Pathophysiological Consequences of Protein N-Homocysteinylation - Homocysteine in Protein Structure/Function and Human Disease - page 103

Chapter 6
Pathophysiological Consequences of Protein
N-Homocysteinylation
Elevated Hcy-thiolactone and N-Hcy-protein levels are found to be associated with
pathological conditions. For example, plasma Hcy-thiolactone and N-Hcy-protein
are elevated under conditions predisposing to atherothrombosis and neurological
abnormalities, such as caused by CBS or MTHFR deficiencies in humans [115] and
mice [113]. In humans, plasma Hcy-thiolactone levels are also associated with the
development and progression of vascular complications in diabetic patients [362],
whereas elevated N-Hcy-protein levels are associated with an increased risk of
heart disease [168]. Furthermore, Hcy-thiolactonase activity of PON1, which
protects against protein N-homocysteinylation in CBS-deficient patients [250],
also predicts cardiovascular disease in humans [269].
The sensitivity of mammalian cells and organisms to hyperhomocysteinemia
raises a broader question of mechanistic basis. On a molecular level, hyperhomo-
cysteinemia is known to activate the expression of genes that are under control of
signaling pathways that respond to a load in the endoplasmic reticulum (ER). These
include the Bip/GRP78 gene, encoding an ER chaperone [363]; CHOP/GADD153,
encoding a transcription factor implicated in cellular responses to ER stress
[364, 365]; and HERP, encoding a protein that may be involved in degradation of
misfolded ER proteins [366]. The cellular response to ER stress is known as the
unfolded protein response (UPR) and includes a conserved transcriptional adapta-
tion by which cell adjusts the biosynthesis of proteins involved in ER function to the
physiological demand. The UPR involves signaling pathways that monitor
the folding environment of the ER and transduce signals across the membrane to
the cytoplasm and nucleus [367, 368].
Relatively high (millimolar) concentrations of Hcy are required to activate the
UPR in ex vivo cultured cells. However, the activation of CHOP/GADD153 gene
expression increases in the liver of mice with diet-induced hyperhomocysteinemia
[369]. These findings suggest that ER dysfunction and UPR have a role in the
pathophysiology of hyperhomocysteinemia in intact organisms in vivo.
During the folding process, proteins form their globular native states in a manner
determined by their primary amino acid sequence [231, 370]. Thus, small changes
in amino acid sequence caused by Hcy incorporation into protein have a potential to