Protein damage in diabetes and uremia--identifying hotspots of proteome damage where minimal modification is amplified to marked pathophysiological effect.
Increased protein glycation, oxidation and nitration are found in diabetes and renal failure. Steady state levels of glycated, oxidized and nitrated proteins are generally low, yet often have significant physiological effects--particularly linked to development and progression of vascular complications, including often fatal cardiovascular disease. Identification of sites activated toward damaging modifications or 'hotspots' in functional domains within proteins appears key to assessing targets of functional impairment. Disease progression is likely linked to instances where change in low level of hotspot damage influences metabolic control or physiological function. Examples discussed are: type IV collagen modification leading to endothelial cell detachment and anoikis, mitochondrial protein modification leading to oxidative stress and apolipoprotein B100 modification in low density lipoprotein leading to vascular retention and atherosclerosis. The role of mathematical systems biology, bioinformatics and proteome dynamics in future investigations is discussed.
Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, UK. p.j.thornalley@warwick.ac.uk
Paul J
PJ
Thornalley
Naila
N
Rabbani
D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D020543:Proteome / Q000378:metabolism*; D014511:Uremia / Q000378:metabolism* / Q000473:pathology
D020543:Proteome; D009569:Nitric Oxide