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There is an increasing realization that structure-based drug design may show improved success rates by understanding the ensemble of conformations and sub-states accessible to an enzyme and how the environment affects this ensemble. Human monoamine oxidase B (MAO-B) catalyzes the oxidation of amines and is inhibited for the treatment of both Parkinson's disease and depression. Despite its clinical importance, its catalytic mechanism remains unclear and routes to drugging this target would be valuable and relevant. Evidence of a radical in either the transition state or resting state of MAO-B is present throughout the literature, and is suggested to be a flavin semiquinone, a tyrosyl radical or both. Here we see evidence of a resting state flavin semiquinone, via absorption redox studies and electron paramagnetic resonance, suggesting that the anionic semiquinone is biologically relevant. Based on enzyme kinetic studies, enzyme variants and molecular dynamics simulations we find evidence for the crucial importance of the membrane environment in mediating the activity of MAO-B and that this mediation is related to effects on the protein dynamics of MAO-B. Further, our MD simulations identify a hitherto undescribed entrance for substrate binding, membrane modulated substrate access, and indications for half-site reactivity: only one active site is accessible to binding at a time. Our study combines both experimental and computational evidence to illustrate the subtle interplay between enzyme activity, protein dynamics and the immediate membrane environment. Understanding key biomedical enzymes to this level of detail will be crucial to inform strategies (and binding sites) for rational drug design for these drug targets.
This article was published in the following journal.
Most membrane proteins exist in complexes that carry out critical cellular functions and exhibit rich dynamics. The bacterial flagellar motor, a large membrane-spanning ion-driven rotary motor that pr...
Membrane protein function fundamentally depends on lipid bilayer fluidity and the composition of the biological membrane. Although dynamic interdependencies between membrane proteins and the surroundi...
To elucidate the structures and dynamics of membrane proteins, highly advanced biophysical methods have been developed that often require significant resources, both for sample preparation and experim...
The cellular membrane constitutes one of the most fundamental compartments of a living cell, where key processes such as selective transport of material and exchange of information between the cell an...
Membrane proteins are the gatekeepers of cellular membranes where they act as enzymes, transporters, signaling receptors, or in energy conversion. Traditionally seen as a difficult field, the last dec...
Pancreatic exocrine insufficiency is known to impair nutrient absorption, especially fat, but few data exist about protein absorption. We aimed to investigate this question and assess the ...
To conduct a randomized, double-blind, controlled clinical trial to determine the independent and combined effects of dietary conjugated linoleic acid (CLA) and vitamin D supplementation o...
Modified perforated membrane (MPM) is considered as a modality that could enable participation of periosteal cells and gingival stem cells which could improve the outcomes of guided tissue...
This study is intended to evaluate the effect of the dietary supplement NEM® brand eggshell membrane versus placebo in reducing exercise-induced joint pain, stiffness & cartilage turnover...
This study is intended to evaluate the effect of the dietary supplement NEM® brand eggshell membrane versus placebo in reducing exercise-induced joint pain & stiffness & cartilage turnove...
An autophagy-related protein that functions in AUTOPHAGOSOME biogenesis. It is conjugated to the ATG12 PROTEIN via a process that is similar to UBIQUITINATION and involves the ATG7 PROTEIN and ATG10 enzyme. The ATG12-ATG5 conjugate acts as an E3 UBIQUITIN LIGASE-like enzyme and is required for the localization of ATG8 PROTEINS to AUTOPHAGOSOME vesicle membranes and modification of membrane lipids.
An abundant lysosomal-associated membrane protein that has been found to shuttle between LYSOSOMES; ENDOSOMES; and the PLASMA MEMBRANE. Loss of expression of lysosomal-associated membrane protein 2 is associated with GLYCOGEN STORAGE DISEASE TYPE IIB.
A FLAVOPROTEIN oxidoreductase that occurs both as a soluble enzyme and a membrane-bound enzyme due to ALTERNATIVE SPLICING of a single mRNA. The soluble form is present mainly in ERYTHROCYTES and is involved in the reduction of METHEMOGLOBIN. The membrane-bound form of the enzyme is found primarily in the ENDOPLASMIC RETICULUM and outer mitochondrial membrane, where it participates in the desaturation of FATTY ACIDS; CHOLESTEROL biosynthesis and drug metabolism. A deficiency in the enzyme can result in METHEMOGLOBINEMIA.
A member of the vesicle-associated membrane protein family involved in the MEMBRANE FUSION of TRANSPORT VESICLES to their target membrane.
An AAA ATPase consisting of the 60 kDa ATPase subunit (p60 subunit A1) which severs MICROTUBULES, and an 80 kDa accessory protein (p80 subunit B1), which targets the enzyme to the CENTROSOME. It releases microtubules from the mitotic SPINDLE POLES to allow depolymerization and poleward motion of chromosomes. It is also a regulator of microtubule dynamics in NEURONAL OUTGROWTH.
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...
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...