Isoleucyl-tRNA synthetase as a target for antibiotic development

Kokić, Goran (2012) Isoleucyl-tRNA synthetase as a target for antibiotic development. Bachelor's thesis, Faculty of Science > Department of Biology.

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Abstract

Aminoacyl-tRNA synthetases (aaRS) are enzymes that produce aminoacylated tRNA molecules needed in protein biosynthesis. During independent evolution in three primary kingdoms; archaeal, bacterial and eukaryotic, some aaRS accumulated recognizable structural differences. Isoleucyl-tRNA synthetase (IleRS) is a good example of such divergent evolution. Shorter C-terminal domain of prokaryotic and eukaryotic mitochondrial IleRS contains cluster of four cysteine residues coordinating a zinc ion. In contrast, eukaryotic and archaeal orthologs possess longer C-terminal domain deprived of the zinc binding motif. Catalytic domain was shown to be much more conserved than the C-terminal domain. Nevertheless, selective inhibitors that discriminate between prokaryotic and eukaryotic catalytic domains have been discovered, revealing potential for drug design. Mupirocin, a natural product produced by Pseudomonas fluorescens, is a potent inhibitor of bacterial IleRS and the only antibiotic targeting this enzyme that is used in medical practice. It is restricted to topical use, given its lack of oral bioavailability. Mupirocin occupies enzyme´s active site by mimicking its natural substrates, L-isoleucine and ATP. When bound to IleRS, it prevents catalytic loop bearing conserved KMSKS signature motif to access the active site, representing additional inhibitory mechanism. Changes introduced in its chemical structure (modification of aminoacyl moiety and phosphate linker) provided much more potent analogs. Thiomarinol derivates, group of antibiotics closely related to mupirocin, exhibit even wider spectrum of activity and better oral bioavailability. Drug-targeting IleRSs are not being used only as antibacterial agents. Reveromycin A induces apoptosis specifically in osteoclasts, revealing its potential in treating bone disorders, including osteoporosis and osteolytic bone metastasis. Icofungipen inactivates eukaryotic IleRS and shows good results in treating dissseminated candidiasis and fungal CNS infection.

Item Type: Thesis (Bachelor's thesis)
Supervisor: Gruić Sovulj, Ita
Date: 2012
Number of Pages: 19
Subjects: NATURAL SCIENCES > Biology
Divisions: Faculty of Science > Department of Biology
Depositing User: Silvana Šehić
Date Deposited: 23 Oct 2014 11:49
Last Modified: 23 Oct 2014 11:49
URI: http://digre.pmf.unizg.hr/id/eprint/3146

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