Identification and characterization of sodium and chloride-dependent gamma-aminobutyric acid (GABA) transporters from eukaryotic pathogens as a potential drug target

ABSTRACTIron limitation and the expression of mycobactin and carboxymycobactin byMycobacterium tuberculosisare known. Here, we report how iron regulated the coordinate expression of these two siderophores and a 28-kDa cell wall-associated iron-regulated protein (Irep-28). Irep-28 is identified as the DNA-binding HU homologue HupB protein (hupB[Rv2986c]). Antibodies to this protein were detected in sera from tuberculosis patients. The location of the protein in the cell wall makes it a potential drug target.

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Medical Treatment of Echinococcus multilocularis and New Horizons for Drug Discovery: Characterization of Mitochondrial Complex II as a Potential Drug Target

Echinococcosis ◽

10.5772/intechopen.68565 ◽

2017 ◽

Cited By ~ 1

Author(s):

Shigehiro Enkai ◽

Kimitoshi Sakamoto ◽

Miho Kaneko ◽

Hirokazu Kouguchi ◽

Takao Irie ◽

...

Keyword(s):

Drug Discovery ◽

Medical Treatment ◽

Echinococcus Multilocularis ◽

Drug Target ◽

Potential Drug Target ◽

Potential Drug ◽

Mitochondrial Complex ◽

Complex Ii ◽

New Horizons

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Molecular Identification and Characterization of an Essential Pyruvate Transporter from Trypanosoma brucei

Journal of Biological Chemistry ◽

10.1074/jbc.m113.473157 ◽

2013 ◽

Vol 288 (20) ◽

pp. 14428-14437 ◽

Cited By ~ 14

Author(s):

Marco A. Sanchez

Keyword(s):

Trypanosoma Brucei ◽

Drug Target ◽

Life Cycle Stage ◽

Bloodstream Form ◽

Potential Drug Target ◽

High Affinity ◽

Physiological Relevance ◽

First Time ◽

Identification And Characterization

Pyruvate export is an essential physiological process for the bloodstream form of Trypanosoma brucei as the parasite would otherwise accumulate this end product of glucose metabolism to toxic levels. In the studies reported here, genetic complementation in Saccharomyces cerevisiae has been employed to identify a gene (TbPT0) that encodes this vital pyruvate transporter from T. brucei. Expression of TbPT0 in S. cerevisiae reveals that TbPT0 is a high affinity pyruvate transporter. TbPT0 belongs to a clustered multigene family consisting of five members, whose expression is up-regulated in the bloodstream form. Interestingly, TbPT family permeases are related to polytopic proteins from plants but not to characterized monocarboxylate transporters from mammals. Remarkably, inhibition of the TbPT gene family expression in bloodstream parasites by RNAi is lethal, confirming the physiological relevance of these transporters. The discovery of TbPT0 reveals for the first time the identity of the essential pyruvate transporter and provides a potential drug target against the mammalian life cycle stage of T. brucei.

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Isolation, purification and characterization of pyruvate kinase from Staphylococcus aureus : a potential drug target

The Journal of Clinical and Scientific Research ◽

10.15380/2277-5706.jcsr.12.019 ◽

2012 ◽

pp. 76-82

Author(s):

Venkatesh K ◽

◽

Srikanth L ◽

Swarupa V ◽

Yeswanth S ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Pyruvate Kinase ◽

Drug Target ◽

Potential Drug Target ◽

Potential Drug ◽

Purification And Characterization

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Search for Structural Basis of Interactions of Biogenic Amines with Human TAAR1 and TAAR6 Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms23010209 ◽

2021 ◽

Vol 23 (1) ◽

pp. 209

Author(s):

Anna V. Glyakina ◽

Constantine D. Pavlov ◽

Julia V. Sopova ◽

Raul R. Gainetdinov ◽

Elena I. Leonova ◽

...

Keyword(s):

Biogenic Amines ◽

Binding Sites ◽

Aminobutyric Acid ◽

Structural Basis ◽

Gamma Aminobutyric Acid ◽

Class A ◽

Trace Amine ◽

First Time ◽

Identification And Characterization

The identification and characterization of ligand-receptor binding sites are important for drug development. Trace amine-associated receptors (TAARs, members of the class A GPCR family) can interact with different biogenic amines and their metabolites, but the structural basis for their recognition by the TAARs is not well understood. In this work, we have revealed for the first time a group of conserved motifs (fingerprints) characterizing TAARs and studied the docking of aromatic (β-phenylethylamine, tyramine) and aliphatic (putrescine and cadaverine) ligands, including gamma-aminobutyric acid, with human TAAR1 and TAAR6 receptors. We have identified orthosteric binding sites for TAAR1 (Asp68, Asp102, Asp284) and TAAR6 (Asp78, Asp112, Asp202). By analyzing the binding results of 7500 structures, we determined that putrescine and cadaverine bind to TAAR1 at one site, Asp68 + Asp102, and to TAAR6 at two sites, Asp78 + Asp112 and Asp112 + Asp202. Tyramine binds to TAAR6 at the same two sites as putrescine and cadaverine and does not bind to TAAR1 at the selected Asp residues. β-Phenylethylamine and gamma-aminobutyric acid do not bind to the TAAR1 and TAAR6 receptors at the selected Asp residues. The search for ligands targeting allosteric and orthosteric sites of TAARs has excellent pharmaceutical potential.

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