Concerted Two-Electron Reduction of Ubiquinone in Respiratory Complex I

2019 ◽  
Vol 123 (25) ◽  
pp. 5265-5273 ◽  
Author(s):  
Muhammad A. Hagras ◽  
Alexei A. Stuchebrukhov
Keyword(s):  
Complex I ◽  
Respiratory Complex ◽  
Respiratory Complex I ◽  
Electron Reduction

scholarly journals Quinone binding in respiratory complex I: Going through the eye of a needle. The squeeze-in mechanism of passing the narrow entrance of the quinone site

2021 ◽  
Author(s):  
Nithin Dhananjayan ◽  
Panyue Wang ◽  
Igor Leontyev ◽  
Alexei A. Stuchebrukhov
Keyword(s):  
Conformational Changes ◽  
Complex I ◽  
Respiratory Complex ◽  
Quinone Binding ◽  
Bacterial Enzyme ◽  
Respiratory Complex I ◽  
Electron Reduction ◽  
Pass Through ◽  
Dynamics Simulations ◽  
Ubiquinone Binding

AbstractAt the joint between the membrane and hydrophilic arms of the enzyme, the structure of the respiratory complex I reveals a tunnel-like Q-chamber for ubiquinone binding and reduction. The narrow entrance of the quinone chamber located in ND1 subunit forms a bottleneck (eye of a needle) which in all resolved structures was shown to be too small for a bulky quinone to pass through, and it was suggested that a conformational change is required to open the channel. The closed bottleneck appears to be a well-established feature of all structures reported so-far, both for the so-called open and closed states of the enzyme, with no indication of a stable open state of the bottleneck. We propose a squeeze-in mechanism of the bottleneck passage, where dynamic thermal conformational fluctuations allow quinone to get in and out. Here, using molecular dynamics simulations of the bacterial enzyme, we have identified collective conformational changes that open the quinone chamber bottleneck. The model predicts a significant reduction—due to a need for a rare opening of the bottleneck—of the effective bi-molecular rate constant, in line with the available kinetic data. We discuss possible reasons for such a tight control of the quinone passage into the binding chamber and mechanistic consequences for the quinone two-electron reduction. Graphic abstract

scholarly journals Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone

Polymers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1840
Author(s):  
Camilo Febres-Molina ◽  
Jorge A. Aguilar-Pineda ◽  
Pamela L. Gamero-Begazo ◽  
Haruna L. Barazorda-Ccahuana ◽  
Diego E. Valencia ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Complex I ◽  
Binding Free Energy ◽  
Biological Activities ◽  
Experimental Studies ◽  
Respiratory Complex ◽  
Mitochondrial Respiratory Complex ◽  
Respiratory Complex I ◽  
Mitochondrial Respiratory

ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.

scholarly journals A salvage pathway maintains highly functional respiratory complex I

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Karolina Szczepanowska ◽  
Katharina Senft ◽  
Juliana Heidler ◽  
Marija Herholz ◽  
Alexandra Kukat ◽  
...  
Keyword(s):  
Complex I ◽  
Salvage Pathway ◽  
Respiratory Complex ◽  
Respiratory Complex I

Molecular Gene Therapy: Overexpression of the Alternative NADH Dehydrogenase NDI1 Restores Overall Physiology in a Fungal Model of Respiratory Complex I Deficiency

2010 ◽  
Vol 399 (1) ◽  
pp. 31-40 ◽  
Author(s):  
Marc F.P.M. Maas ◽  
Carole H. Sellem ◽  
Frank Krause ◽  
Norbert A. Dencher ◽  
Annie Sainsard-Chanet
Keyword(s):  
Gene Therapy ◽  
Complex I ◽  
Nadh Dehydrogenase ◽  
Respiratory Complex ◽  
Complex I Deficiency ◽  
Respiratory Complex I
Sign in / Sign up

Export Citation Format

Share Document