Adverse Impact of Aminoglycosides on Selenoprotein Biosynthesis

• Applicant: Dr. Kostja Renko
• Subject Area: Endocrinology, Diabetology, Metabolism ; Nutritional Sciences
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 244526763

Despite of their severe side effects, aminoglycosides (AG) are used in the treatment of life-threatening bacterial infections. AG provoke misreading during mRNA translation in prokaryotes. To a lesser extent, this disturbance of translation also affects the treated patient. Stop codons are misinterpreted and overread by insertion of additional amino acids. This side effect might be of special pathophysiological relevance for the synthesis of selenoproteins, because their essential selenocystein (SeCys) is coded by the UGA codon. UGA therefore serves as Stop- as well as SeCys-codon in the human. The AG-induced misinterpretation of the UGA-codon and inclusion of a wrong amino acid into their primary structure will most often lead to an inactive selenoenzyme. In all characterized selenoproteins with enzymatic activity identified thus far, SeCys is part of the active center and replacement by other amino acids leads to partial of complete loss-of-function. The consequences of a disturbed selenoprotein biosynthesis are documented by various mouse models as well as human patients with a heritable defect in an essential factor for selenoprotein biosynthesis (OMIM: 607693).In mammals Selenoprotein P (SEPP1), which contains up to ten SeCys, has a prominent role as a liver-derived selenium transporter. Our preliminary data provide solid evidence for severe interference of AG with biosynthesis and Se-content of SEPP1, leading to the synthesis of a Se-depleted variant. This secreted Se-depleted SEPP1 might serve as a direct competitor for the receptor-mediated uptake of its own physiological, Se-containing entity into target organs. A competition would therefore lead to a Se-deficiency within the SEPP1-target cells (e.g. endocrine glands, the CNS and the kidneys) and might, in consequence, amplify side effects of AG. All selenoproteins (e.g. glutathione-peroxidases, thioredoxin-reductases, iodothyronine-deiodinases) might therefore be affected on two different levels. First of all, AG might interfere with the biosynthesis of each selenoenzyme, secondary by reduced Se-supply via Se-depleted SEPP1. Therefore the question arises, if, and to what extend Se-supplementation could prevent these side effects.The project will include testing of various AG used in the clinics (Gentamycin, Tobramicin, Amikacin) in established cell culture models upon their influence on activity and expression of various selenoproteins. Physiological consequences will be analyzed in related mouse models with specific changes in Sepp1-expression and compared to the corresponding in vitro results.This project will provide the missing detailed description of AG-specific effects on Se-metabolism. Furthermore it will evaluate Se-supplementation during AG-treatment as a therapeutic alternative, reducing AG-induced side effects.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Lutz Schomburg