A strong developmental isotope effect in Caenorhabditis elegans induced by 5,5-deuterated lysine.
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.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
Tatyana V
TV
Korneenko
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia. korn@mail.ibch.ru.
Nikolay B
NB
Pestov
Institute of Physical Organic Chemistry, Minsk, Belarus.
Alaksiej L
AL
Hurski
Institute of Physical Organic Chemistry, Minsk, Belarus.
Artsiom M
AM
Fedarkevich
Institute of Physical Organic Chemistry, Minsk, Belarus.
Vadim V
VV
Shmanai
Dell Pediatric Research Institute, University of Texas at Austin, Austin, TX, USA.
J Thomas
JT
Brenna
Retrotope, Inc., Los Altos, CA, USA. misha@retrotope.com.
Mikhail S
MS
Shchepinov
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003903:Deuterium / Q000378:metabolism*; D004435:Eating; D004926:Escherichia coli / Q000737:chemistry / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008239:Lysine / Q000138:chemical synthesis / Q000378:metabolism*; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013696:Temperature
D029742:Caenorhabditis elegans Proteins; D034741:RNA, Small Interfering; D003903:Deuterium; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D008239:Lysine
Development; Isotope effect; Lysine; Lysyl-hydroxylase