Disorders affecting the kynurenine pathway may be primary (of
genetic origin) or secondary (due to
inflammatory conditions).
Peripheral inflammation can lead to a build up of kynurenine in the brain, and this is associated with
major depressive disorder, Kynurenine clearance in exercised muscle cells can suppress the build up in the brain.
Hydroxykynureninuria Also known as
kynureninase deficiency, this extremely rare inherited disorder is caused by the defective enzyme
kynureninase which leads to a block in the pathway from
tryptophan to nicotinic acid mononucleotide (NaMN). As a result, tryptophan is no longer a source of
niacin, hence not producing
NAD, leading to
pellagra (niacin deficiency). Both B6-responsive and B6-unresponsive forms are known. Patients with this disorder excrete excessive amounts of xanthurenic acid, kynurenic acid, 3-hydroxykynurenine, and kynurenine after tryptophan loading and are said to suffer from tachycardia, irregular breathing, arterial hypotension, cerebellar ataxia, developmental retardation, coma, renal tubular dysfunction, renal or metabolic acidosis, and even death. The only biochemical abnormality noted in affected patients was a massive hyperkynureninuria, seen only during periods of coma or after intravenous protein loading. This disturbance was temporarily corrected by large doses of
vitamin B6. The activity of kynureninase in the liver was markedly reduced. The activity was appreciably restored by the addition of pyridoxal phosphate.
Acquired and inherited enzyme deficiencies Downregulation of
kynurenine 3-monooxygenase (KMO) can be caused by genetic
polymorphisms,
cytokines, or both. KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan
metabolic pathway towards kynurenic acid and
anthranilic acid. Deficiencies of one or more enzymes on the kynurenine pathway leads to an accumulation of intermediate metabolic products which can cause effects depending on their concentration, function and their inter-relation with other metabolic products. •
HIV dementia •
Tourette syndrome •
Tic disorders •
Attention deficit hyperactivity disorder (ADHD) •
Psychiatric disorders ==Research==