scholarly journals The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour

2021 ◽  
Author(s):  
A. Sofia F. Oliveira ◽  
Deborah K. Shoemark ◽  
Amaurys Avila Ibarra ◽  
Andrew D. Davidson ◽  
Imre Berger ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Acid Site ◽  
Spike Protein

scholarly journals The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour

2021 ◽  
Author(s):  
Ana Sofia Oliveira ◽  
Deborah Shoemark ◽  
Amaurys Avila Ibarra ◽  
Andrew D. Davidson ◽  
Imre Berger ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Site ◽  
Acid Site ◽  
Host Cells ◽  
Spike Protein ◽  
Nonequilibrium Molecular Dynamics ◽  
Binding Motif ◽  
Fatty Acid Binding ◽  
Furin Cleavage Site ◽  
Fatty Acid Binding Site

The SARS-CoV-2 spike protein is the first contact point between the SARS-CoV-2 virus and host cells and mediates membrane fusion. Recently, a fatty acid binding site was identified in the spike (Toelzer et al. Science 2020). The presence of linoleic acid at this site modulates binding of the spike to the human ACE2 receptor, stabilizing a locked conformation of the protein. Here, dynamical-nonequilibrium molecular dynamics simulations reveal that this fatty acid site is coupled to functionally relevant regions of the spike, some of them far from the fatty acid binding pocket. Removal of a ligand from the fatty acid binding site significantly affects the dynamics of distant, functionally important regions of the spike, including the receptor-binding motif, furin cleavage site and fusion-peptide-adjacent regions. The results also show significant differences in behaviour between clinical variants of the spike: e.g. the D614G mutation shows a significantly different conformational response for some structural motifs relevant for binding and fusion. The simulations identify structural networks through which changes at the fatty acid binding site are transmitted within the protein. These communication networks significantly involve positions that are prone to mutation, indicating that observed genetic variation in the spike may alter its response to linoleate binding and associated allosteric communication.

scholarly journals Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands binding the Free Fatty Acid Pocket of SARS-CoV-2 Spike Protein

2020 ◽  
Author(s):  
Deborah Shoemark ◽  
Charlotte Colenso ◽  
Christine Toelzer ◽  
Kapil Gupta ◽  
Richard Sessions ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Site ◽  
Spike Protein ◽  
Fatty Acid Binding ◽  
Open Conformation ◽  
Interaction Interface ◽  
Approved Drugs ◽  
Dynamics Simulations ◽  
Fatty Acid Binding Site

<p>Following our recent identification of a fatty acid binding site in the SARS-CoV-2 spike protein (Toelzer <i>et al., Science</i> eabd3255 (2020)), we investigate the binding of linoleate and other potential ligands at this site using molecular dynamics simulations. The results support the hypothesis that linoleate stabilises the locked form of the spike, in which its interaction interface for the ACE2 receptor is occluded. The simulations indicate weaker binding of linoleate to the partially open conformation. Simulations of dexamethasone bound at this site indicate that it binds similarly to linoleate, and thus may also stabilize a locked spike conformation. In contrast, simulations suggest that cholesterol bound at this site may destabilize the locked conformation, and in the open conformation, may preferentially bind at an alternative site in the hinge region between the receptor binding domain and the domain below, which could have functional relevance. We also use molecular docking to identify potential ligands that may bind at the fatty acid binding site, using the Bristol University Docking Engine (BUDE). BUDE docking successfully reproduces the linoleate complex and also supports binding of dexamethasone at the spike fatty acid site. Virtual screening of a library of approved drugs identifies vitamins D, K and A, as well as retinoid ligands with experimentally demonstrated activity against SARS-CoV-2 replication <i>in vitro</i>, as also potentially able to bind at this site. Our data suggest that the fatty acid binding site of the SARS-CoV-2 spike protein may bind a diverse array of candidate ligands. Targeting this site with small molecules, including dietary components such as vitamins, which may stabilise its locked conformation and represents a potential avenue for novel therapeutics or prophylaxis for COVID-19.</p>

scholarly journals Fatty Acid Synthase inhibition prevents palmitoylation of SARS-CoV2 Spike Protein and improves survival of mice infected with murine hepatitis virus

2020 ◽  
Author(s):  
Minhyoung Lee ◽  
Michael Sugiyama ◽  
Katrina Mekhail ◽  
Elyse Latreille ◽  
Negar Khosraviani ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Neutralizing Antibodies ◽  
Fatty Acid Synthase ◽  
Hepatitis Virus ◽  
Spike Protein ◽  
Target Cells ◽  
Murine Hepatitis Virus ◽  
Cell Monolayers ◽  
Decoy Receptors ◽  
Protein Palmitoylation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the causative agent of COVID19 that has infected >76M people and caused >1.68M deaths. The SARS-CoV2 Spike glycoprotein is responsible for the attachment and infection of target cells. The viral Spike protein serves the basis for many putative therapeutic countermeasures including vaccines, blocking and neutralizing antibodies, and decoy receptors. Here we investigated the cytosolic domain of Spike and its interaction with the protein palmitoyltransferase ZDHHC5. The Spike protein is palmitoylated on multiple juxtamembrane cysteine residues conserved among coronavirus. Increased abundance of ZDHHC5 resulted in hyper-palmitoylation, while silencing of ZDHHC5 reduced the ability of the human CoV 229E to form viral plaques in cell monolayers. Inhibition of fatty acid synthase using the pharmacological inhibitor TVB-3166 eliminated palmitoylation of SARS-CoV2 Spike. Additionally, TVB-3166 attenuated plaque formation and promoted the survival of mice from a lethal murine CoV infection. Thus, inhibition of the Spike protein palmitoylation has the potential to treat SARS-CoV-2 and other CoV infections.

scholarly journals Frontispiz: Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS‐CoV‐2 Spike Protein

2021 ◽  
Vol 133 (13) ◽  
Author(s):  
Deborah K. Shoemark ◽  
Charlotte K. Colenso ◽  
Christine Toelzer ◽  
Kapil Gupta ◽  
Richard B. Sessions ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Molecular Simulations ◽  
Spike Protein ◽  
Acid Pocket

scholarly journals Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands of the Free Fatty Acid Pocket of the SARS‐CoV‐2 Spike Protein**

2021 ◽  
Author(s):  
Deborah K. Shoemark ◽  
Charlotte K. Colenso ◽  
Christine Toelzer ◽  
Kapil Gupta ◽  
Richard B. Sessions ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Molecular Simulations ◽  
Spike Protein ◽  
Acid Pocket

scholarly journals A DFT Study for Catalytic Deoxygenation of Methyl Butyrate on a Lewis Acid Site of ZSM-5 Zeolite

Catalysts ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1233
Author(s):  
Xiaobo Chen ◽  
Ruiying Li ◽  
Hao Yan ◽  
Yibin Liu ◽  
Chaohe Yang
Keyword(s):  
Fatty Acid ◽  
Lewis Acid ◽  
Acid Site ◽  
Activation Barrier ◽  
Lewis Acid Site ◽  
Fatty Acid Esters ◽  
Brönsted Acid ◽  
Methyl Butyrate ◽  
Catalytic Deoxygenation ◽  
Acid Esters

The catalytic deoxygenation mechanism of fatty acid esters on a Lewis acid site of ZSM-5 zeolite was elucidated via density functional theory (DFT) by using a methyl butyrate (MB) as the model compound for fatty acid esters. The configurations of the initial reactant, transition states, and products together with the activation barrier of each elementary reaction were determined. The activation barrier of different initial cracking reactions decreases in the order of α-C–C > β-C–C > α-C–O > β-C–O. The best reaction path for catalytic deoxygenation of methyl butyrate over Lewis acid site is CH3CH2CH2C(OCH3)=O⋯Lewis → CH3CH2⋯Lewis⋯C(=CH2)OCH3 → CH2=CH2 + CH3COOCH3 + Lewis. The oxygen of methyl butyrate is mainly removed as CO2, methyl acetate, formaldehyde, and butyraldehyde, while ethylene, propylene, and butane are the main hydrocarbon products. In addition, the group generated by cracking of methyl butyrate form a bond with the Lewis acid site, promoting the transformation between a Lewis acid and a Brønsted acid. The corresponding intermediates have a high single point energy, but the poor stability leads to further deoxygenation and cracking reactions. This work provides a theoretical basis for the modification in the number of Brønsted acid and Lewis acid sites in the ZSM-5 zeolite.

Engineering Arabidopsis long-chain acyl-CoA synthetase 9 variants with enhanced enzyme activity

2019 ◽  
Vol 476 (1) ◽  
pp. 151-164 ◽  
Author(s):  
Yang Xu ◽  
Kristian Mark P. Caldo ◽  
Roman Holic ◽  
Elzbieta Mietkiewska ◽  
Jocelyn Ozga ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Fatty Acid ◽  
Amino Acid ◽  
Amino Acid Residue ◽  
Acid Site ◽  
Amino Acid Site ◽  
Acyl Donor ◽  
Evolutionary Analysis ◽  
Chain Acyl ◽  
Long Chain

Abstract Long-chain acyl-CoA synthetase (LACS, EC 6.2.1.3) catalyzes the ATP-dependent activation of free fatty acid to form acyl-CoA, which, in turn, serves as the major acyl donor for various lipid metabolic pathways. Increasing the size of acyl-CoA pool by enhancing LACS activity appears to be a useful approach to improve the production and modify the composition of fatty acid-derived compounds, such as triacylglycerol. In the present study, we aimed to improve the enzyme activity of Arabidopsis thaliana LACS9 (AtLACS9) by introducing random mutations into its cDNA using error-prone PCR. Two AtLACS9 variants containing multiple amino acid residue substitutions were identified with enhanced enzyme activity. To explore the effect of each amino acid residue substitution, single-site mutants were generated and the amino acid substitutions C207F and D238E were found to be primarily responsible for the increased activity of the two variants. Furthermore, evolutionary analysis revealed that the beneficial amino acid site C207 is conserved among LACS9 from plant eudicots, whereas the other beneficial amino acid site D238 might be under positive selection. Together, our results provide valuable information for the production of LACS variants for applications in the metabolic engineering of lipid biosynthesis in oleaginous organisms.

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