In living organisms,
proteins are progressively modified by spontaneous non-enzymatic reactions generating many post-translational modification derived products (PTMDPs) which exert deleterious effects and may be considered endogenous toxins in
diabetes mellitus and
chronic renal failure. Non-enzymatic glycation, which refers to the spontaneous binding of reducing
sugars to free amino groups, is increased in
diabetes mellitus because of
hyperglycemia and is amplified by oxidative processes ('glycoxidation'). Glycoxidation leads to the formation of '
advanced glycation end products' (AGEs), together with products of other oxidative pathways. AGEs alter tissue organization and cell-
protein interactions, mainly in the case of long-lived
extracellular matrix proteins, and interact with membrane receptors, among which RAGE (receptor of AGEs), a multiligand receptor which triggers intracellular signaling pathways stimulating inflammatory functions. Another major
protein modification, carbamylation, is increased in
chronic renal failure, which may occur during the course of
diabetes mellitus. Carbamylation is due to the binding of
isocyanic acid on the α-NH2 extremity of
proteins or
amino acids, or on ε-NH2
lysine groups, generating
homocitrulline, a potential
biomarker in
atherosclerosis.
Isocyanic acid is formed in vivo either by spontaneous dissociation of
urea or by
myeloperoxidase action on
thiocyanate. Carbamylated
proteins exhibit altered properties. For example, carbamylated
collagen is unable to stimulate oxidative functions of polymorphonuclear neutrophils but increases
matrix metalloproteinase-9 production by monocytes.
Lipoprotein functions are altered by carbamylation and may contribute to
atherogenesis. Thus, the numerous PTMDPs may be considered both hallmarks of
protein damage in
chronic diseases and endogenous toxins acting at the molecular and cellular levels.