The Synthesis of Kynurenic Acid in Mammals: An Updated Kynurenine Aminotransferase Structural KATalogue

Abstract

Kynurenic acid (KYNA) is a bioactive compound that is produced along the kynurenine pathway (KP) during tryptophan degradation. In a few decades, KYNA shifted from being regarded a poorly characterized by-product of the KP to being considered a main player in many aspects of mammalian physiology, including the control of glutamatergic and cholinergic synaptic transmission, and the coordination of immunomodulation. The renewed attention being paid to the study of KYNA homeostasis is justified by the discovery of selective and potent inhibitors of kynurenine aminotransferase II, which is considered the main enzyme responsible for KYNA synthesis in the mammalian brain. Since abnormally high KYNA levels in the central nervous system have been associated with schizophrenia and cognitive impairment, these inhibitors promise the development of novel anti-psychotic and pro-cognitive drugs. Here, we summarize the currently available structural information on human and rodent kynurenine aminotransferases (KATs) as the result of global efforts aimed at describing the full complement of mammalian isozymes. These studies highlight peculiar features of KATs that can be exploited for the development of isozyme-specific inhibitors. Together with the optimization of biochemical assays to measure individual KAT activities in complex samples, this wealth of knowledge will continue to foster the identification and rational design of brain penetrant small molecules to attenuate KYNA synthesis, i.e., molecules capable of lowering KYNA levels without exposing the brain to the harmful withdrawal of KYNA-dependent neuroprotective actions.

Tryptophan Metabolism via the Kynurenine Pathway: Implications for Graft Optimization during Machine Perfusion

“…Though KYNA levels were not reported, this highlights the therapeutic potential of this metabolic pathway. The activity of kynurenine aminotransferase (KAT), which converts KYN to KYNA [ 32 ], is temperature dependent and may explain why livers undergoing SNMP produced less KYNA. KAT exists as four isozymes (KAT I, II, III, and IV) in humans and rodents [ 32 ].…”

“…The activity of kynurenine aminotransferase (KAT), which converts KYN to KYNA [ 32 ], is temperature dependent and may explain why livers undergoing SNMP produced less KYNA. KAT exists as four isozymes (KAT I, II, III, and IV) in humans and rodents [ 32 ]. Both human and murine KAT II demonstrate maximum activity near 50 °C [ 33 , 34 ].…”

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.…”

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

“…A cofactor, PLP, the active form of vitamin B 6 , and a cosubstrate, α-ketoacid, are required for KATs. [126]. A main source of PLP is food and degraded PLP-dependent enzymes by salvage pathway enzymes in humans.…”