Rabbani, Naila, Xue, Mingzhan and Thornalley, Paul J. (2016) Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics. Glycoconjugates Journal, 33 . 513. doi:10.1007/s10719-016-9705-z ISSN 0282-0080.

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Abstract

The reactive dicarbonyl metabolite methylglyoxal (MG) is the precursor of the major quantitative advanced glycation endproducts (AGEs) in physiological systems - argininederived hydroimidazolones and deoxyguanosine-derived imidazopurinones. The glyoxalase system in the cytoplasm of cells provides the primary defence against dicarbonyl glycation by catalysing the metabolism of MG and related reactive dicarbonyls. Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. It is produced endogenously by increased formation and/or decreased metabolism of dicarbonyl metabolites. Dicarbonyl stress contributes to ageing, disease and activity of cytotoxic chemotherapeutic agents. It contributes to ageing through age-related decline in glyoxalase 1 (Glo1) activity. Glo1 has a dual role in cancer as a tumour suppressor protein prior to tumour development and mediator of multi-drug resistance in cancer treatment, implicating dicarbonyl glycation of DNA in carcinogenesis and dicarbonyl-driven cytotoxicity in mechanism of action of anticancer drugs. Glo1 is a driver of cardiovascular disease, likely through dicarbonyl stress-driven dyslipidemia and vascular cell dysfunction. Dicarbonyl stress is also a contributing mediator of obesity and vascular complications of diabetes. There are also emerging roles in neurological disorders. Glo1 responds to dicarbonyl stress to enhance cytoprotection at the transcriptional level through stress-responsive increase of Glo1 expression. Small molecule Glo1 inducers are in clinical development for improved metabolic, vascular and renal health and Glo1 inhibitors in preclinical development for multidrug resistant cancer chemotherapy.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
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
Library of Congress Subject Headings (LCSH):	Glycosylation, Glyoxalase , Obesity, Diabetes, Cancer, Cardiovascular system -- Diseases , Therapeutics
Journal or Publication Title:	Glycoconjugates Journal
Publisher:	Springer New York LLC
ISSN:	0282-0080
Official Date:	12 July 2016
Dates:	Date Event 12 July 2016 Available 10 June 2016 Accepted
Volume:	33
Article Number:	513
DOI:	10.1007/s10719-016-9705-z
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Date of first compliant deposit:	13 June 2016
Date of first compliant Open Access:	10 August 2016

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