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Dicarbonyl proteome and genome damage in metabolic and vascular disease
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Rabbani, Naila and Thornalley, Paul J. (2014) Dicarbonyl proteome and genome damage in metabolic and vascular disease. Biochemical Society Transactions, Volume 42 (Number 2). pp. 425-32. doi:10.1042/BST20140018
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Official URL: http://dx.doi.org/10.1042/BST20140018
Abstract
Methylglyoxal is a potent protein-glycating agent. It is an arginine-directed glycating agent and often modifies functionally important sites in proteins. Glycation forms mainly MG-H1 [Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine] residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis-MS/MS and also by immunoblotting with specific monoclonal antibodies. Methylglyoxal-modified proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation end-product in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and aging. Proteins susceptible to methylglyoxal modification with related functional impairment are called the DCP (dicarbonyl proteome). The DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and others. DCP component proteins are linked to mitochondrial dysfunction in diabetes and aging, oxidative stress, dyslipidaemia, cell detachment and anoikis and apoptosis. Methylglyoxal also modifies DNA where deoxyguanosine residues are modified to imidazopurinone MGdG {3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one} isomers. MGdG was the major quantitative adduct detected in vivo. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell-permeant glyoxalase I inhibitor. Glyoxalase I metabolizes >99% methylglyoxal and thereby protects the proteome and genome. Gene deletion of GLO1 is embryonically lethal and GLO1 silencing increases methylglyoxal concentration, MG-H1 and MGdG, premature aging and disease. Studies of methylglyoxal glycation have importance for human health, longevity and treatment of disease.
| Item Type: | Journal Article | ||||||
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | Biochemical Society Transactions | ||||||
| Publisher: | Portland Press Ltd | ||||||
| ISSN: | 0300-5127 | ||||||
| Official Date: | April 2014 | ||||||
| Dates: |
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| Volume: | Volume 42 | ||||||
| Number: | Number 2 | ||||||
| Page Range: | pp. 425-32 | ||||||
| DOI: | 10.1042/BST20140018 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access |
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