Role of Glutamine Transaminases in Nitrogen, Sulfur, Selenium, and 1-Carbon Metabolism

Glutamine metabolism is largely controlled by two enzyme pathways: 1) Conversion of glutamine to glutamate catalyzed by glutaminases, followed by conversion of glutamate to α-ketoglutarate by a glutamate-linked aminotransferases (or by the action of glutamate dehydrogenase); and 2) conversion of glutamine to α-ketoglutaramate (KGM) catalyzed by glutamine-utilizing transaminases (aminotransferases), followed by conversion of KGM to α-ketoglutarate by the action of ω-amidase. The former pathway has been well documented and intensively studied for over 60 years, whereas only recently has research focused on the latter pathway, its importance in homeostasis and the control of anaplerotic metabolites. The glutamine transaminases are of fundamental importance 1) as repair enzymes (salvage of α-keto acids), 2) in nitrogen and sulfur homeostasis (closure of the methionine salvage pathway), 3) in 1-carbon metabolism, and 4) in metabolism of seleno amino acids. As a result of their broad substrate specificity the two principal mammalian glutamine transaminases (i.e. glutamine transaminases L and K) have also been characterized as kynurenine aminotransferases (KAT I and KAT III, respectively), responsible for the production of neuroactive kynurenate. The glutamine transaminases are also active with a variety of sulfur- and selenium-containing amino acids. Some of the products derived from the transamination of these amino acids may also be neuroactive (e.g. certain sulfur-containing cyclic ketimines) as well as chemopreventive (e.g. the α-keto acids derived from seleno amino acids). Of relevance to human health and disease, the glutamine transaminases may contribute to the bioactivation (toxification) of halogenated alkenes (and possibly other xenobiotic electrophiles), some of which are environmental contaminants. Finally, the role of the glutamine transaminases and ω-amidase in cancer biology has been little studied. However, the “glutamine addiction” of many tumors suggests that the glutamine transaminases together with ω-amidase may have a fundamental and influential role in regulating cancer progression