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Proceedings of the Japan Academy.... 2023L-DOPA is an amino acid that is used as a treatment for Parkinson's disease. A simple enzymatic synthesis method of L-DOPA had been developed using bacterial L-tyrosine... (Review)
Review
L-DOPA is an amino acid that is used as a treatment for Parkinson's disease. A simple enzymatic synthesis method of L-DOPA had been developed using bacterial L-tyrosine phenol-lyase (Tpl). This review describes research on screening of bacterial strains, culture conditions, properties of the enzyme, reaction mechanism of the enzyme, and the reaction conditions for the production of L-DOPA. Furthermore, molecular bleeding of constitutively Tpl-overproducing strains is described, which were developed based on mutations in a DNA binding protein, TyrR, which controls the induction of tpl gene expression.
Topics: Tyrosine Phenol-Lyase; Levodopa; Bacteria
PubMed: 36908174
DOI: 10.2183/pjab.99.006 -
DNA Research : An International Journal... Aug 2022Mucuna pruriens, commonly called velvet bean, is the main natural source of levodopa (L-DOPA), which has been marketed as a psychoactive drug for the clinical management...
Mucuna pruriens, commonly called velvet bean, is the main natural source of levodopa (L-DOPA), which has been marketed as a psychoactive drug for the clinical management of Parkinson's disease and dopamine-responsive dystonia. Although velvet bean is a very important plant species for food and pharmaceutical manufacturing, the lack of genetic and genomic information about this species severely hinders further molecular research thereon and biotechnological development. Here, we reported the first velvet bean genome, with a size of 500.49 Mb and 11 chromosomes encoding 28,010 proteins. Genomic comparison among legume species indicated that velvet bean speciated ∼29 Ma from soybean clade, without specific genome duplication. Importantly, we identified 21 polyphenol oxidase coding genes that catalyse l-tyrosine to L-DOPA in velvet bean, and two subfamilies showing tandem expansion on Chr3 and Chr7 after speciation. Interestingly, disease-resistant and anti-pathogen gene families were found contracted in velvet bean, which might be related to the expansion of polyphenol oxidase. Our study generated a high-quality genomic reference for velvet bean, an economically important agricultural and medicinal plant, and the newly reported L-DOPA biosynthetic genes could provide indispensable information for the biotechnological and sustainable development of an environment-friendly L-DOPA biosynthesis processing method.
Topics: Catechol Oxidase; Chromosomes; Dopamine; Levodopa; Mucuna; Pharmaceutical Preparations; Research; Tyrosine
PubMed: 35980175
DOI: 10.1093/dnares/dsac031 -
The FEBS Journal Mar 2018The C-terminal tyrosine (Tyr) of the α-tubulin chain is subjected to post-translational removal and readdition in a process termed the "detyrosination/tyrosination...
The C-terminal tyrosine (Tyr) of the α-tubulin chain is subjected to post-translational removal and readdition in a process termed the "detyrosination/tyrosination cycle". We showed in previous studies using soluble rat brain extracts that l-3,4-dihydroxyphenylalanine (l-Dopa) is incorporated into the same site as Tyr. We now demonstrate that l-Dopa incorporation into tubulin also occurs in living cells. We detected such incorporation by determining the "tyrosination state" of tubulin before and after incubation of cells in the presence of l-Dopa. The presence of a tubulin isospecies following l-Dopa incubation that was not recognized by antibodies specific to Tyr- and deTyr-tubulin was presumed to reflect formation of Dopa-tubulin. l-Dopa was identified by HPLC as the C-terminal compound bound to α-tubulin. l-Dopa incorporation into tubulin was observed in Neuro 2A cells and several other cell lines, and was not due to de novo protein biosynthesis. Dopa-tubulin had microtubule-forming capability similar to that of Tyr- and deTyr-tubulin. l-Dopa incorporation into tubulin did not notably alter cell viability, morphology, or proliferation rate. CAD cells (a neuron-like cell line derived from mouse brain) are easily cultured under differentiating and nondifferentiating conditions, and can be treated with l-Dopa. Treatment of CAD cells with l-Dopa and consequent increase in l-Dopa-tubulin resulted in reduction of microtubule dynamics in neurite-like processes.
Topics: Animals; CHO Cells; COS Cells; Cell Line, Tumor; Chlorocebus aethiops; Cricetulus; Levodopa; Mice; Microtubules; Neurons; Protein Processing, Post-Translational; Rats, Wistar; Tubulin; Tyrosine
PubMed: 29341414
DOI: 10.1111/febs.14386 -
CNS Drugs Feb 2021Infusion of levodopa-carbidopa intestinal gel (LCIG; also designated carbidopa-levodopa enteral suspension) for 16 hours is a standard treatment for patients with... (Review)
Review
Infusion of levodopa-carbidopa intestinal gel (LCIG; also designated carbidopa-levodopa enteral suspension) for 16 hours is a standard treatment for patients with advanced Parkinson's disease, and clinical observations suggest that 24-hour LCIG infusion may further reduce symptoms. This review provides practical advice on the management of patients transitioning to 24-hour LCIG infusion. We review available clinical data for 24-hour infusion and discuss adjustments to dosing, recommendations for monitoring, and management of patient concerns, based on our clinical experience. Data from multiple studies suggest that LCIG may improve non-motor symptoms. Although few studies have examined 24-hour LCIG infusion, available data indicate that certain patients may benefit from around-the-clock treatment. Studies of 24-hour LCIG infusion are limited by small sample sizes and open-label study designs, which may hamper translation to clinical practice. In our experience, we have found that patients may benefit from 24-hour infusion when reductions in nocturnal symptoms and improvements to quality of sleep are needed. Levodopa-unresponsive freezing of gait or poorly controlled troublesome dyskinesias may also indicate a patient may benefit from 24-hour infusion. Dose adjustments, especially of the nocturnal rate, are typically necessary and, as with 16-hour infusion, patients should be monitored for autonomic dysfunction; overnight wearing off symptoms; weight changes; fluctuations in plasma levels of vitamins B/B, folate, and homocysteine; changes in sleep patterns; or worsening of hallucinations, delusions, and/or nightmares. Available data and our clinical experience suggest that 24-hour LCIG may be warranted among selected patients who have poorly controlled nocturnal fluctuations or early morning "off" symptoms.
Topics: Antiparkinson Agents; Carbidopa; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Gels; Humans; Levodopa; Parkinson Disease; Time Factors
PubMed: 33582982
DOI: 10.1007/s40263-020-00782-w -
The European Journal of Neuroscience Jan 2023L-dopa variably influences transcranial magnetic stimulation (TMS) parameters of motor cortex (M1) excitability and plasticity in Parkinson's disease (PD). In patients...
L-dopa variably influences transcranial magnetic stimulation (TMS) parameters of motor cortex (M1) excitability and plasticity in Parkinson's disease (PD). In patients OFF dopaminergic medication, impaired M1 plasticity and defective GABA-A-ergic inhibition can be restored by boosting gamma (γ) oscillations via transcranial alternating current stimulation (tACS) during intermittent theta-burst stimulation (iTBS). However, it is unknown whether L-dopa modifies the beneficial effects of iTBS-γ-tACS on M1 in PD. In this study, a PD patients group underwent combined iTBS-γ-tACS and iTBS-sham-tACS, each performed both OFF and ON dopaminergic therapy (four sessions in total). Motor evoked potentials (MEPs) elicited by single TMS pulses and short-interval intracortical inhibition (SICI) were assessed before and after iTBS-tACS. We also evaluated possible SICI changes during γ-tACS delivered alone in OFF and ON conditions. The amplitude of MEP elicited by single TMS pulses and the degree of SICI inhibition significantly increased after iTBS-γ-tACS. The amount of change produced by iTBS-γ-tACS was similar in patients OFF and ON therapy. Finally, γ-tACS (delivered alone) modulated SICI during stimulation and this effect did not depend on the dopaminergic condition of patients. In conclusion, boosting cortical γ oscillatory activity via tACS during iTBS improved M1 plasticity and enhanced GABA-A-ergic transmission in PD patients to the same extent regardless of dopaminergic state. These results suggest a lack of interaction between L-dopa and γ-tACS effects at the M1 level. The possible neural substrate underlying iTBS-γ tACS effects, that is, γ-resonant GABA-A-ergic interneurons activity, may explain our findings.
Topics: Humans; Transcranial Direct Current Stimulation; Parkinson Disease; Levodopa; Motor Cortex; Transcranial Magnetic Stimulation; Evoked Potentials, Motor; Dopamine; gamma-Aminobutyric Acid; Neuronal Plasticity
PubMed: 36382537
DOI: 10.1111/ejn.15867 -
British Journal of Clinical Pharmacology Oct 2018SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor... (Comparative Study)
Comparative Study Randomized Controlled Trial
Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects.
AIMS
SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077.
METHODS
Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16).
RESULTS
Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for C , AUC , and AUC were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P < 0.0001) for C and AUC and a concomitant reduction in the ratio of 3,4-dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O-methyltransferase (COMT) reaction, 3-methoxytyramine (3-MT) and 3-O-methyldopa (3-OMD) with GMRs (90% CI) for SD-1077/CD to L-DOPA/CD for 3-MT exposure of 1.33 (1.14-1.56; P = 0.0077) and 1.66 (1.42-1.93; P < 0.0001) for C and AUC , respectively and GMRs (90% CI) for 3-OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for C and AUC . SD-1077/CD exhibited comparable tolerability and safety to L-DOPA/CD.
CONCLUSIONS
SD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.
Topics: Administration, Oral; Adult; Antiparkinson Agents; Area Under Curve; Carbidopa; Cross-Over Studies; Deuterium; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Levodopa; Male; Parkinson Disease; Prodrugs
PubMed: 29959802
DOI: 10.1111/bcp.13702 -
Psychopharmacology May 2024The ability to monitor the consequences of our actions for others is imperative for flexible and adaptive behavior, and allows us to act in a (pro)social manner. Yet,... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
The ability to monitor the consequences of our actions for others is imperative for flexible and adaptive behavior, and allows us to act in a (pro)social manner. Yet, little is known about the neurochemical mechanisms underlying alterations in (pro)social performance monitoring.
OBJECTIVE
The aim of this functional magnetic resonance imaging (fMRI) study was to improve our understanding of the role of dopamine and oxytocin and their potential overlap in the neural mechanisms underlying performance monitoring for own versus others' outcomes.
METHOD
Using a double-blind placebo-controlled cross-over design, 30 healthy male volunteers were administered oxytocin (24 international units), the dopamine precursor L-DOPA (100 mg + 25 mg carbidopa), or placebo in three sessions. Participants performed a computerized cannon shooting game in two recipient conditions where mistakes resulted in negative monetary consequences for (1) oneself or (2) an anonymous other participant.
RESULTS
Results indicated reduced error-correct differentiation in the ventral striatum after L-DOPA compared to placebo, independent of recipient. Hence, pharmacological manipulation of dopamine via L-DOPA modulated performance-monitoring activity in a brain region associated with reward prediction and processing in a domain-general manner. In contrast, oxytocin modulated the BOLD response in a recipient-specific manner, such that it specifically enhanced activity for errors that affected the other in the pregenual anterior cingulate cortex (pgACC), a region previously implicated in the processing of social rewards and prediction errors. Behaviorally, we also found reduced target sizes-indicative of better performance-after oxytocin, regardless of recipient. Moreover, after oxytocin lower target sizes specifically predicted higher pgACC activity when performing for others.
CONCLUSIONS
These different behavioral and neural patterns after oxytocin compared to L-DOPA administration highlight a divergent role of each neurochemical in modulating the neural mechanisms underlying social performance monitoring.
Topics: Humans; Male; Levodopa; Oxytocin; Dopamine; Brain; Adaptation, Psychological; Magnetic Resonance Imaging; Double-Blind Method; Administration, Intranasal
PubMed: 38286857
DOI: 10.1007/s00213-024-06541-9 -
Journal of Pharmacy & Pharmaceutical... 2017Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the... (Review)
Review
BACKGROUND
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the management of Parkinson's disease, the accurate determination of this optimal dosage is complicated by marked between-subject and between-occasion variability in this population. This review presents a synthesis of the population pharmacokinetic and pharmacodynamic models of levodopa described in Parkinson's disease.
METHODS
A literature search was conducted from the PubMed database, from their inception through April 2016, using the following terms: levodopa, pharmacokinetic(s), pharmacodynamic(s) population, model(ling) and nonlinear mixed effect. Articles were excluded if they were not pertinent. References of all selected articles were also evaluated.
RESULTS
A total of 12 articles were finally retained. The following covariates were selected as interindividual variability factors: body weight, age, sex, creatinine clearance and levodopa dose. The clinical response versus effect site concentration relationship was described with different sigmoidal Emax models. Different pharmacodynamic effects were described: UPDRS, Tapping, Dyskinesia, CURSΣ and treatment response scale.
DISCUSSION
This review allows us to realize interpretation of a patient's clinical picture and confirmed the appropriateness of the pharmacokinetic-pharmacodynamic modeling for levodopa. External evaluation of previous published models should be also continued to evaluate these previous studies. New pharmacokinetic and/or pharmacodynamic population modelling studies could be consider to improve future models and decrease variability, to better understand the evolution of patients with Parkinson's disease treated by levodopa. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Animals; Humans; Levodopa; Parkinson Disease
PubMed: 28719359
DOI: 10.18433/J30H04 -
Journal of Neurology Jun 2022Over the past two decades, animal models of Parkinson's disease (PD) have helped to determine the plausible underlying mechanism of levo-dihydroxyphenylalanine... (Review)
Review
Over the past two decades, animal models of Parkinson's disease (PD) have helped to determine the plausible underlying mechanism of levo-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia following L-DOPA treatment. However, our understanding of the mechanisms related to this phenomenon remains incomplete. The purpose of this manuscript is to provide a comprehensive review of treatment protocols used for assessing the occurrence of L-DOPA-induced dyskinesia, L-DOPA absorption, distribution, drug/food interaction, and discuss current strategies and future directions. This review offers a historical perspective using L-DOPA in animal models of PD and the occurrence of L-DOPA-induced dyskinesia.
Topics: Animals; Antiparkinson Agents; Disease Models, Animal; Dopamine; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease
PubMed: 35039902
DOI: 10.1007/s00415-022-10963-w -
Metabolic Engineering May 2021L-DOPA, also known as Levodopa or L-3,4-dihydroxyphenylalanine, is a non-standard amino acid, and the gold standard drug for the treatment for Parkinson's Disease (PD)....
L-DOPA, also known as Levodopa or L-3,4-dihydroxyphenylalanine, is a non-standard amino acid, and the gold standard drug for the treatment for Parkinson's Disease (PD). Recently, a gene encoding the enzyme that is responsible for its synthesis, as a precursor of the coloured pigment group betalains, was identified in beetroot, BvCYP76AD6. We have engineered tomato fruit enriched in L-DOPA through overexpression of BvCYP76AD6 in a fruit specific manner. Analysis of the transgenic fruit revealed the feasibility of accumulating L-DOPA in a non-naturally betalain-producing plant. Fruit accumulating L-DOPA also showed major effects on the fruit metabolome. Some of these changes included elevation of amino acids levels, changes in the levels of intermediates of the TCA and glycolysis pathways and reductions in the levels of phenolic compounds and nitrogen-containing specialised metabolites. Furthermore, we were able to increase the L-DOPA levels further by elevating the expression of the metabolic master regulator, MYB12, specifically in tomato fruit, together with BvCYP76AD6. Our study elucidated new roles for L-DOPA in plants, because it impacted fruit quality parameters including antioxidant capacity and firmness. The L-DOPA levels achieved in tomato fruit were comparable to the levels in other non-seed organs of L-DOPA - accumulating plants, offering an opportunity to develop new biological sources of L-DOPA by widening the repertoire of L-DOPA-accumulating plants. These tomato fruit could be used as an alternative source of this important pharmaceutical.
Topics: Betalains; Fruit; Levodopa; Solanum lycopersicum; Metabolic Engineering
PubMed: 33242649
DOI: 10.1016/j.ymben.2020.11.011