Imine Reductases: A Comparison of Glutamate Dehydrogenase to Ketimine Reductases in the Brain

Abstract

A key intermediate in the glutamate dehydrogenase (GDH)-catalyzed reaction is an imine. Mechanistically, therefore, GDH exhibits similarities to the ketimine reductases. In the current review, we briefly discuss (a) the metabolic importance of the GDH reaction in liver and brain, (b) the mechanistic similarities between GDH and the ketimine reductases, (c) the metabolic importance of the brain ketimine reductases, and (d) the neurochemical consequences of defective ketimine reductases. Our review contains many historical references to the early work on amino acid metabolism. This work tends to be overlooked nowadays, but is crucial for a contemporary understanding of the central importance of ketimines in nitrogen and intermediary metabolism. The ketimine reductases are important enzymes linking nitrogen flow among several key amino acids, yet have been little studied. The cerebral importance of the ketimine reductases is an area of biomedical research that deserves far more attention.

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

“…Subsequent studies demonstrated that this enzyme is identical to GTK, and investigations by Han et al using a recombinant human enzyme (hKAT I) reported on the K cat /K m values for glutamine and five other "best" substrate amino acids using α-ketobutyrate as α-keto acid co-substrate [3]. Han et al reported K cat /K m values for glutamine, phenylalanine, leucine, kynurenine, tryptophan and methionine of 157, 54, 45,43,36, and 34 min −1 mM −1 , respectively [3]. In another study, Han et al investigated the amino acid specificity of another kynurenine aminotransferase, namely mouse kynurenine aminotransferase III (mKAT III) [4].…”

“…Thus, several sulfur-containing amino acids (e.g., cystathionine, cystine, lanthionine, and thialysine) have been shown to be substrates of glutamine transaminases (reviewed in refs. [12,[41][42][43]). Figure 3.5 illustrates the metabolic origin of the sulfur-containing amino acids and the importance of the glutamine transaminases in converting these compounds to α-keto acids.…”

“…These compounds exist in equilibrium with their open-chain and enamine forms. The relative concentrations of open-chain-, ketimine-and enamine forms are strongly pH dependent [41][42][43].…”

“…For original references on the potential neuroactive roles of the cyclic sulfur-containing cyclic ketimines see refs. [42,43].…”

“…The cyclic ketimines formed by glutamine transaminase are subsequently reduced by ketimine reductases, one of which has been identified as the protein μ-crystallin (CRYM) [42,43]. The activity of this enzyme was shown to be regulated by the thyroid hormone triiodothyronine (T3) and, reciprocally, a role is implied for the enzyme in regulating the bioavailability of intracellular T3 (reviewed in refs.…”