d-DOPA IS UNIDIRECTIONALLY CONVERTED TO l-DOPA BY d-AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE
| Autor: | Yong-Xiang Wang, Mei Wu, Xiang-Jun Zhou, Ryuichi Konno |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
D-Amino-Acid Oxidase
Physiology D-amino acid oxidase Kidney Transaminase Levodopa Rats Sprague-Dawley Mice chemistry.chemical_compound Sodium Benzoate Physiology (medical) medicine Animals Enzyme Inhibitors Pharmacology Oxidase test Chemistry D-DOPA Carbidopa Kidney metabolism Dihydroxyphenylalanine Rats nervous system diseases Biochemistry Sodium benzoate Enantiomer medicine.drug |
| Zdroj: | Clinical and Experimental Pharmacology and Physiology. 33:1042-1046 |
| ISSN: | 1440-1681 0305-1870 |
| DOI: | 10.1111/j.1440-1681.2006.04484.x |
| Popis: | 1. Many studies have shown that administration of d-3, 4-dihydroxyphenylalanine (D-dopa) produces contralateral rotation in hemi-parkinsonian animals comparable to L-dopa, with less potency and slower onset. It was postulated that D-dopa was converted to L-dopa to produce these effects. 2. To investigate the postulated chiral inversion of D-dopa to L-dopa and the related mechanism, an enantiomeric separation method for D- and L-dopa using HPLC was first established. Then, rat kidney homogenates containing D-dopa or L-dopa were incubated and subjected to HPLC to detect traces of respective enantiomer generation. The mechanism of the chiral inversion of d-dopa was explored by direct measurement of the production of L-dopa in kidney homogenates. D-dopa incubations containing different concentrations of an inhibitor of D-amino acid oxidase (DAAO) and an inhibitor of dopa transaminase were measured for L-dopa generation using HPLC. The role of DAAO in the chiral inversion of D-dopa to L-dopa was further investigated by using purified DAAO and mutant ddY/DAAO- mouse kidney lacking DAAO activity. 3. In rat kidney homogenate, D-dopa was, indeed, converted to L-dopa, whereas L-dopa was not converted to D-dopa. Sodium benzoate, a selective inhibitor of DAAO, blocked L-dopa generation in a concentration-dependant manner. In contrast with kidney homogenates of wild-type ddY/DAAO+ mice, those of mutant ddY/DAAO- mice lacking DAAO activity did not convert D-dopa to L-dopa unless exogenous DAAO protein was added. Conversely, when carbidopa, an inhibitor of dopa transaminase, was added to the homogenates, significant inhibition of L-dopa production was noted. 4. These results prove the proposal that d-dopa undergoes unidirectional chiral inversion and further suggest that D-dopa is first oxidatively deaminated by DAAO to its alpha-keto acid and then transaminated by dopa transaminase to L-dopa. |
| Databáze: | OpenAIRE |
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