisms of membrane potential generation; reactive oxygen species; fast kinetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proton pumps are integral membrane proteins that create and maintain an electrochemical gradient of protons across biological membranes by driving protons through the membrane. Proton pumps are divided into various large classes, which differ in the use of different energy sources, and have different polypeptide composition and evolutionary origin. The source of free energy for pumping protons in proton pumps can be light energy (e.g., bacteriorhodopsin and other retinal proton pumps), electron transfer energy (e.g., electron transfer complexes of the mitochondrial respiratory chain), or chemical energy from energy-rich metabolites (e.g., adenosine triphosphate (ATP) and proton ATPases, pyrophosphate (PPi) and proton pumping pyrophosphatase, proton-translocating transhydrogenase). The transfer of a positively charged proton in a proton pump is usually electrogenic, and is accompanied by the formation of an electric membrane potential. However, there are also nonelectrogenic proton pumps, such as hydrogen potassium ATPase (H+/K+ ATPase) of the gastric mucosa, which is primarily responsible for acidification of the stomach contents. Due to the diversity of the structural and functional organization and the evolutionary origin of various classes of proton pumps, their cellular and physiological functions, and their significance for medicine and biotechnology, important and interesting tasks include studying the general principles of the devices and mechanisms of their operation, determining the trajectories and mechanisms of proton transport, the functional role of proton-conducting pathways, the role and scale of conformational changes during proton pumping, searching for low-molecular-weight and high-molecular-weight inhibitors and activators of proton transport, as well as general and specific mechanisms of inhibition and activation of proton pumps. The study of the mechanisms of the functioning of these natural nanoscale devices could contribute to the creation of artificial efficient energy converters, the rational use of biomimetic technologies, fine regulation of cellular processes in normal and pathological states, the creation of specific drugs and pharmaceuticals, the development of new tools in optogenetics and neurobiology, and new approaches in medicine.

Through this Special Issue, we hope to gather papers that allow readers to appreciate a new understanding of the molecular mechanisms, structure, and functional properties of proton pumps and related enzymes, their physiological roles, mechanisms of inhibition and activation, ways of assembly and maturation, as well as biotechnological and medical applications. Original research articles and up-to-date reviews on these and related topics are welcome in this Special Issue.

Prof. Dr. Sergey Siletsky
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • proton pumps
  • retinal
  • bacteriorhodopsin
  • photosynthesis
  • respiratory chain
  • complex I
  • NADH dehydrogenase
  • terminal oxidase
  • complex IV
  • cytochrome
  • pyrophosphatase
  • transhydrogenase
  • proton-translocating ATPase
  • H+/K+ ATPase
  • gastric proton pump
  • proton pump inhibitor
  • inhibition
  • activation

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

4 pages, 189 KiB  
Editorial
Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping
by Sergey A. Siletsky
Int. J. Mol. Sci. 2023, 24(10), 9070; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24109070 - 22 May 2023
Cited by 2 | Viewed by 1017
Abstract
Protein molecular machines, also known as proton pumps, are the most important element of biological membranes [...] Full article
(This article belongs to the Special Issue Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping)

Research

Jump to: Editorial, Review

18 pages, 2828 KiB  
Article
Mechanism of ADP-Inhibited ATP Hydrolysis in Single Proton-Pumping FoF1-ATP Synthase Trapped in Solution
by Iván Pérez, Thomas Heitkamp and Michael Börsch
Int. J. Mol. Sci. 2023, 24(9), 8442; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098442 - 08 May 2023
Cited by 3 | Viewed by 1844
Abstract
FoF1-ATP synthases in mitochondria, in chloroplasts, and in most bacteria are proton-driven membrane enzymes that supply the cells with ATP made from ADP and phosphate. Different control mechanisms exist to monitor and prevent the enzymes’ reverse chemical reaction of [...] Read more.
FoF1-ATP synthases in mitochondria, in chloroplasts, and in most bacteria are proton-driven membrane enzymes that supply the cells with ATP made from ADP and phosphate. Different control mechanisms exist to monitor and prevent the enzymes’ reverse chemical reaction of fast wasteful ATP hydrolysis, including mechanical or redox-based blockade of catalysis and ADP inhibition. In general, product inhibition is expected to slow down the mean catalytic turnover. Biochemical assays are ensemble measurements and cannot discriminate between a mechanism affecting all enzymes equally or individually. For example, all enzymes could work more slowly at a decreasing substrate/product ratio, or an increasing number of individual enzymes could be completely blocked. Here, we examined the effect of increasing amounts of ADP on ATP hydrolysis of single Escherichia coli FoF1-ATP synthases in liposomes. We observed the individual catalytic turnover of the enzymes one after another by monitoring the internal subunit rotation using single-molecule Förster resonance energy transfer (smFRET). Observation times of single FRET-labeled FoF1-ATP synthases in solution were extended up to several seconds using a confocal anti-Brownian electrokinetic trap (ABEL trap). By counting active versus inhibited enzymes, we revealed that ADP inhibition did not decrease the catalytic turnover of all FoF1-ATP synthases equally. Instead, increasing ADP in the ADP/ATP mixture reduced the number of remaining active enzymes that operated at similar catalytic rates for varying substrate/product ratios. Full article
(This article belongs to the Special Issue Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping)
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13 pages, 785 KiB  
Article
Appropriateness of Proton Pump Inhibitor Prescription Evaluated by Using Serological Markers
by Michele Russo, Kryssia Isabel Rodriguez-Castro, Marilisa Franceschi, Antonio Ferronato, Maria Piera Panozzo, Lorenzo Brozzi, Francesco Di Mario, Pellegrino Crafa, Giovanni Brandimarte and Antonio Tursi
Int. J. Mol. Sci. 2023, 24(3), 2378; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032378 - 25 Jan 2023
Cited by 1 | Viewed by 1429
Abstract
Inappropriate prescription of proton pump inhibitors (PPI) has been widely reported, often lacking initial exclusion of Helicobacter pylori (HP) infection and evaluation of gastric functional status. The aim of this study was to evaluate the utility of gastric functional tests to define the [...] Read more.
Inappropriate prescription of proton pump inhibitors (PPI) has been widely reported, often lacking initial exclusion of Helicobacter pylori (HP) infection and evaluation of gastric functional status. The aim of this study was to evaluate the utility of gastric functional tests to define the acid output, as well as HP status, in order to better direct PPI therapy prescription. Dyspeptic patients without alarm symptoms from a primary care population were evaluated. For each patient, serum Pepsinogen I (PGI) and II (PGII), gastrin 17 (G17) and anti-HP IgG antibodies (Biohit, Oyj, Finland) were determined. For each subject, data were collected regarding symptoms, past medical history of HP infection, and PPI use. Therapeutic response to PPIs was determined according to PGI and G17 values, where G17 > 7 in the presence of elevated PGI and absence of chronic atrophic gastritis (CAG) was considered an adequate response. Among 2583 dyspeptic patients, 1015/2583 (39.3%) were on PPI therapy for at least 3 months before serum sampling, and were therefore included in the study. Active HP infection and CAG were diagnosed in 206 (20.2%) and 37 (3.6%) patients, respectively. Overall, an adequate therapeutic response to PPIs was observed in 34.9%, reaching 66.7% at the highest dose. However, 41.1% and 20.4% of patients showed low (G17 1-7) or absent (G17 < 1) response to PPI, regardless of the dosage used. According to gastric functional response, most patients currently on PPI maintenance therapy lack a proper indication for continuing this medication, either because acid output is absent (as in CAG) or because gastrin levels fail to rise, indicating absence of gastric acid negative feedback. Lastly, HP eradication is warranted in all patients, and gastric function testing ensures this pathogen is sought for and adequately treated prior to initiating long-term PPI therapy. Full article
(This article belongs to the Special Issue Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping)
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16 pages, 2108 KiB  
Article
Involvement of Diamine Oxidase in Modification of Plasma Membrane Proton Pump Activity in Cucumis sativus L. Seedlings under Cadmium Stress
by Małgorzata Janicka, Małgorzata Reda, Natalia Napieraj, Adrianna Michalak, Dagmara Jakubowska and Katarzyna Kabała
Int. J. Mol. Sci. 2023, 24(1), 262; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010262 - 23 Dec 2022
Cited by 3 | Viewed by 1437
Abstract
Cucumber (Cucumis sativus L.) is a crop plant being the third most-produced vegetable developed as a new model plant. Heavy metal pollution is a serious global problem that affects crop production. An industrial activity has led to high emissions of Cd into [...] Read more.
Cucumber (Cucumis sativus L.) is a crop plant being the third most-produced vegetable developed as a new model plant. Heavy metal pollution is a serious global problem that affects crop production. An industrial activity has led to high emissions of Cd into the environment. Plants realize adaptive strategies to diminish the toxic effects of Cd. They can remove excess toxic ions of heavy metals from the cytoplasm to the outside of cells using the metal/proton antiport. The proton gradient needed for the action of the antiporter is generated by the plasma membrane (PM) H+-ATPase (EC 3.6.3.14). We have shown that treatment of cucumber plants with Cd stimulated the diamine oxidase (DAO, EC 1.4.3.6) activity in roots. Under cadmium stress, the PM H+-ATPase activity also increased in cucumber seedlings. The stimulating effect of Cd on the PM H+-ATPase activity and expression of three genes encoding this enzyme (CsHA2, CsHA4, CsHA8) was reduced by aminoguanidine (AG, a DAO inhibitor). Moreover, we have observed that H2O2 produced by DAO promotes the formation of NO in the roots of seedlings. The results presented in this work showed that DAO may be an element of the signal transduction pathway, leading to enhanced PM H+-ATPase activity under cadmium stress. Full article
(This article belongs to the Special Issue Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping)
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16 pages, 1989 KiB  
Article
Radical in the Peroxide-Produced F-Type Ferryl Form of Bovine Cytochrome c Oxidase
by Tereza Sztachova, Adriana Tomkova, Erik Cizmar, Daniel Jancura and Marian Fabian
Int. J. Mol. Sci. 2022, 23(20), 12580; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232012580 - 20 Oct 2022
Cited by 2 | Viewed by 1387
Abstract
The reduction of O2 in respiratory cytochrome c oxidases (CcO) is associated with the generation of the transmembrane proton gradient by two mechanisms. In one of them, the proton pumping, two different types of the ferryl intermediates of the catalytic heme a [...] Read more.
The reduction of O2 in respiratory cytochrome c oxidases (CcO) is associated with the generation of the transmembrane proton gradient by two mechanisms. In one of them, the proton pumping, two different types of the ferryl intermediates of the catalytic heme a3-CuB center P and F forms, participate. Equivalent ferryl states can be also formed by the reaction of the oxidized CcO (O) with H2O2. Interestingly, in acidic solutions a single molecule of H2O2 can generate from the O an additional F-type ferryl form (F•) that should contain, in contrast to the catalytic F intermediate, a free radical at the heme a3-CuB center. In this work, the formation and the endogenous decay of both the ferryl iron of heme a3 and the radical in F• intermediate were examined by the combination of four experimental approaches, isothermal titration calorimetry, electron paramagnetic resonance, and electronic absorption spectroscopy together with the reduction of this form by the defined number of electrons. The results are consistent with the generation of radicals in F• form. However, the radical at the catalytic center is more rapidly quenched than the accompanying ferryl state of heme a3, very likely by the intrinsic oxidation of the enzyme itself. Full article
(This article belongs to the Special Issue Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping)
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Review

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20 pages, 1400 KiB  
Review
Complex Interplay of Heme-Copper Oxidases with Nitrite and Nitric Oxide
by Jinghua Chen, Peilu Xie, Yujia Huang and Haichun Gao
Int. J. Mol. Sci. 2022, 23(2), 979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020979 - 17 Jan 2022
Cited by 8 | Viewed by 2415
Abstract
Nitrite and nitric oxide (NO), two active and critical nitrogen oxides linking nitrate to dinitrogen gas in the broad nitrogen biogeochemical cycle, are capable of interacting with redox-sensitive proteins. The interactions of both with heme-copper oxidases (HCOs) serve as the foundation not only [...] Read more.
Nitrite and nitric oxide (NO), two active and critical nitrogen oxides linking nitrate to dinitrogen gas in the broad nitrogen biogeochemical cycle, are capable of interacting with redox-sensitive proteins. The interactions of both with heme-copper oxidases (HCOs) serve as the foundation not only for the enzymatic interconversion of nitrogen oxides but also for the inhibitory activity. From extensive studies, we now know that NO interacts with HCOs in a rapid and reversible manner, either competing with oxygen or not. During interconversion, a partially reduced heme/copper center reduces the nitrite ion, producing NO with the heme serving as the reductant and the cupric ion providing a Lewis acid interaction with nitrite. The interaction may lead to the formation of either a relatively stable nitrosyl-derivative of the enzyme reduced or a more labile nitrite-derivative of the enzyme oxidized through two different pathways, resulting in enzyme inhibition. Although nitrite and NO show similar biochemical properties, a growing body of evidence suggests that they are largely treated as distinct molecules by bacterial cells. NO seemingly interacts with all hemoproteins indiscriminately, whereas nitrite shows high specificity to HCOs. Moreover, as biologically active molecules and signal molecules, nitrite and NO directly affect the activity of different enzymes and are perceived by completely different sensing systems, respectively, through which they are linked to different biological processes. Further attempts to reconcile this apparent contradiction could open up possible avenues for the application of these nitrogen oxides in a variety of fields, the pharmaceutical industry in particular. Full article
(This article belongs to the Special Issue Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping)
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22 pages, 2526 KiB  
Review
Proton Pumping and Non-Pumping Terminal Respiratory Oxidases: Active Sites Intermediates of These Molecular Machines and Their Derivatives
by Sergey A. Siletsky and Vitaliy B. Borisov
Int. J. Mol. Sci. 2021, 22(19), 10852; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910852 - 07 Oct 2021
Cited by 14 | Viewed by 2443
Abstract
Terminal respiratory oxidases are highly efficient molecular machines. These most important bioenergetic membrane enzymes transform the energy of chemical bonds released during the transfer of electrons along the respiratory chains of eukaryotes and prokaryotes from cytochromes or quinols to molecular oxygen into a [...] Read more.
Terminal respiratory oxidases are highly efficient molecular machines. These most important bioenergetic membrane enzymes transform the energy of chemical bonds released during the transfer of electrons along the respiratory chains of eukaryotes and prokaryotes from cytochromes or quinols to molecular oxygen into a transmembrane proton gradient. They participate in regulatory cascades and physiological anti-stress reactions in multicellular organisms. They also allow microorganisms to adapt to low-oxygen conditions, survive in chemically aggressive environments and acquire antibiotic resistance. To date, three-dimensional structures with atomic resolution of members of all major groups of terminal respiratory oxidases, heme-copper oxidases, and bd-type cytochromes, have been obtained. These groups of enzymes have different origins and a wide range of functional significance in cells. At the same time, all of them are united by a catalytic reaction of four-electron reduction in oxygen into water which proceeds without the formation and release of potentially dangerous ROS from active sites. The review analyzes recent structural and functional studies of oxygen reduction intermediates in the active sites of terminal respiratory oxidases, the features of catalytic cycles, and the properties of the active sites of these enzymes. Full article
(This article belongs to the Special Issue Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping)
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