Curiosity to kill the KAT (kynurenine aminotransferase): structural insights into brain kynurenic acid synthesis

Kynurenine aminotransferases are pyridoxal-5′-phosphate-dependent enzymes, which catalyze the synthesis of kynurenic acid, a highly neuroactive metabolite whose impairment is associated with a number of severe brain disorders. Crystallographic studies of these enzymes from different organisms, including humans, have revealed distinctive structural traits of type I and type II kynurenine aminotransferases. A striking difference concerns domain swapping of the N-terminal regions, which play equivalent key functional roles in both an unswapped and swapped structure in type I and type II isozymes. Different conformational changes during catalysis create divergent active sites in the two isozymes and affect substrate specificity. Structural investigations indicate intriguing evolutionary relationships and pave the way for the design of isozyme-specific inhibitors, which are of interest for the treatment of catastrophic brain diseases such as Alzheimer’s disease and schizophrenia.