The 2-oxoaldehyde
methylglyoxal (MeG) is the precursor to a number of the known
advanced glycation endproducts (AGE) implicated in the development of
diabetic complications. Other 2-oxoaldehydes that are important in AGE formation, such as
glyoxal,
glucosone, deoxyglucosone,
xylosone and deoxyxylosone, are produced by nonenzymatic reactions. By contrast, MeG is produced by both enzymatic and nonenzymatic processes, most of which appear to be enhanced in diabetes. MeG may be a major precursor to formation of AGE, and rates of production of MeG depend upon physiological conditions such as
hyperglycemia and
ketoacidosis. MeG is also unique compared to the other 2-oxoaldehydes in its complex metabolism. At least four pathways contribute to detoxification of MeG: (1)
aldose reductase, a member of the
aldo-keto reductase superfamily, catalyzes the
NADPH-dependent reduction of a wide range of
aldehydes. MeG is the best of the known physiological
aldehyde substrates of
aldose reductase. The distribution of
aldose reductase in human tissue is restricted; there is little expression in liver; (2) the ubiquitous and highly active glyoxalase system converts MeG into D-
lactate. However, this system depends upon the availability of
glutathione; activity is severely limited by conditions of oxidative stress that impact levels of
glutathione; (3)
betaine aldehyde dehydrogenase, also known as ALDH9, is able to catalyze the oxidation of MeG to
pyruvate, although less efficiently than with its substrate
betaine aldehyde; (4) the long-known but not widely studied 2-oxoaldehyde
dehydrogenases (2-ODHs) catalyze the oxidation of MeG to
pyruvate, primarily in liver. There are two
NADP-dependent 2-ODHs in human liver. Both of these require an activating
amine. The physiological activator is unknown.