The Lathyrus excitotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid is a substrate of the L-cystine/L-glutamate exchanger system xc-.
Beta-N-oxalyl-L-alpha-beta-diaminopropionic acid (beta-L-ODAP) is an unusual amino acid present in seeds of plants from the Lathyrus genus that is generally accepted as the causative agent underlying the motor neuron degeneration and spastic paraparesis in human neurolathyrism. Much of the neuropathology produced by beta-L-ODAP appears to be a direct consequence of its structural similarities to the excitatory neurotransmitter L-glutamate and its ability to induce excitotoxicity as an agonist of non-NMDA receptors. Its actions within the CNS are, however, not limited to non-NMDA receptors, raising the likely possibility that the anatomical and cellular specificity of the neuronal damage observed in neurolathyrism may result from the cumulative activity of beta-L-ODAP at multiple sites. Accumulating evidence suggests that system xc-, a transporter that mediates the exchange of L-cystine and L-glutamate, is one such site. In the present work, two distinct approaches were used to define the interactions of beta-L-ODAP with system xc-: Traditional radiolabel-uptake assays were employed to quantify inhibitory activity, while fluorometrically coupled assays that follow the exchange-induced efflux of L-glutamate were used to assess substrate activity. In addition to confirming that beta-L-ODAP is an effective competitive inhibitor of system xc-, we report that the compound exhibits a substrate activity comparable to that of the endogenous substrate L-cystine. The ability of system xc- to transport and accumulate beta-L-ODAP identifies additional variables that could influence its toxicity within the CNS, including the ability to limit its access to EAA receptors by clearing the excitotoxin from the extracellular synaptic environment, as well as serving as a point of entry through which beta-L-ODAP could have increased access to intracellular targets.
COBRE Center for Structural and Functional Neuroscience, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula 59812, USA.
Brady A
BA
Warren
Sarjubhai A
SA
Patel
Peter B
PB
Nunn
Richard J
RJ
Bridges
D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000599:Amino Acids, Diamino / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D000087522:Cyanobacteria Toxins; D003553:Cystine / Q000378:metabolism; D005470:Fluorometry; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D016318:Quisqualic Acid / Q000494:pharmacology*; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism
D027182:Amino Acid Transport System y+; D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D009498:Neurotoxins; D017470:Receptors, Glutamate; C118895:SLC7A11 protein, human; C453101:carboxyphenylglycine; C001824:beta-N-methylamino-L-alanine; C100126:oxalyldiaminopropionic acid; D018698:Glutamic Acid; D003553:Cystine; D016318:Quisqualic Acid; D005998:Glycine