Screening marine natural products for selective inhibitors of key kynurenine pathway enzymes.
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.
Department of Chemistry, James Cook University, Townsville, Queensland, Australia.
Y
Y
Feng
B F
BF
Bowden
V
V
Kapoor
D000818:Animals; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase; D008190:Lyases; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011161:Porifera / Q000737:chemistry*; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000637:Transaminases / Q000378:metabolism*
D004791:Enzyme Inhibitors; C033396:5-hydroxytryptamine O-sulfate; D012701:Serotonin; D007737:Kynurenine; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D006867:Hydrolases; C021480:kynureninase; D008190:Lyases