Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). VI. Metabolism of D-DOPA in rat kidney.

Shindo, Hideyo; Maeda, Toshihiko

doi:10.1248/cpb.22.1721

Cited by 13 publications

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“…Conversely, in vitro studies revealed that the addition of d ‐dopa (100 µmol/L) to cultures of embryonic mesencephalic dopamine neurons triggered significant death of tyrosine hydroxylase‐positive neurons, whereas l ‐dopa had the same effect but at a much lower concentration (10 nmol/L), giving a d ‐dopa/ l ‐dopa concentration ratio of 10 000 5 . Combining the observations of the delayed onset of the in vivo effect of d ‐dopa compared with l ‐dopa 2–4 and the difference between the in vivo and in vitro potency ratios of d ‐dopa and l ‐dopa, it was postulated that d ‐dopa exerted its effect following inversion to l ‐dopa in vivo 2,3,6 . Indeed, d ‐amino acids, such as N G ‐nitro‐ d ‐arginine ( d ‐NNA), d ‐leucine and d ‐serine have been shown to be converted to the l ‐isomers in vivo 7–11 .…”

Section: Introductionmentioning

confidence: 95%

“…5 Combining the observations of the delayed onset of the in vivo effect of d-dopa compared with l-dopa [2][3][4] and the difference between the in vivo and in vitro potency ratios of d-dopa and l-dopa, it was postulated that d-dopa exerted its effect following inversion to l-dopa in vivo. 2,3,6 Indeed, d-amino acids, such as N G -nitro-d-arginine (d-NNA), d-leucine and d-serine have been shown to be converted to the l-isomers in vivo. [7][8][9][10][11] It is believed that chiral inversion is a novel and common metabolism pathway for d-amino acids in mammals.…”

Section: Introductionmentioning

confidence: 99%

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d‐DOPA IS UNIDIRECTIONALLY CONVERTED TO l‐DOPA BY d‐AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE

Zhou

Konno

et al. 2006

Clin Exp Pharma Physio

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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.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

d‐DOPA IS UNIDIRECTIONALLY CONVERTED TO l‐DOPA BY d‐AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE

Zhou

Konno

et al. 2006

Clin Exp Pharma Physio

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“…When D‐DOPA (Fig. 4A), the stereoisomer of L‐DOPA, is administered, it is converted to dihydroxyphenylpyruvic acid by DAO, which is followed by transamination from α‐keto acid to L‐DOPA via what is known as the alternative pathway for dopamine biosynthesis (summarized in Scheme ) 12,13. Indeed, the slower utilization of D‐DOPA, as well as the longer retention of its metabolites in the brain,31 makes the combination of the two isomers a more efficacious treatment for Parkinson's disease than does L‐DOPA alone 32…”

Section: Oxidation Of D‐dopa By Hdao: Alternative Pathway For Dopaminmentioning

confidence: 99%

“… General and alternative dopamine synthetic pathways. When administered, D‐DOPA is converted to DHPPA by D‐amino acid oxidase, after which the α‐keto acid is transaminated to L‐DOPA 12,13. Hypothetical reactions are indicated by dashed lines.…”

Section: Oxidation Of D‐dopa By Hdao: Alternative Pathway For Dopaminmentioning

confidence: 99%

“…In this context, it is also noteworthy that 3,4‐dihydroxy‐ D ‐phenylalanine (D‐DOPA), the stereoisomer of 3,4‐dihydroxy‐ L ‐phenylalanine (L‐DOPA), which is commonly used in the treatment of Parkinson's disease, is reportedly metabolized by DAO. In fact, when D‐DOPA is administered, it is converted to dopamine via an alternative biosynthetic pathway 12,13. Thus, the potential clinical importance of D‐amino acid oxidase in humans (hDAO) highlights the need for structural and functional analyses of this enzyme because inhibitors acting selectively on hDAO are being intensively sought for clinical purposes 14…”

Section: Introductionmentioning

confidence: 99%

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Human D‐amino acid oxidase: an update and review

Kawazoe

Park

Iwana

et al. 2007

The Chemical Record

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The flavoprotein D-amino acid oxidase (DAO) degrades the gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type glutamate receptors. A body of evidence suggests that DAO, together with its activator, G72 protein, may play a key role in the pathophysiology of schizophrenia. It has also been suggested that 3,4-dihydroxy-D-phenylalanine (D-DOPA), the stereoisomer of 3,4-dihydroxy-L-phenylalanine (L-DOPA), is oxidized by DAO and converted to dopamine via an alternative biosynthetic pathway. We determined the crystal structures of human DAO in complex with the reaction products of two clinically important substrates, D-Ser and D-DOPA. Kinetic data show that the maximum velocity is much greater for D-DOPA than that for D-Ser, which strongly supports the proposed alternative pathway for dopamine biosynthesis in the treatment of Parkinson's disease. In addition, biochemical characterization of human DAO indicates that it binds FAD more weakly than does porcine D-amino acid oxidase (pDAO) and exists as a stable homodimer, even in the apoprotein form. Determination of the structures of human DAO in various states reveals that, in contrast to pDAO, the hydrophobic-Val-Ala-Ala-Gly-Leu (VAAGL) stretch (residues 47-51, structurally ambivalent peptide) located at the si-face of the flavin ring assumes a uniquely stable conformation, which provides a structural basis for the unique kinetic features of human DAO.

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An improved fluorimetric method for assay of Dopa in urine and tissues and its use for determination of urinary Dopa, at endogenous level, in different species

Cottet-Émard¹,

Peyrin²

1977

J. Neural Transmission

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An optimized fluorimetric method is presented which permits the analysis of DOPA in urine or tissues, at endogenous levels. A wide variety of eluates can be analyzed by applying the manual or the automated schedule. The automated manifold, developed for DOPA assay, may be used to estimate norepinephrine (NE) in other samples, by only changing the nature of reagents to be pumped. Amounts of DOPA as low as 0.3 ng/ml of eluate can be detected. Determinations of endogenous DOPA are reported in urinary samples of Humans, Rats, Dogs and Sheeps, and in brain of Rats. The pattern of changes in DOPA urinary excretion has been investigated as a function of time in Rats. Dietary influences have been studied in Man, Rat and Dog. It is concluded that the greatest part of free and conjugated DOPA excreted in urine of these animals has an endogenous origin.

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Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). VI. Metabolism of D-DOPA in rat kidney.

Cited by 13 publications

References 0 publications

d‐DOPA IS UNIDIRECTIONALLY CONVERTED TO l‐DOPA BY d‐AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE

d‐DOPA IS UNIDIRECTIONALLY CONVERTED TO l‐DOPA BY d‐AMINO ACID OXIDASE, FOLLOWED BY DOPA TRANSAMINASE

Human D‐amino acid oxidase: an update and review

An improved fluorimetric method for assay of Dopa in urine and tissues and its use for determination of urinary Dopa, at endogenous level, in different species

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