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A strong developmental isotope effect in Caenorhabditis elegans induced by 5,5-deuterated lysine

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Abstract

Effects exerted by heavy isotope substitution in biopolymers on the functioning of whole organisms have not been investigated. We report on the decrease of permissive temperature of nematodes fed with bacteria containing 5,5-d2-lysine. We synthesized 5,5-dideuterolysine and, taking advantage of lysine being an essential amino acid, showed that C. elegans with modified lysine poorly develop from larvae into fertile adult hermaphrodites. This effect occurs only at high temperature within the permissible range for C. elegans (25 °C) and completely vanishes at 15 °C. The only known metabolic involvement of C5 in lysine is in post-translational modification through lysyl hydoxylases. Indeed, siRNA experiments showed that deficiency of let-268/plod lysyl-hydroxylase/glycosydase further amplifies the isotope effect making it apparent even at 20 °C, whereas control siRNAs as well as another lysyl-hydroxylase (psr-1/jmjdD) siRNA do not. We report for the first time that a site-specific deuteration may strongly affect the development of the whole animal organism especially under the conditions of deficiency of the corresponding enzyme. These findings provide the basis for our ongoing efforts to employ isotope effects for fine tuning of metabolic pathways to mitigate pathological processes.

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Abbreviations

IRMS:

Isotope ratio mass spectrometry

KIE:

Kinetic isotope effect

LOX:

Lysyl oxidase

PBS:

Phosphate buffered saline

PLOD:

Procollagen-lysine 5-dioxygenase

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Acknowledgements

We are grateful to S. Clarke and C. Kenyon for helpful advice. This work was supported by the Russian Foundation for Basic Research (Grant 16-04-00828), and MCB program of Russian Academy of Sciences.

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Authors and Affiliations

  1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia

    Tatyana V. Korneenko & Nikolay B. Pestov

  2. Institute of Physical Organic Chemistry, Minsk, Belarus

    Alaksiej L. Hurski, Artsiom M. Fedarkevich & Vadim V. Shmanai

  3. Dell Pediatric Research Institute, University of Texas at Austin, Austin, TX, USA

    J. Thomas Brenna

  4. Retrotope, Inc., Los Altos, CA, USA

    Mikhail S. Shchepinov

Authors
  1. Tatyana V. Korneenko
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  2. Nikolay B. Pestov
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  3. Alaksiej L. Hurski
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  4. Artsiom M. Fedarkevich
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  5. Vadim V. Shmanai
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  6. J. Thomas Brenna
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  7. Mikhail S. Shchepinov
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Corresponding authors

Correspondence to Nikolay B. Pestov or Mikhail S. Shchepinov.

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Conflict of interest

M. S. Shchepinov declares a competing financial interest as the Chief Scientific Officer of Retrotope, Inc.

Funding

This work was supported by the Russian Foundation for Basic Research (Grant 16-04-00828 to TVK) and MCB program of Russian Academy of Sciences (NBP).

Research involving human participants and/or animals

This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Korneenko, T.V., Pestov, N.B., Hurski, A.L. et al. A strong developmental isotope effect in Caenorhabditis elegans induced by 5,5-deuterated lysine. Amino Acids 49, 887–894 (2017). https://doi.org/10.1007/s00726-017-2386-5

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