scholarly journals Statin-activation of RyR1 is a class effect but separable from HMG-CoA reductase inhibition

2021 ◽  
Author(s):  
Chris Lindsay ◽  
Maria Musgaard ◽  
Angela Russell ◽  
Rebecca Sitsapesan
Keyword(s):  
Experimental Approach ◽  
Ryanodine Receptors ◽  
Structural Features ◽  
Hmg Coa Reductase ◽  
Patient Tolerance ◽  
Life Threatening ◽  
Cardioprotective Effects ◽  
Coa Reductase ◽  
Insight Into

Background and purpose Statins, inhibitors of HMG-CoA reductase, are mainstay treatment for hypercholesterolemia. However, muscle pain and weakness prevent many patients from benefiting from their cardioprotective effects. We previously demonstrated that simvastatin activates skeletal ryanodine receptors (RyR1), an effect that could be important in initiating myopathy. We therefore investigated if RyR1 activation is a standard property of commonly-prescribed statins. Using a range of structurally-diverse statin analogues we examined structural features associated with RyR1 activation, aiming to identify statins lacking this property. Experimental Approach Compounds were screened for RyR1 activity utilising [H]ryanodine binding. Mechanistic insight into RyR1 activity was studied by incorporating RyR1 channels from sheep, mouse or rabbit skeletal muscle into bilayers. Key Results All UK-prescribed statins activated RyR1 at nanomolar concentrations. Cerivastatin, withdrawn from the market due to life-threatening muscle-related side effects, was more effective than currently-prescribed statins and possessed the unique ability to open RyR1 channels independently of cytosolic Ca. We synthesised the statin pharmacophore and it did not activate RyR1. We also identified five analogues retaining potent HMG-CoA reductase inhibition that inhibited RyR1 and four analogues that lacked the ability to activate RyR1. Conclusion and Implications That cervistatin activates RyR1 most strongly supports the hypothesis that RyR1 activation is implicated in statin-induced myopathy. Demonstrating that statin-regulation of RyR1 and HMG-CoA reductase are separable effects allows the role of RyR1 in statin-induced myopathy to be further elucidated by the tool compounds identified, thus paving the way for the development of effective cardioprotective statins with improved patient tolerance.

scholarly journals Chemical Phenotypes of the hmg1 and hmg2 Mutants of Arabidopsis Demonstrate the In-planta Role of HMG-CoA Reductase in Triterpene Biosynthesis

2007 ◽  
Vol 55 (10) ◽  
pp. 1518-1521 ◽  
Author(s):  
Kiyoshi Ohyama ◽  
Masashi Suzuki ◽  
Kazuo Masuda ◽  
Shigeo Yoshida ◽  
Toshiya Muranaka
Keyword(s):  
In Planta ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Triterpene Biosynthesis

scholarly journals An autonomous, but INSIG-modulated, role for the Sterol Sensing Domain in mallostery-regulated ERAD of yeast HMG-CoA reductase

2020 ◽  
pp. jbc.RA120.015910
Author(s):  
Margaret A Wangeline ◽  
Randolph Y Hampton
Keyword(s):  
Binding Site ◽  
Quaternary Structure ◽  
Limited Proteolysis ◽  
Hmg Coa Reductase ◽  
Coa Reductase ◽  
Level Analysis

HMG-CoA reductase (HMGR) undergoes feedback-regulated degradation as part of sterol pathway control. Degradation of the yeast HMGR isozyme Hmg2 is controlled by the sterol pathway intermediate GGPP, which causes misfolding of Hmg2, leading to degradation by the HRD pathway; we call this process mallostery. We evaluated the role of the Hmg2 sterol sensing domain (SSD) in mallostery, as well as the involvement of the highly conserved INSIG proteins. We show that the Hmg2 SSD is critical for regulated degradation of Hmg2 and required for mallosteric misfolding of GGPP as studied by in vitro limited proteolysis. The Hmg2 SSD functions independently of conserved yeast INSIG proteins, but its function was modulated by INSIG, thus imposing a second layer of control on Hmg2 regulation. Mutant analyses indicated that SSD-mediated mallostery occurred prior to and independent of HRD-dependent ubiquitination. GGPP-dependent misfolding was still extant but occurred at a much slower rate in the absence of a functional SSD, indicating that the SSD facilitates a physiologically useful rate of GGPP response, and implying that the SSD is not a binding site for GGPP. Non-functional SSD mutants allowed us to test the importance of Hmg2 quaternary structure in mallostery:  a non-responsive Hmg2 SSD mutant strongly suppressed regulation of a co-expressed, normal Hmg2. Finally, we have found that GGPP-regulated misfolding occurred in detergent-solubilized Hmg2, a feature that will allow next-level analysis of the mechanism of this novel tactic of ligand-regulated misfolding.

scholarly journals The Role of Microbiome in Cancer Cell Stimulation and Therapy

2021 ◽  
pp. 97-115
Author(s):  
Shahira Hassoubah
Keyword(s):  
Immune Response ◽  
Human Microbiome ◽  
Future Research ◽  
Published Data ◽  
Disease States ◽  
Life Threatening ◽  
Indigenous Microbiota ◽  
Symbiotic Microbiota ◽  
Insight Into

In recent times, the microbiome has been increasingly recognized as having a hand in various disease states that include cancer as a part. Our commensal and symbiotic microbiota, in addition to pathogens with oncogenesis features, have tumor-suppressive characteristics. Our nutrition and other environmental influences can modulate some microbial species representatives within our digestive system and other systems. The microbiota has recently shown a two-way link to cancer immunotherapy for both the prognosis and the therapeutic aspects. Preclinical results indicated that microbiota modification could be transformed into a novel technique to improve cancer therapy's effectiveness. This article aimed to review recent development in our understanding of the microbiome and its relationship to cancer cells and discuss how the microbiome stimulates cancer and its clinical and therapeutic applications. Such information was selected and extracted from the PubMed, Web of Science, and Google Scholar databases for published data from 2000 to 2020 using relevant keywords containing a combination of terms, including the microbiome, cancer, immune response, immune response, and microbiota. Finally, we concluded that studying the human microbiome is necessary because it provides a thorough understanding of humans' interaction and their indigenous microbiota. The microbiome provides useful insight into future research studies to optimize these species to fight life-threatening diseases such as cancer and has rendered the microbiome a successful cancer treatment strategy.

scholarly journals The role of conformational entropy in the determination of structural-kinetic relationships for helix-coil transitions

2017 ◽  
Author(s):  
Joseph F. Rudzinski ◽  
Tristan Bereau
Keyword(s):  
Simulation Models ◽  
Structural Features ◽  
Coarse Grained ◽  
Kinetic Properties ◽  
Conformational Entropy ◽  
Peptide Backbone ◽  
The Relationship ◽  
Insight Into

Coarse-grained molecular simulation models can provide significant insight into the complex behavior of protein systems, but suffer from an inherently distorted description of dynamical properties. We recently demonstrated that, for a heptapeptide of alanine residues, the structural and kinetic properties of a simulation model are linked in a rather simple way, given a certain level of physics present in the model. In this work, we extend these findings to a longer peptide, for which the representation of configuration space in terms of a full enumeration of sequences of helical/coil states along the peptide backbone is impractical. We verify the structural-kinetic relationships by scanning the parameter space of a simple native-biased model and then employ a distinct transferable model to validate and generalize the conclusions. Our results further demonstrate the validity of the previous findings, while clarifying the role of conformational entropy in the determination of the structural-kinetic relationships. More specifically, while the global, long timescale kinetic properties of a particular class of models with varying energetic parameters but approximately fixed conformational entropy are determined by the overarching structural features of the ensemble, a shift in these kinetic observables occurs for models with a distinct representation of steric interactions. At the same time, the relationship between structure and more local, faster kinetic properties is not affected by varying the conformational entropy of the model.

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