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عنوان فارسی مقاله:
اثر معرفی حفره های کوچک بر مهار آلوستریک فسفوفروکتوکیناز از باسیلوس استیروترموفیلوس
عنوان انگلیسی مقاله:
The effect of introducing small cavities on the allosteric inhibition of phosphofructokinase from Bacillus stearothermophilus
سال انتشار : 2016
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مقدمه انگلیسی مقاله:
1. Introduction
The enzymes that catalyze the commitment steps of metabolic pathways are subject to intense regulation via allosteric mechanisms. However, the molecular basis of allosteric regulation is still not well understood in most cases. Due to the key role these enzymes play, the ability to manipulate allosteric control mechanisms holds promise for drug design [1e6]. For this reason, an enhanced understanding of the molecular mechanisms behind the regulation of allosteric enzymes is a prerequisite for rational drug design. Prokaryotic phosphofructokinase-1 (PFK) is one such enzyme that has been extensively studied and characterized, resulting in an abundance of kinetic, structural, and thermodynamic information [7e19]. PFK from Bacillus stearothermophilus (BsPFK) in particular serves as model allosteric enzyme to explore the molecular mechanisms of allosteric regulation as well as the thermodynamic basis of the allosteric coupling. From the X-ray crystallography structures of BsPFK, one can identify an extensive hydrogen-bonding network that stretches through the region between the allosteric site and the closest active site that are roughly 22 Å apart. The allosteric coupling between these sites has been previously shown to make the largest contribution to the overall heterotropic allosteric coupling free energy in BsPFK [18]. We recently probed the role of the residues in this region in the allosteric interaction by examining the influence of 3 chimeric substitutions on the allosteric coupling in PFK from the extreme thermophile Thermus thermophilus (TtPFK) [20]. Interestingly, restoring the entire network of hydrogen-bonded residues apparently linking the 2 sites enhanced the strength of the allosteric communication in TtPFK to levels comparable to, or even greater than, those of BsPFK. However, this overall enhancement was achieved as the sum of enhancements (in free energy terms) realized from each modification individually suggesting that the basis of the interaction is derived from properties that are more complex than a single, continuous chain of interacting residues might suggest. One possibility is that it is the ligand binding perturbations of the thermodynamic stability of the protein structure in this region that are important so that each amino acid substitution can influence the overall coupling essentially independently without the ‘all or none’ feature that a quasi-mechanical linkage would require. To further probe the relationship between the structuralproperties in this region and the strength of allosteric coupling, we investigated the sensitivity of the allosteric behavior of BsPFK to 3 isoleucine to valine substitutions at 3 different positions in this general region. The substitution effectively removes only a single methylene group, thus creating a small cavity at each of the positions. In this way we intended to modestly perturb the configurational entropy in the immediate vicinity of each substitution without otherwise altering the structure of the protein to a significant extent. We have previously observed that the coupling free energy between PEP and Fru-6-P in BsPFK, which quantitatively describes both the nature and the magnitude of the allosteric effect, is dominated by its constituent entropy component [21]. We have also discussed previously that ligand-induced perturbations in configurational degeneracy and/or protein dynamics may be a major cause of this type of allosteric behavior [22,23].
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کلمات کلیدی:
Enhancing Allosteric Inhibition in Thermus ... - ACS Publications pubs.acs.org/doi/abs/10.1021/bi501127a by MS McGresham - 2015 - Cited by 3 - Related articles Dec 22, 2014 - Despite the fact that the allosteric activator of the bacterial PFK, MgADP, ... small cavities on the allosteric inhibition of phosphofructokinase from ... Equilibrium Binding Studies of a Tryptophan-Shifted Mutant of ... pubs.acs.org/doi/abs/10.1021/bi002448i by MR Riley-Lovingshimer - 2001 - Cited by 17 - Related articles Feb 8, 2001 - Allosteric Regulation in Phosphofructokinase from the Extreme ... small cavities on the allosteric inhibition of phosphofructokinase from Bacillus ... Kinetic Characterisation of Phosphofructokinase Purified from Setaria ... https://www.hindawi.com/journals/er/2011/939472/ by B Sharma - 2011 - Cited by 10 - Related articles Jun 28, 2011 - S. cervi PFK, when assayed at inhibitory concentration of ATP (>0.1 mM), ... PFK has served as a model in studies of allosteric regulation of enzymes. ... filarial parasite, dwelling in the intraperitoneal cavity and lymphatics, ... Phosphofructokinase 1 - Wikipedia https://en.wikipedia.org/wiki/Phosphofructokinase_1 Jump to Regulation - PFK1 is allosterically inhibited by high levels of ATP but AMP reverses the inhibitory action of ATP. Therefore, the activity of the ... Enhancing Allosteric Inhibition in Thermus thermophilus ... dx.doi.org/10.1021/bi501127a Dec 22, 2014 - From the crystal structures of Bacillus stearothermophilus PFK (BsPFK) ... The effect of introducing small cavities on the allosteric inhibition of ... Mechanisms of Cooperativity and Allosteric Regulation in Proteins https://books.google.com/books?isbn=0521386489 Max F. Perutz - 1990 - Science Phosphorylase is a more complex allosteric system than either haemoglobin or phosphofructokinase, because both a and b can take up at least two alternative ... [PDF]Allosteric regulation of mammalian fructose-1,6-bisphosphatase lib.dr.iastate.edu/cgi/viewcontent.cgi?article=4131&context=etd by Y Gao - 2013 - Related articles 71. Chapter IV. Linkage of Central Cavity to Synergism in AMP/Fructose 2,6- .... inhibitors for FBPase, while both serve as activators for PFK (6-12). During ...
