Wednesday, June 24, 2009

Response to Zhang: another trick of heavy isotopes

Deuterium cannot be kept for long enough at
exchangeable DNA sites to achieve this desired effect in
vivo because it will readily (within a few minutes) be
replaced by hydrogen atoms from normal water, the major
component of live cells, owing to fluctuational openings
of DNA base pairs (DNA ‘breathing’). Otherwise,
normal water would have to be almost completely replaced
by heavy water, which is not possible owing to the
known lethal toxicity of heavy water for mammals at
concentrations >35%. This was the reason that high
KIE was only observed in the condensed phase or in waterfree
solutions whereas even traces of natural water basically
abolished this effect.
For this reason, to achieve the goal of reducing the
amount of unfavorable tautomers it was suggested that
deuterium be placed at non-exchangeable sites of DNA
purines and pyrimidines. In this case, other heavy
isotopes can also be used for KIE (Figure).

caution should be exercised in choosing sites for isotopic
replacement because certain studies estimated an unusually
highamount of unfavorable tautomers in tRNAwhen
the natural 14N isotope was completely replaced with its
heavier 15Nsubstitute.Note that thishighamount of
unfavorable tautomers exceeds the amount of mutationcausing
tautomer of a highly mutagenic analog of cytosine. It is noteworthy that isotopic changes in non-exchangeable
DNA sites might reduce the level of age-related
mutations, including epigenomic modifications, by other
mechanisms too.

Vadim V. Demidov
Trends in Biotechnology
Volume 26, Issue 3, March 2008

No comments:

Post a Comment