Screening marine natural products for selective inhibitors of key kynurenine pathway enzyme

Feng, Yunjiang, Bowden, Bruce, and Kapoor, Vimal (2000) Screening marine natural products for selective inhibitors of key kynurenine pathway enzyme. Redox Report, 5 (2-3). pp. 95-97.

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Abstract

Kynurenine, a metabolite of tryptophan along the 'kynurenine pathway', is at a branch point of the pathway which can lead to the synthesis of both quinolinic acid (QUIN) and kynurenic acid (KYNA). KYNA is an antagonist of glutamate receptors; however, QUIN is a selective agonist of NMDA receptors, and has been shown to act as an excitotoxic agent. A high QUIN/KYNA ratio has been implicated in a variety of neurological diseases in which excitotoxic neuronal cell death is found, e.g. AIDS-related dementia, stroke, etc. Inhibiting the key enzymes of this pathway (i.e. kynureninase and kynurenine 3-hydroxylase) would lower the QUIN/KYNA ratio, which may potentially have neuroprotective effects. We have developed high through-put assays for kynurenine pathway enzymes which allow us to screen extracts from marine organisms for selective enzyme inhibitors. Active metabolites are purified, isolated and identified by HPLC, high-field NMR and mass spectral techniques. Extracts from a sponge of the Aka species were found to contain a selective inhibitor of kynureninase. We have recently purified and identified the active principal as being serotonin sulfate. Related indoleamines, serotonin and 5-hydroxyindoleacetic acids are inactive. This finding may be suggestive of a novel interaction between the serotoninergic and excitatory amino acid pathways.

Item ID: 13014
Item Type: Article (Refereed Research - C1)
ISSN: 1351-0002
Date Deposited: 07 Dec 2012 06:36
FoR Codes: 03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry > 030499 Medicinal and Biomolecular Chemistry not elsewhere classified @ 51%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060107 Enzymes @ 49%
SEO Codes: 96 ENVIRONMENT > 9608 Flora, Fauna and Biodiversity > 960808 Marine Flora, Fauna and Biodiversity @ 34%
96 ENVIRONMENT > 9611 Physical and Chemical Conditions of Water > 961104 Physical and Chemical Conditions of Water in Marine Environments @ 33%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920111 Nervous System and Disorders @ 33%
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