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Paul Thornalley

Research summary

My main research goal is to study and model the life-essential, protective function of the glyoxalase system and manipulate it for improved health and treatment of disease. The glyoxalase system consists of two enzymes, glyoxalase-1 (Glo1) and glyoxalase-2, and a catalytic amount of reduced glutathione in the cytosol of all cells. Glo1 catalyses the removal of the reactive dicarbonyl metabolite, methylglyoxal. It thereby suppresses methylglyoxal modification of protein and DNA to low, tolerable levels. The major methylglyoxal-derived protein and DNA adducts are arginine-derived hydroimidazolone MG-H1 and deoxyguanosine-derived imidazopurinone MGdG, respectively. Methylglyoxal is mainly formed by trace non-enzymatic degradation of triosephosphates. Its formation is thereby unavoidable in the human body. Abnormal accumulation of methylglyoxal is called “dicarbonyl stress”. Glo1 expression is increased by transcription factor Nrf2 binding to an antioxidant response element in the GLO1 gene.

Functional genomics studies in C elegans have shown that Glo1 is a determinant of lifespan. Studies in mice have shown Glo1 is influential factor in metabolic, vascular and renal health with overexpression of Glo1 preventing obesity, insulin resistance and type 2 diabetes, vascular complications of diabetes, cardiovascular disease and renal disease. In non-malignant states Glo1 is a tumour suppressor whereas in cancer, Glo1 overexpression causes multidrug resistance.

My team has a first-in-class pharmaceutical, a Glo1 inducer, in development for treatment of complications of obesity, diabetes and renal failure – at clinical trial Phase 2 readiness. Further pre-clinical studies focus on mechanism of Nrf2 activation, induction of Glo1 expression (and other cytoprotective genes) and therapeutic efficacy and related biomarkers.

Cell permeable Glo1 inhibitors are also in development for treatment of drug-resistant tumours – particular breast and lung cancer. Pre-clinical studies focus on improved inhibitor delivery, metabolic analysis and modelling of the glyoxalase system in tumours to identify biomarkers of tumour sensitivity and tumour-type focus for treatment development.

Selected publications:

  • Bierhaus, A., Stoyanov, S., Fleming, T., Sauer, S.K., Leffler, A., Babes, A., Kichko, T.I., Neacsu, C., Konrade, I., Pirags, V., Lukic, I.K., Morcos, M., Dehmer, T., Rabbani, N., Thornalley, P.J., Edelstein, D., Nau, C., Forbes, J., Stern, D.M., Cooper, M.E, Humpert, P.M., Brownlee, M., Reeh, P. and Nawroth, P.P. (2012) Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nature Medicine 18, 926–933.
  • Rabbani, N. and Thornalley, P.J. (2014) Measurement of methylglyoxal by stable isotopic dilution analysis LC-MS/MS with corroborative prediction in physiological samples. Nature Protocols 9, 1969 – 1979.
  • Xue, M., Momiji, H., Rabbani, N., Barker, G., Shmygol, A., Bretschneider, T., Rand, D.A. and Thornalley, P.J. (2015) Frequency modulated translocational oscillations of Nrf2 mediate the ARE cytoprotective transcriptional response. Antioxidants & Redox Signalling 23, 613 - 629.
  • Rabbani, N. and Thornalley, P.J. (2015) Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease. Biochem. Biophys. Res. Commun. 458, 221-226, 2015.