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Chemical Basis of the Action of Glyoxalase I, an Anticancer Target Enzyme
Author(s) -
Douglas Kenneth T.,
Shinkai Seiji
Publication year - 1985
Publication title -
angewandte chemie international edition in english
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 0570-0833
DOI - 10.1002/anie.198500311
Subject(s) - methylglyoxal , lactoylglutathione lyase , glutathione , enzyme , chemistry , mechanism of action , biochemistry , stereochemistry , mechanism (biology) , philosophy , in vitro , epistemology
Although glyoxalase I was discovered in 1913 the physiological role of this ubiquitous enzyme is still far from clear. It catalyzes the reaction of α‐ketoaldehydes and glutathione to produce S ‐D‐lactoylglutathione, from which D‐lactate and glutathione are produced by glyoxalase II. Argument raged for many decades about the nature of the natural substrate. Was it methylglyoxal? Was methylglyoxal ever formed metabolically or was it purely artifactual? Some of these questions have been resolved in that a number of metabolic processes which produce α‐ketoaldehydes have now been recognized. Equally unsuccessful have been attempts to ascribe a physiological role to glyoxalase. This is clearly an important question since glyoxalase I occurs in cells at all levels of evolution. Time and time again glyoxalase I has been claimed to be linked to cancer, and a number of research groups worldwide are using it as a model for designing potential anticancer drugs. In this review article the mechanism of action of the enzyme is discussed, knowledge of which enables stronger inhibitors to be synthesized. Until roughly ten years ago when powerful NMR techniques were used to study it for the first time, it was assumed that the key step in the mechanism was a hydride ion transfer. Today, the mechanism is envisaged as a proton transfer.