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Carbohydrates are the primordial source of energy and carbon for certain unicellular organisms as well as for the complex mammalian brain and its synaptic functions [1]. However, for all these cells the degradation of carbohydrates poses several problems, e.g. the formation of toxic by-products such as the glycating electrophile methylglyoxal (MG, also named 2-oxo-propanal) or the excessive generation of lactic acid with ensuing pH change [2]. Under conditions of high carbon flux and under limited availability of NAD+, e.g. during anaerobic glycolysis [3], the triose phosphates dihydroxyacetone phosphate and glyceraldehyde-3-phosphate spontaneously decompose to MG, a compound known to contribute to the generation of advanced glycation endproducts (AGEs) [4] – with possibly irreversible damage to lipids, nucleic acids and proteins, in particular of mitochondria [5] – and to the induction of ubiquitin conjugates [6]. In a pathway with very high conservation during evolution, all these cells use the enzyme glyoxalase I (lactoylglutathione lyase) in the presence of glutathione (GSH) to convert MG into S-lactoyl-glutathione (SLG) and then use glyoxalase II (hydroxyacylglutathione hydrolase) to liberate D-lactate and glutathione. In spite of this toxicity of MG, some bacteria use the enzyme methylglyoxal synthase to generate MG, apparently to regulate carbon flux and growth rate [7]. Furthermore, the ratio between GSH and SLG in such bacteria modulates potassium efflux and intracellular acidification [8]. Acting as a signal initiator, MG activates the osmosensor Sln1, the HOG-MAP kinase cascade and the calcium(2+) signalling pathway in yeast [9]. In human cells, MG has a well established anti-proliferative effect in cancerous cells with enhanced glycolysis (Warburg-effect) [10, 11]. MG was recently reported to play a physiological role in the modulation of hypoxia-induced-factor-1α (HIF-1alpha) levels and thus in the modulation of the balance between anaerobic and aerobic bioenergetics [12]. Interestingly, an anxiety-suppressing effect of MG infusions into the brain was observed in mice [13]. And in patients with ditary dyskinesias, episodic disorders of spontaneous movement, it is now known that either defects in the cerebral glucose transport or defects in the putative neuronal SLG sensor protein MR-1 can be responsible for these symptoms [14,15]. These observations suggest that MG and SLG are not simply toxic by-products to be eliminated, but might play an important physiological function in bioenergetic signaling.

The role of glyoxalases for sugar stress and aging, with relevance for dyskinesia, anxiety, dementia and Parkinson's disease