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′-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.
Highlights
Tryptophan, an essential amino acid obtained from the diet, is able to cross the blood brain barrier (BBB) with the aid of its specialized transporter protein
It is noteworthy that the irreversible inhibition of pyridoxal-51 -phosphate (PLP) has a range of potential undesirable and dangerous side effects due the interference with the activity of over 300 PLP-dependent enzymes and proteins [21]
The second component is based on the development of BFF-122 and PF-04859989, both selective kynurenine aminotransferase-2 (KAT-2) inhibitors, and indole-3-acetic acid
Summary
Tryptophan, an essential amino acid obtained from the diet, is able to cross the blood brain barrier (BBB) with the aid of its specialized transporter protein. Serotonin is transformed to an active metabolite, melatonin, via two-steps of enzymatic catabolism. Transformed to an active metabolite, melatonin, via two-steps of enzymatic catabolism. Second is known as the kynurenine converting normelatonin to melatonin. Thetosecond route The is known asroute the kynurenine pathway, which is pathway, which is the main route of tryptophan metabolism. Anthranilic acid and After the 3-HK transformed by and hydroxylation a mutual product: acid (3-HANA), and in the second step the branchand the in. Anisauto oxidation second of the of branch the isoenzymes, 3-HK acts asand a substrate of the KAT isoenzymes, and catalysed into reaction converts. In the lastacid steps3,4-dioxygenase of this branch, is transformed into quinolinic acid (QUIN) by 3-hydroxyanthranilic.
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