Sulphur-containing excitatory amino acids in intercellular communication

Cuénod, Michel; Grandes, Pedro; Zängerle, Leo; Streit, P.; Q., Kim

doi:10.1042/bst0210072

Cited by 36 publications

(6 citation statements)

References 10 publications

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“…Cysteine was reported to be a good substrate for glutamine transaminase K [38], but its effect on hKAT‐I activity has not been tested. In mammals, endogenous cysteine displays neuroexcitatory actions similar to those of glutamate [39,40]. Cysteine derivatives, homocysteine, cysteine sulfinate, homocysteine sulfinate and cysteate, were able to reduce the production of KYNA in cortical slices in rats, due presumably to their interaction with KATs, and they were considered endogenous modulators of KYNA formation in the brain [31,32].…”

Section: Discussionmentioning

confidence: 99%

pH dependence, substrate specificity and inhibition of human kynurenine aminotransferase I

Han

2004

European Journal of Biochemistry

134

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Human kynurenine aminotransferase I/glutamine transaminase K (hKAT-I) is an important multifunctional enzyme. This study systematically studies the substrates of hKAT-I and reassesses the effects of pH, Tris, amino acids and a-keto acids on the activity of the enzyme. The experiments were comprised of functional expression of the hKAT-I in an insect cell/baculovirus expression system, purification of its recombinant protein, and functional characterization of the purified enzyme. This study demonstrates that hKAT-I can catalyze kynurenine to kynurenic acid under physiological pH conditions, indicates indo-3-pyruvate and cysteine as efficient inhibitors for hKAT-I, and also provides biochemical information about the substrate specificity and cosubstrate inhibition of the enzyme. hKAT-I is inhibited by Tris under physiological pH conditions, which explains why it has been concluded that the enzyme could not efficiently catalyze kynurenine transamination. Our findings provide a biochemical basis towards understanding the overall physiological role of hKAT-I in vivo and insight into controlling the levels of endogenous kynurenic acid through modulation of the enzyme in the human brain.Keywords: cysteine; indo-3-pyruvate; kynurenic acid; kynurenine aminotransferase; pH effect.In mammals, kynurenine aminotransferase I/glutamine transaminase K (EC 2.6.1.64; KAT-I) is a multifunctional enzyme. In vitro, the enzyme catalyzes the transamination of several amino acids (e.g. glutamine, methionine, aromatic amino acids including kynurenine) and also possesses cysteine S-conjugate b-lyase activity (EC 4.4.1.13) [1]. Kynurenic acid (KYNA), the stable product derived from the kynurenine transamination pathway [2][3][4], is involved in several physiological aspects of the central nervous system (CNS) by acting as an antagonist at both the glutamatebinding site and the allosteric glycine site of the N-methyl-D-aspartate receptor and possibly by blocking the 7-nicotinic acetylcholine receptor [5][6][7][8]. Low KYNA levels in the central nervous system are correlated to cerebral diseases such as schizophrenia and Huntington's disease [9][10][11][12][13]. Only two pyridoxal 5¢-phosphate (PLP)-dependent aminotransferases that are able to catalyze the transamination of kynurenine to KYNA, arbitrarily termed KAT-I and II, have been described in rat and human brains [14][15][16].In addition, KYNA is involved in maintaining physiological arterial blood pressure. In rats, the region of the rostral and caudal medulla in the CNS plays an important role in regulating cardiovascular function [17][18][19][20]. Spontaneously hypertensive rats that have higher arterial blood pressure were found to have significantly lower KAT activity and KYNA content in their rostral and caudal medulla than the control rats [20]. Injection of KYNA into the rostral ventrolateral medulla of these rats significantly decreased their arterial pressure [21], which suggests that KYNA is involved in maintaining physiological arterial blood pressure. Recently, the mutan...

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Section: Discussionmentioning

confidence: 99%

pH dependence, substrate specificity and inhibition of human kynurenine aminotransferase I

Han

2004

European Journal of Biochemistry

134

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“…Nevertheless the possibility must be considered that Hcy export and homocysteic acid export only appear to be distinct phenomena because of interconversion between the two amino acids. This is unlikely because rat brain homogenates did not convert Hcy to homocysteic acid (Cuenod et al, 1993) and astrocytes did not convert homocysteic acid to Hcy (present study). Further, Hcy export and homocysteic acid export occurred with very different time courses.…”

Section: Discussionmentioning

confidence: 54%

Activation of catechol‐O‐methyltransferase in astrocytes stimulates homocysteine synthesis and export to neurons

Huang

Dragan

Freeman

et al. 2005

Glia

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Elevation of the total homocysteine (tHcy) concentration in plasma has been implicated in neurodegeneration in patients with stroke, dementia, Alzheimer disease, and Parkinson disease. Because the mechanisms controlling brain tHcy are unknown, the present study investigated its synthesis and transport in primary rat brain cell cultures. We found that the catechol-O-methyltransferase (COMT) substrate 3,4-dihydroxybenzoic acid (DHB) increased export of tHcy in astrocytes, but not in neurons. The export mechanism was selective for tHcy over cyst(e)ine, total glutathione (tGSH) or cysteinylglycine (Cys-Gly). tHcy export from astrocytes was also induced by the COMT substrates levodopa (L-DOPA), dopamine and quercetin, and it was blocked by the COMT inhibitors tropolone and entacapone. This export was associated with increased synthesis of tHcy because both intracellular and extracellular tHcy concentrations rose during COMT activation. Incubation in cyst(e)ine-deficient medium inhibited the tHcy export response to COMT activation. Exogenous tHcy (100 muM) was accumulated into neurons, but not into astrocytes. We conclude that activation of COMT causes sustained synthesis of Hcy in astrocytes and transport of this amino acid to neurons.

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“…Glial kainate-receptor channels have been considered to be activated by the transmitter glutamate that is released from parallel fibre synapses at the dendritic spines of the Purkinje cell (for review, see Steinhauser, 1993). This led to the suggestion that the glutamate-induced Ca2+-entry into Bergmann glial cells activates second messenger cascades (Burnashev ct al., 1992) or triggers the secretion of homocysteate, a transmitter-like substance (Grandes et al, 1991; for review, see Cuenod et al, 1993). Concerning the present demonstration of NOS I in Bergmann glia and astrocytes there is reason to believe that a glutamateinduced entry of Ca2-into glia cells may also result in generation of NO via a Ca"-calmodulin dependent activation of NOS I.…”

Section: Discussionmentioning

confidence: 85%