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Fumarate, an electron acceptor in anaerobic respiration of Escherichia coli, has an additional function of assisting the flagellar motor to shift from counterclockwise to clockwise rotation, with a consequent modulation of the bacterial swimming behavior. Fumarate transmits its effect to the motor via the fumarate reductase complex (FrdABCD), shown to bind to FliG - one of the motor's switch proteins. How binding of the FrdABCD respiratory enzyme to FliG enhances clockwise rotation and how fumarate is involved in this activity, have remained puzzling. Here we show that the FrdA subunit in the presence of fumarate is sufficient for binding to FliG and for clockwise enhancement. We further demonstrate by in vitro binding assays and super-resolution microscopy in vivo that the mechanism by which fumarate-occupied FrdA enhances clockwise rotation involves its preferential binding to the clockwise state of FliG (FliG). Continuum electrostatics combined with docking analysis and conformational sampling endorsed the experimental conclusions and suggested that the FrdA-FliG interaction is driven by the positive electrostatic potential generated by FrdA and the negatively charged areas of FliG. They further demonstrated that fumarate changes FrdA's conformation to one that can bind to FliG. These findings also show that the reason for the failure of the succinate dehydrogenase flavoprotein SdhA (an almost-identical analog of FrdA shown to bind to FliG equally well) to enhance clockwise rotation is that it has no binding preference for FliG. We suggest that this mechanism is physiologically important as it can modulate the magnitude of ΔG between the clockwise and counterclockwise states of the motor to tune the motor to the growth conditions of the bacteria.
This article was published in the following journal.
Name: Journal of molecular biology
Switching tenofovir disoproxil fumarate to tenofovir alafenamide results in a significant decline in parathyroid hormone levels: uncovering the mechanism of tenofovir disoproxil fumarate-related bone loss?
: An increasing number of patients have been switched from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide because of its improved bone safety profile, although the pathophysiological mec...
During tissue ischemia succinate accumulates. Herein, literature spanning the past nine decades is reviewed leaning towards the far greater role of Krebs cycle's canonical activity yielding succinate ...
Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy.
To compare on-treatment efficacy and discontinuation outcomes in teriflunomide (TFL) and dimethyl fumarate (DMF) in the treatment of relapsing-remitting multiple sclerosis (RRMS) in a real-world setti...
Urinary biomarkers of kidney injury may have potential to identify subclinical injury attributable to tenofovir disoproxil fumarate (TDF) toxicity.
To assess the bronchodilation of three doses of formoterol fumarate (6 μg, 12 μg and 24 μg) twice daily (BID) administered via Pressair® compared to placebo and to open-label nebulized ...
The aim is to investigate the mechanism by which galacto-oligosaccharide acutely increases iron absorption by using stable isotope appearance curves. This will allow the evaluation of chan...
The primary purpose was to evaluate the efficacy of SKP FlutiForm HFA MDI compared to placebo or fluticasone and formoterol administered concurrently or alone in asthma patients.
The purpose of this study is to evaluate the efficacy of this multicenter, randomized, double-blind, placebo-controlled, 4-period, incomplete-block crossover, dose-ranging study comparing ...
This study allows patients who need a new anti-HIV treatment to take tenofovir disoproxil fumarate (tenofovir DF), an experimental drug. This study also looks at any side effects the drug ...
A fumarate derivative that is used as a DERMATOLOGIC AGENT in the treatment of PSORIASIS and SKIN DISEASES. It also may be used as an IMMUNOSUPPRESSIVE AGENT in the treatment of MULTIPLE SCLEROSIS.
A pharmaceutical preparation of budesonide and formoterol fumarate that is used as an ANTI-ASTHMATIC AGENT and for the treatment of CHRONIC OBSTRUCTIVE PULMONARY DISEASE.
A pharmaceutical preparation of mometasone furoate and formoterol fumarate that is used as an inhaled dosage form for the treatment of ASTHMA.
A pharmaceutical preparation of the ANTI-HIV AGENTS elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate that is used in the treatment of HIV INFECTIONS.
A histamine H1 antagonist used as the hydrogen fumarate in hay fever, rhinitis, allergic skin conditions, and pruritus. It causes drowsiness.
Asthma COPD Cystic Fibrosis Pneumonia Pulmonary Medicine Respiratory Respiratory tract infections (RTIs) are any infection of the sinuses, throat, airways or lungs. They're usually caused by viruses, but they can also ...
Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...