title: Post-translational modification derived products (PTMDPs): toxins in chronic diseases?
abstract: 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.
authors: Philippe
authors: P
authors: Gillery
authors: Stéphane
authors: S
authors: Jaisson
mesh_terms: D002219:Carbamates / Q000737:chemistry; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism*
chemical_list: D002219:Carbamates; D017127:Glycation End Products, Advanced; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011506:Proteins; D014118:Toxins, Biological