Wednesday, June 3, 2009

New anti-ageing strategy on course: Kinetik Isotope Effect vs. ROS

Oxford-based researcher Mikhail Shchepinov noticed that ROS oxidize cellular substrates by a mechanism typically involving hydrogen abstraction in a rate-limiting step. Through his university background in chemical kinetics, Shchepinov also knew about the effect of an isotope substitution on a rate of chemical transformation. The strength of a covalent bond is subtly influenced by the atomic masses at either end of the bond: heavier isotopes form stronger bonds than light isotopes of the same elements, and so reactions involving the breaking of those bonds proceed more slowly. For example, hydrogen comes in two stable isotopes, the common ‘light’ hydrogen isotope (H) and its twice-heavier sibling, deuterium (D). The C–D bond is significantly stronger than the C–H bond, and therefore a cleavage of the former bond will occur several times more slowly than the corresponding cleavage of the latter bond. The common ‘light’ carbon atom 12C of the C–H bond can also be substituted for a heavier, stable 13C isotope, but the bond-cleavage-rate decrease will be smaller than that involving substitution of H for D because 13C is only 8% heavier than 12C. This is called the kinetic isotope effect (KIE).

Shchepinov's idea is to use the KIE to make proteins, nucleic acids and lipids more resistant to ROS damage. It is summarized as follows: replace all ‘light’ atoms at the ROS-targeted sites of biomolecules with their heavier isotopes, which should evidently be both non-radioactive (stable) so as not to damage the cell and non-exchangeable with the intracellular environment to avoid their loss via exchange with normal ‘light’ isotopes. Besides non-radioactive D and 13C, stable 15N and 18O ‘heavy’ isotopes can also be used to take the place of common ‘light’ nitrogen and oxygen constituents of biomolecules. Note that such isotopic ‘make-up’ will not change the chemical nature of the compounds: the bonding structure of isotopical ‘twins’ will be identical, and their chemistry will basically be similar. However, the heavier sibling will be less reactive. Also note that even if the ‘heavy’ isotope is not a part of the bond that is cleaved by ROS, a small decrease in the oxidation rate, known as a secondary KIE, can nevertheless usually be observed.

Vadim V. Demidov (2007) Heavy isotopes to avert ageing?
Trends in Biotechnology, Volume 25, Issue 9, September 2007, Pages 371-375

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