Hyperhomocysteinemia was first associated with degenerative disease by observation of accelerated
arteriosclerosis in children with inherited disorders of
cystathionine synthase, methionine synthase, and methylene tetrohydrofolate
reductase. The metabolic blockade of
sulfate synthesis from
homocysteine thiolactone in malignant cells is ascribed to a deficiency of a chemopreventive derivative of
homocysteine thiolactone that occurs in normal cells. Its chemical structure was elucidated by the organic synthesis of
thioretinamide from
retinoic acid and
homocysteine thiolactone. Oxidation of the
sulfur atom of
homocysteine is inhibited in scorbutic guinea pigs, demonstrating ascorbate function in
sulfate synthesis from
homocysteine. Studies of
homocysteine metabolism in
protein energy malnutrition led to the conclusion that the biosynthesis of
thioretinamide from the
retinol of
transthyretin is catalyzed by dehydroascorbate and
superoxide generated from the
heme oxygenase group of
cystathionine synthase. Newly synthesized
thioretinamide is complexed with
cobalamin to form
thioretinaco, which is activated by
ozone and
oxygen to function as the active site of oxidative phosphorylation. In accordance with the trophoblastic theory of
cancer, pancreatic enzymes are believed to be oncolytic because they hydrolyze the homocysteinylated
proteins,
nucleic acids and
glycosaminoglycans of malignant tissues. The clonal selection of malignant cells that are deficient in the
heme oxygenase function of
cystathionine synthase produces cells dependent upon glycolysis for
ATP synthesis, since they are deficient in synthesis of
thioretinamide,
thioretinaco and
thioretinaco ozonide. The vulnerable plaque of
arteriosclerosis originates from complexes of microbes with homocysteinylated
lipoproteins, obstructing vasa vasorum narrowed by endothelial dysfunction, causing arterial
ischemia, and intimal micro-
abscesses. Degenerative diseases may be ameliorated by a proposed therapeutic protocol of
thioretinamide with pancreatic
enzymes.