Inhibition of Tyrosine Aminotransferase by β‐N‐Oxalyl‐l‐α,β‐Diaminopropionic Acid, the Lathyrus sativus Neurotoxin

Abstract

Species differences in susceptibility are a unique feature associated with the neurotoxicity of β‐N‐oxalyl‐l‐α,β‐diaminopropionic acid (l‐ODAP), the Lathyrus sativus neurotoxin, and the excitotoxic mechanism proposed for its mechanism of toxicity does not account for this feature. The present study examines whether neurotoxicity of l‐ODAP is the result of an interference in the metabolism of any amino acid and if it could form the basis to explain the species differences in susceptibility. Thus, Wistar rats and BALB/c (white) mice, which are normally resistant to l‐ODAP, became susceptible to it following pretreatment with tyrosine (or phenylalanine), exhibiting typical neurotoxic symptoms. C57BL/6J (black) mice were, however, normally susceptible to l‐ODAP without any pretreatment with tyrosine. Among the various enzymes associated with tyrosine metabolism examined, the activity of only tyrosine aminotransferase (TAT) was inhibited specifically by l‐ODAP. The inhibition was noncompetitive with respect to tyrosine (Ki = 2.0 ± 0.1 mM) and uncompetitive with respect to α‐ketoglutarate (Ki = 8.4 ± 1.5 mM). The inhibition of TAT was also reflected in a marked decrease in the rate of oxidation of tyrosine by liver slices, an increase in tyrosine levels of liver, and also a twofold increase in the dopa and dopamine contents of brain in l‐ODAP‐injected black mice. The dopa and dopamine contents in the brain of only l‐ODAP‐injected white mice did not show any change, whereas levels of these compounds were much higher in tyrosine‐pretreated animals. Also, the radioactivity associated with tyrosine, dopa, and dopamine arising from [14C]tyrosine was twofold higher in both liver and brain of l‐ODAP‐treated black mice. Thus, a transient increase in tyrosine levels following the inhibition of hepatic TAT by l‐ODAP and its increased availability for the enhanced synthesis of dopa and dopamine and other likely metabolites (toxic?) resulting therefrom could be the mechanism of neurotoxicity and may even underlie the species differences in susceptibility to this neurotoxin.

European medicinal and edible plants associated with subacute and chronic toxicity part II: Plants with hepato-, neuro-, nephro- and immunotoxic effects

“…Furthermore, L-ODAP was found to have much weaker binding affinity to glutamate receptors than compunds which were shown to be without neurotoxic effects (Jain et al, 1998;Omelchenko et al, 1999). Thus, neurotoxicity associated with L-ODAP must be in some way attributed at least partially to other factors, such as to its abilitiy to chelate divalent ions, i.e., zinc, copper and manganese(Nunn et al, 1989), to the inhibition of the mitochondrial complex I due to the generation of the reactive oxygen species in the motor cortex and lumbar spinal cord(Colegate et al, 1979;Spencer et al, 1986), to the inhibition of the tyrosine amino transferase associated with the increase of the neurotoxic levels of certain catecholamine derivatives in the brain(Olney et al, 1990;Shasi Vardhan et al, 1997), and/or to the insufficiency of sulphur-containing amino acids in the human diet leading to oxidative stress and glutathione depletion(Kusama-Eguchi et al, 2011). other hand, osteolathyrism is characterized by kyphoscoliosis of the spine, pathologic curvatures of the long bones and also aortic aneurysms (hence the term angiolathyrism)(Smiley et al, 1962).…”

Determination of β-ODAP by various methods with special emphasis on biosensors: A mini-review

“…TAT was the only enzyme identified so far that was substantially inhibited by l-ODAP. C57BL/6J black mice following ODAP treatment showed a significant increase in brain 3,4-dihydroxyphenylalanine (DOPA) and other chatecholamines [18]. BALB/c mice which normally did not respond to l-ODAP, became susceptible, when predosed with tyrosine.…”

3-N-oxalyl-L-2,3-diaminopropanoic acid, a multifunctional plant metabolite of toxic reputation

“…22 This is corroborated by the fact that ODAP does not affect any of the enzymes of glutamate biosynthesis but that the enzyme tyrosine aminotransferase is inhibited by β-ODAP in a noncompetitive manner. 23 The most popular method of quantitative analysis is the Rao-method involving alkaline hydrolysis and spectrophotometric measurement of the adduct between 2,3-diaminopropanoic acid that is formed during hydrolysis and O-phthaldialdehyde in the presence of mercaptoethanol. With mono-amino acids this reaction yields 1-alkylthio-2-alkylisoindoles with λ max = 340, while 2,3-diaminopropanoic acid will yield an imidazo-isoindol derivative 5-(2-hydroxyethylsulfanyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindole-3-carboxylic acid (together with the isomeric -2-carboxilic acid) as shown below with λ max = 426.…”