Glyoxalase reaction

The factors leading to isoracemisation can lead to misinterpretation of isotope-ex-change experiments. The lack of exchange of the proton with solvent protons is classical evidence for hydride transfer in the Cannizzaro reaction and Meerwein-Pondorff-Verley reduction and in the rearrangements involved in steroid biosynthesis. For some time the lack of deuterium exchange in the glyoxalase reaction was attributed to a hydride-transfer mechanism (Eqn. 64). 

But we can assign to GSH more specific functions also. It participates in transpeptidations and oxidation reductions as well as in hydration-dehydration reactions. Perhaps this large variety of reactions has more in common than appears at first sight. Many of the transpeptidation reactions have been shown to occur with enzymes such as the cathepsins which require SH groups for activity. Hydrolysis of thiol esters by papain has been recently demonstrated (66) and the formation of thiol esters as intermediates in transpeptidations still remains to be explored. In the glyoxalase reaction the actual substrate may be the hydrated form of the aldehyde, in which case the reaction mechanism would be one of dehydration and hydrolysis rather than of a hydrogen shift. Thus the reaction will bear some similarity to the aconitase reaction which is stimulated by SH compounds and ferrous ions (67). 

Another enzymatic reaction in which glutathione functions as a coenzyme in a manner similar to the glyoxalase reaction described above,... 

Hopkins and Morgan 12S) identified two enzymes participating in the glyoxalase reaction and Racker 124) clarified the individual steps [see Eq. (22)1. 

The mercapturic acids and related compounds can then be exported from cells by an ATP-dependent export pump. Glutathione is a coenzyme for glyoxalase (Eq. 13-33), maleylacetoacetate isomerase (Eq. 13-20), and DDT dehydrochlorinase. The latter enzyme catalyzes elimination of HC1 from molecules of the insecticide and is especially active in DDT-resistant flies.3 Glutathione is said to be the specific factor eliciting the feeding reaction of Hydra that is, the release of glutathione from injured cells causes the little animal to engulf food. 

The glyoxalase system is able to convert a-oxoaldehydes into the corresponding a-hydroxyacids, a reaction that lowers oxidative stress. Glyoxalase I (EC 4.4.1.5) mimetic activity has been associated with imidazole derivatives, such as histidine and camosine, and their activity in liberating lactic acid from. S -lactoylglutathionc has been confirmed.613 However, mammalian tissue displays about 4000 times this activity. 

The obtaining of the optically pure (Ss)-26 was achieved in 20% yield by crystallization from the 1 1 mixture of epimers at sulfur resulting from the oxidation of the corresponding thioether. The reaction of (Ss)-26 with 2-methoxy-furan (6 days, 0°C, toluene) afforded only compound 27 (in a complete regio, endo, and 7r-facial selective manner), which was transformed into glyoxalase I inhibitor 28 [42] in a seven-step sequence (Scheme 13). 

Feierberg, I., Luzhkov, V. and Aqvist, J. (2000). Computer simulation of primary kinetic isotope effects in the proposed rate limiting step of the glyoxalase I catalyzed reaction. J. Biol. Chem. 275, 22657-22662... 

Lacking GSH-dependent peroxidases, Plasmodium spp. rely on a Prx-linked detoxification for hydroperoxides and reduced GSH acts primarily as the principal redox buffer. It is also important in detoxification reactions as a co-factor for GST and glyoxalase and has been shown to be involved in the breakdown of free ferriprotoporphyrin IX. The lack of two major antioxidants present in other cells (catalase and GSH peroxidase) suggests that malaria parasites would be vulnerable to disturbances in their anti-oxidant systems. As a consequence, pro-oxidant drugs such as the artemisinins, which increase the oxidative stress, are efficient antimalarials. It has been proposed that a novel approach to malaria chemotherapy would be to develop drugs that disrupt the anti-oxidant and redox system of Plasmodium (Muller, 2004 Nickel et al., 2006 Rahlfs and Becker, 2005). 

M. Huntley, C. Frederick, D. S. Hamilton, D. J. Creighton, and B. Ganem, Reaction of COTC with glutathione. Structure of the putative glyoxalase inhibition, Org. Lett., 2 (2000) 3143-3144. 

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