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A Caenorhabditis elegans ortholog of human selenium-binding protein 1 is a pro-aging factor protecting against selenite toxicity.

ABSTRACT: Human selenium-binding protein 1 (SELENBP1) was originally identified as a protein binding selenium, most likely as selenite. SELENBP1 is associated with cellular redox and thiol homeostasis in several respects, including its established role as a methanethiol oxidase that is involved in degradation of methanethiol, a methionine catabolite, generating hydrogen sulfide (H2S) and hydrogen peroxide (H2O2). As both H2S and reactive oxygen species (such as H2O2) are major regulators of Caenorhabditis elegans lifespan and stress resistance, we hypothesized that a SELENBP1 ortholog in C. elegans would likely be involved in regulating these aspects. Here we characterize Y37A1B.5, a putative selenium-binding protein 1 ortholog in C. elegans with 52% primary structure identity to human SELENBP1. While conferring resistance to toxic concentrations of selenite, Y37A1B.5 also attenuates resistance to oxidative stress and lowers C. elegans lifespan: knockdown of Y37A1B.5 using RNA interference resulted in an approx. 10% increase of C. elegans lifespan and an enhanced resistance against the redox cycler paraquat, as well as enhanced motility. Analyses of transgenic reporter strains suggest hypodermal expression and cytoplasmic localization of Y37A1B.5, whose expression decreases with worm age. We identify the transcriptional coregulator MDT-15 and transcription factor EGL-27 as regulators of Y37A1B.5 levels and show that the lifespan extending effect elicited by downregulation of Y37A1B.5 is independent of known MDT-15 interacting factors, such as DAF-16 and NHR-49. In summary, Y37A1B.5 is an ortholog of SELENBP1 that shortens C. elegans lifespan and lowers resistance against oxidative stress, while allowing for a better survival under toxic selenite concentrations.

SUBMITTER: Kohnlein K

PROVIDER: S-EPMC6812014 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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A Caenorhabditis elegans ortholog of human selenium-binding protein 1 is a pro-aging factor protecting against selenite toxicity.

Köhnlein Karl K Urban Nadine N Guerrero-Gómez David D Steinbrenner Holger H Urbánek Pavel P Priebs Josephine J Koch Philipp P Kaether Christoph C Miranda-Vizuete Antonio A Klotz Lars-Oliver LO

Redox biology 20190911

Human selenium-binding protein 1 (SELENBP1) was originally identified as a protein binding selenium, most likely as selenite. SELENBP1 is associated with cellular redox and thiol homeostasis in several respects, including its established role as a methanethiol oxidase that is involved in degradation of methanethiol, a methionine catabolite, generating hydrogen sulfide (H2S) and hydrogen peroxide (H2O2). As both H2S and reactive oxygen species (such as ...[more]

PMID: 31557719

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Project description:BackgroundChagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds.MethodsTrypanocidal activity: Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC50). Toxicity assays: Lethal dose 50% (LD50) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure. Structure-activity relationship: A classificatory model was built using 3D descriptors.ResultsTwo of these coumarins demonstrated near equipotency to Nifurtimox (IC50 = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC50 = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC50 = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds.ConclusionTwo coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs.

Dataset Information

A Caenorhabditis elegans ortholog of human selenium-binding protein 1 is a pro-aging factor protecting against selenite toxicity.

Publications

A Caenorhabditis elegans ortholog of human selenium-binding protein 1 is a pro-aging factor protecting against selenite toxicity.

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