Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

Abstract

Abnormal levels of kynurenic acid (KYNA) in the human brain are believed to be connected to several central nervous system (CNS) diseases, therefore compounds which affect the production of this crucial metabolite are of interest in CNS drug development. The majority of KYNA production is accounted for by kynurenine aminotransferase-2 (KAT-2) in the mammalian brain; hence this enzyme is one of the most interesting targets with which to modulate KYNA levels. Recently developed human KAT-2 inhibitors with high potencies are known to irreversibly bind to the enzyme cofactor, pyridoxal-5 1 -phosphate (PLP), which may lead to severe side effects due to the abundance of PLP-dependent enzymes. In this study, we report a reversible and competitive inhibitor of KAT-2. Its inhibitory activities were examined using HPLC and surface plasmon resonance (SPR) and compare favorably with other recently reported KAT-2 inhibitors. Our inhibitor, NS-1502, demonstrates suitable inhibitory activity, almost 10 times more potent than the known reversible KAT-2, (S)-ESBA.

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…In the CNS work has been concentrated on inhibitors of KMO to reduce quinolinic acid synthesis and thereby reduce neural activity and excitotoxicity in neurodegenerative disorders as well as in the suppression of peripheral inflammation, especially in the pancreas (223)(224)(225)(226). A different approach is in the development of KAT inhibitors intended to reduce kynurenic acid formation in psychiatric disorders such as schizophrenia (227)(228)(229)(230). Of course these two approaches, being essentially contrary in their objectives, raise concerns that schizoid symptoms might be induced in response to KMO inhibition, or that KAT inhibition could divert more kynurenine via KMO to quinolinic acid.…”

The role of kynurenine pathway and kynurenic aminotransferase alleles in postpartum depression following cesarean section in Chinese women

“…It is also of note that women with PDS showed higher levels of kynurenine pathway activity at antenatal day 1, indicating heightened kynurenine pathway activity perinatally and possibly over the course of pregnancy. As stress and antenatal depression are risk factors for PDS, this could suggest that activated kynurenine pathway activity may contribute to poorer fetal and maternal outcomes in such pregnancies, which is supported by a wide array of preclinical studies (Hanson et al, ; Hanson et al, ; Nematollahi et al, ; Wang et al, ; Zunszain et al, ). This also links to our previous data showing heightened IDO levels in parturients with PDS (Duan et al, ) .…”

“…Although other enzymes can modulate levels of KYNA synthesis, KAT activity is a major determinant of KYNA levels and thereby important to the etiology and course of a number of medical disorders, including depression (Han, Cai, Tagle, & Li, ). KAT is the main rate‐limiting enzyme in KYNA generation, with KAT blockers significantly determining cerebral KYNA levels in animal models (Nematollahi, Sun, Jayawickrama, Hanrahan, & Church, ). Unlike IDO and KMO, KAT is not induced by pro‐inflammatory factors, but can be regulated by pharmacological interventions and physical activity (Yu et al, ).…”

Kynurenic acid and cancer: facts and controversies

“…On the other hand, decrease of endogenous KYNA production may be also achieved by administration of KATs inhibitors. Although potent inhibitors of KATs are currently tested in the treatment of some brain disorders including Alzheimer's disease and dementia, the use of KAT inhibitors in anticancer therapy has not been studied [119,120]. Both strategies are possible for immediate implementation.…”