http://www.chemistrymag.org/cji/1999/011006le.htm |
Dec.31,
1999 Vol.1 No.1 P.6 Copyright |
Protein radical mechanism in bovine
spongiform encephalopathies (BSE) and Creutzfeldt-Jakob disease (CJD)
Yang Chiming
(Institute for Life Science & Health and University of California, San Diego, CA
92039, USA)
Received
Nov. 17, 1999
The intriguing features of the transmissible infectious agent in prions have received
world-wide concern in the past few years(1). Consider the importance of oxygen in
the brains of mammals, based on the previously unraveled feature of prion particles and
prion disease, in the Spring of 1999 I made a suggestion that protein radicals produced
from oxidative damage to proteins can likely be responsible for the transmissible
infectivity (2), although the details of the protein free radical chemistry-based
pathogenic mechanism remain to be further investigated.
Oxidative damage to biomacromolecules has long been suspected to be
central to the etiology of many diseases in mammalian species (3,4), and it is not
unfamiliar for free radical biochemists that a protein radical could be a
long-lived, sequence-specific and transmissible initiator for a chain propagation
process. But why a protein radical mechanism has been ignored for almost half a
century? In addition to the fact that detailed free radical chemistry mechanism is only
familiar to very few chemists, I summarize here several other points, which might be
considered for interdisciplinary scientists who may have difficulties in understanding the
enigma.
1. For science history reasons, it is virologists?obligation to search for new
viruses and virus-associated nucleic acids, nevertheless there are always difficulties in
searching for new viruses;
2. Complexity in both the investigation into neuron systems and in the study of
infectious diseases. Besides, technical problems exists, for example, whether
Edman sequencing procedure is able to tell unambiguously newly-formed covalent bonds in a
free radical-damaged protein molecule, and unfortunately, damaged protein molecules
have not been widely analyzed by Edman-degradation sequencing. Meanwhile, electrospray
ionization-mass spectroscopy was not developed until late 1980's, it was unclear whether
its accuracy was high enough to reveal a new covalent bond in a modified protein molecule
in early 1990's;
3. There was a relative isolation of biophysical study from biochemistry, and
biophysical study of protein folding has so far been the major focus in our modern
molecular biology;
4. Research on protein radical biochemistry is still at its infancy stage;
5. There is still no clear definition for a subviral pathogen, and it is a big
concept barrier whether a protein radical or protein molecule can be
recognized as a subviral pathogen;
6. Chemistry basis of genetic disease is much far from a well-recognized
subject and molecular genetics has long been believed to be the ultimate basis of genetic
diseases;
7. A free radical mechanism is sketchy in the life science research horizon, for
example, although free radical damage has been widely implicated in aging, DNA damage,
cancer and Alzheimer's disease", evidence still looks sketchy and conclusive evidence
is difficult to obtain;
8. A concept of "molecular replication" still remains to be clearly
defined.
REFERENCES
[1] Caughey B, Chesebro B. Trends Cell Biol., 1997, 7: 56-62.
[2] Yang C M. Chemistry Online (Huaxue Tongbao), 1999, (13): 86. (http://www.chemistrymag.org/col/1999/c99086.htm
)
[3] Yatin S M, Aksenov M, Butterfield D A. Neurochemical Chemical Research in
Toxicology, 1999, 24: 427-435.
[4] Stadtman E R. Annu. Rev. Biochem., 1993, 62: 797-821.