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Assembly of the bacterial cell wall requires not only the biosynthesis of cell wall components, but also the transport of these metabolites to the cell exterior for assembly into polymers and membranes required for bacterial viability and virulence. LprG is a cell wall protein that is required for the virulence of Mycobacterium tuberculosis and is associated with lipid transport to the outer lipid layer or mycomembrane. Motivated by available co-crystal structures of LprG with lipids, we searched for potential inhibitors of LprG by performing a computational docking screen of ~250,000 commercially available small molecules. We identified several structurally related dimethylaminophenyl hydrazides that bind to LprG with moderate micromolar affinity and inhibit mycobacterial growth in a LprG-dependent manner. We found that mutation of F123 within the binding cavity of LprG conferred resistance to one of the most potent compounds. These findings provide evidence that the large hydrophobic substrate-binding pocket of LprG can be realistically and specifically targeted by small molecule inhibitors.
This article was published in the following journal.
Name: ACS infectious diseases
Vitamin E, which includes both tocopherols and tocotrienols, comprises lipid-soluble antioxidants that modulate lipid peroxidation. Recently, significant advances have been made in our understanding o...
Mycobacteria, including the infamous pathogen , are high-GC Gram-positive bacteria with a distinctive cell envelope. Although there is a typical inner membrane, the mycobacterial cell envelope is unus...
Developing protein tyrosine phosphatase-1B (PTP1B) inhibitors is an important strategy to treat type 2 diabetes mellitus (T2DM). Most existing ionic PTP1B inhibitors aren't of clinical useful due to t...
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Use of oral clarithromycin for treatment of chronic lung disease due to Mycobacterium avium-intracellulare and other non-tuberculous Mycobacteria
Current study evaluates the relationship between cell immunity and lipid transport systems in patients with severe bacterial infections (on the model of pneumonia, infective endocarditis, ...
The purpose of this study is to find out whether taking protease inhibitors (anti-HIV drugs) together with lipid-lowering drugs (drugs which lower the amount of fat in the blood) has an ef...
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Protein components on the surface of LIPOPROTEINS. They form a layer surrounding the hydrophobic lipid core. There are several classes of apolipoproteins with each playing a different role in lipid transport and LIPID METABOLISM. These proteins are synthesized mainly in the LIVER and the INTESTINES.
The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport.
An autosomal recessive disorder of lipid metabolism. It is caused by mutation of the microsomal triglyceride transfer protein that catalyzes the transport of lipids (TRIGLYCERIDES; CHOLESTEROL ESTERS; PHOSPHOLIPIDS) and is required in the secretion of BETA-LIPOPROTEINS (low density lipoproteins or LDL). Features include defective intestinal lipid absorption, very low serum cholesterol level, and near absent LDL.
A UBIQUITIN-like modifier protein that functions in AUTOPHAGOSOME formation, CYTOPLASM to VACUOLE transport, MITOPHAGY, and nucleophagy. Conjugation with ATG5 PROTEIN or ATG10 is essential for its function. The ATG12-ATG5 conjugate acts as an E3 UBIQUITIN LIGASE-like enzyme for lipid modification of ATG8 FAMILY PROTEINS and their localization to vesicle membranes.
A perilipin that localizes to LIPID DROPLETS; CYTOPLASM; ENDOSOMES; and PLASMA MEMBRANE, especially in MACROPHAGES. It functions as a transporter of free fatty acids to lipid droplets to promote their biogenesis and growth. It is also required for the transport of the MANNOSE-6-PHOSPHATE RECEPTOR from endosomes to the TRANS-GOLGI NETWORK. Its structure consists of four helix bundles that interact with the hydrophobic lipid droplet surface.
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