From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Tue Apr 29 2003 - 19:55:29 MDT
For many years I have always suspected there was a reason that
antioxidant vitamin supplements (Vit E, C, etc.) didn't extend
lifespan more. I ran across hints that various oxidized molecules
such as superoxide or hydrogen peroxide might be used as signal
molecules and the genetic program was designed to keep them
within certain ranges.
Well, now I finally have a concrete example of this. Others on
the list may have been more aware of this but I was not so I'm
sharing it.
These two articles from Science last week:
Wood ZA, Poole LB, Karplus PA.
Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling.
Science. 2003 Apr 25;300(5619):650-3.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12714747&dopt=Abstract
Woo HA, Chae HZ, Hwang SC, Yang KS, Kang SW, Kim K, Rhee SG.
Reversing the inactivation of peroxiredoxins caused by cysteine sulfinic acid formation.
Science. 2003 Apr 25;300(5619):653-6.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12714748&dopt=Abstract
make things *much* clearer.
It turns out there is a class of enzymes known as "peroxiredoxins" (which I didn't
even know existed back when I was "into" aging 7+ years ago) that are responsible
for keeping hydrogen peroxide (H2O2) at low levels. They have a well understood
catalytic mechanism. In their normal mechanism they allow the H2O2 to "oxidize"
one of the cysteine amino acids in the enzyme (forming Cys-S-OH, which they gets
by a hydrogen attached to another cysteine (H-S-Cys) to produce water (HOH and a
disulfied bond Cys-S-S-Cys), then the enzyme is regenerated by a disulfide reductase
returning the cysteines to their original states. One of the articles suggests
that this is the primary H2O2 management agent and that the glutathione/catalase
systems are only backups (that was an eye opener).
At any rate, it turns out that when the cell wants to use H2O2 as a "signaling"
molecule, the overproduction of H2O2 can overwhelm the peroxiredoxins such that
the catalytic cysteine becomes "over-oxidized" (becoming Cys--S-OOH instead of -S-OH)
and ceases to function as an enzyme that can remove H2O2. The cell has to do this
because if the peroxiredoxins eliminate all the H2O2 it cannot function as a signalling
molecule.
This differentiates higher level organisms from bacteria where the peroxiredoxins
do not have the same structure and do not appear to use H2O2 as a signaling molecule.
The bottom line from my perspective is that if the cell wants to use H2O2 as a
signaling molecule it will do so and taking all the Vitamin E and C in the world
isn't going to prevent that. (Which isn't to say that Vitamin E might be
highly useful to keep cholesterol from becoming oxidized and contributing to
the formation of plaques). It seems unlikely that antioxidants are going to
impact much on oxidative damage to DNA (and therefore cancer and some aspects
of aging).
Robert
This archive was generated by hypermail 2.1.5 : Tue Apr 29 2003 - 20:05:28 MDT