AndrewMcCaddon, Honorary Research Fellow, University of Wales College of Medicine[email protected]
Bjorn Regland, Peter Hudson, Gareth Davies.
Submitted September 30, 2002
Fuchs, Schroecksnadel and Frick make the interesting and important
observation that oxidative stress may have an additional impact on the
methionine synthase reaction by irreversibly oxidizing methyl-folate. We
agree that this would contribute to methionine synthase inactivation.
Following our publication, we learned that the
zinc site in methionine synthase, essential for binding and activating
homocysteine, might also be oxidized. Current experiments in E.coli
indicate that this site is readily oxidized on treatment of cells to
induce oxidative stress [1].
It seems likely that, for a variety of reasons, the methionine
synthase reaction will be physiologically compromised by oxidative stress.
The differential effects of such stress on this enzyme and cystathionine
beta synthase may explain the observed age-related decline in
methionine synthase activity and the switch from methionine conservation
to transsulfuration with aging [2]. Tissues without an alternative means
of metabolizing homocysteine will be particularly affected by such stress.
Their consequent increased cellular export of homocysteine might
contribute to elevated plasma levels.
Neurones and vascular endothelium both lack an intact
transsulfuration pathway and also lack the B12 and folate independent
enzyme betaine:homocysteine methyltransferase. Homocysteine levels in
these tissues should therefore prove to be an excellent marker of
oxidative stress. Rather than constituting a “risk-factor” for vascular
disease, dementia and other neurological conditions, elevated plasma
homocysteine might best be considered a “risk-marker” signifying the
effects of oxidative stress in such diseases.
1) E. Manning and R. G. Matthews, unpublished data.
2) J.Finkelstein. Regulation of Homocysteine Metabolism. In: Carmel R,
Jacobsen DW, eds. Homocysteine in Health and Disease. Cambridge University
Press, 2001: 92-99.
Fuchs, Schroecksnadel and Frick make the interesting and important observation that oxidative stress may have an additional impact on the methionine synthase reaction by irreversibly oxidizing methyl-folate. We agree that this would contribute to methionine synthase inactivation. Following our publication, we learned that the zinc site in methionine synthase, essential for binding and activating homocysteine, might also be oxidized. Current experiments in E.coli indicate that this site is readily oxidized on treatment of cells to induce oxidative stress [1].
It seems likely that, for a variety of reasons, the methionine synthase reaction will be physiologically compromised by oxidative stress. The differential effects of such stress on this enzyme and cystathionine beta synthase may explain the observed age-related decline in methionine synthase activity and the switch from methionine conservation to transsulfuration with aging [2]. Tissues without an alternative means of metabolizing homocysteine will be particularly affected by such stress. Their consequent increased cellular export of homocysteine might contribute to elevated plasma levels.
Neurones and vascular endothelium both lack an intact transsulfuration pathway and also lack the B12 and folate independent enzyme betaine:homocysteine methyltransferase. Homocysteine levels in these tissues should therefore prove to be an excellent marker of oxidative stress. Rather than constituting a “risk-factor” for vascular disease, dementia and other neurological conditions, elevated plasma homocysteine might best be considered a “risk-marker” signifying the effects of oxidative stress in such diseases.
1) E. Manning and R. G. Matthews, unpublished data.
2) J.Finkelstein. Regulation of Homocysteine Metabolism. In: Carmel R, Jacobsen DW, eds. Homocysteine in Health and Disease. Cambridge University Press, 2001: 92-99.