Kynurenine—oxoglutarate transaminase

Kynurenine—oxoglutarate transaminase (KOT), also known as kynurenine aminotransferase (KAT), is an enzyme that in humans is encoded by the CCBL1 and CCBL2 genes. KOT plays a crucial role in the tryptophan metabolism pathway, specifically in the kynurenine pathway, which is responsible for the catabolism of tryptophan into nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in cellular redox reactions.

Function

Kynurenine—oxoglutarate transaminase catalyzes the transamination of kynurenine to kynurenic acid (KYNA) using alpha-ketoglutarate as an amino group acceptor. This reaction is a key step in the kynurenine pathway of tryptophan degradation, leading to the production of NAD+. KYNA acts as a neuroprotective agent by blocking N-methyl-D-aspartate (NMDA) receptors and alpha7-nicotinic acetylcholine receptors, implicating KOT in various neurological disorders.

Clinical Significance

Alterations in the activity of KOT have been associated with several diseases, including schizophrenia, Alzheimer's disease, and Huntington's disease. Elevated levels of KYNA in the brain, resulting from increased KOT activity, have been linked to the pathophysiology of schizophrenia and cognitive dysfunction in Alzheimer's disease. Conversely, reduced KOT activity and subsequent decreased KYNA levels may contribute to the neurodegenerative processes observed in Huntington's disease.

Genetics

The human KOT enzyme is encoded by two genes: CCBL1 (Cysteine Conjugate-Beta Lyase, Kynurenine Aminotransferase 1) and CCBL2 (Cysteine Conjugate-Beta Lyase 2, Kynurenine Aminotransferase 2). These genes are located on different chromosomes and encode for isoenzymes that differ in their biochemical properties and tissue distribution, but both contribute to the overall KOT activity in the body.

Isoenzymes

Kynurenine—oxoglutarate transaminase exists in multiple isoenzymic forms, including KAT I, KAT II, KAT III, and KAT IV, each encoded by different genes and having distinct tissue distributions and enzymatic activities. KAT II is considered the primary form involved in the synthesis of kynurenic acid in the brain.

Therapeutic Potential

Given the role of KOT and KYNA in neurological disorders, modulating the activity of this enzyme represents a potential therapeutic strategy. Inhibitors of KOT could decrease KYNA levels, offering a novel approach to treating schizophrenia and cognitive deficits. Conversely, enhancing KOT activity may be beneficial in neurodegenerative diseases like Huntington's disease by increasing KYNA levels and providing neuroprotection.

See Also

• Tryptophan metabolism
• Kynurenic acid
• Neurotransmitter
• Enzyme