Journal
BIOCHEMICAL SOCIETY TRANSACTIONS
Volume 42, Issue -, Pages 419-424Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BST20140008
Keywords
aging; cancer; chronic renal disease; diabetes; methylglyoxal; obesity
Categories
Funding
- Biotechnology and Biological Sciences Research Council
- Medical Research Council
- Wellcome Trust
- British Heart Foundation
- Cancer Research UK
- Juvenile Diabetes Research Fund
- British Council
- Biotechnology and Biological Sciences Research Council [BB/D006295/2] Funding Source: researchfish
- BBSRC [BB/D006295/2] Funding Source: UKRI
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Molecular, catalytic and structural properties of glyoxalase pathway enzymes of many species are now known. Current research has focused on the regulation of activity and expression of 6101 (glyoxalase I) and Glo2 (glyoxalase II) and their role in health and disease. Human 6101 has MRE (metal-response element), IRE (insulin-response element), E2F4 (early gene 2 factor isoform 4), AP-2 alpha (activating enhancer-binding protein 2 alpha) and ARE (antioxidant response-element) regulatory elements and is a hotspot for copy number variation. The human 6102 gene, HAGH (hydroxyacylglutathione hydrolase), has a regulatory p53-response element. Glo1 is linked to healthy aging, obesity, diabetes and diabetic complications, chronic renal disease, cardiovascular disease, other disorders and multidrug resistance in cancer chemotherapy. Mathematical modelling of the glyoxalase pathway predicts that pharmacological levels of increased 6101 activity markedly decrease cellular methylglyoxal and related glycation, and pharmacological 6101 inhibition markedly increases cellular methylglyoxal and related glycation. Glo1 inducers are in development to sustain healthy aging and for treatment of vascular complications of diabetes and other disorders, and cell-permeant Glo1 inhibitors are in development for treatment of multidrug-resistant tumours, malaria and potentially pathogenic bacteria and fungi.
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