The human pyridoxal kinase, a plausible target for ginkgotoxin from <i>Ginkgo biloba</i>

Kästner, Uta; Hallmen, Christian; Wiese, Michael; Leistner, Eckhard; Drewke, Christel

doi:10.1111/j.1742-4658.2007.05654.x

Cited by 63 publications

(72 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, human pyridoxal kinase is inhibited by a range of substances of natural and synthetic origin, especially by small heterocyclic compounds, e.g. ginkgotoxin or theophylline [12][13][14][15] . Hence, inhibition of pyridoxal kinase by THI does not appear unlikely and we considered a detailed investigation worthwhile.…”

Section: Resultsmentioning

confidence: 99%

“…Human pyridoxal kinase has been shown to be inhibited by a range of substances of natural and synthetic origin, especially by small heterocyclic compounds. Some well-known drugs inhibit human pyridoxal kinase, causing a number of unwanted neurotoxic side effects [12][13][14][15] . Some reports, however, question that the pyridoxal kinase inhibiting properties of class III caramel colourings actually originate from THI 16 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

Elsinghorst

Salvo

Parroni

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

2-Acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI) is observed as a minor contaminant in caramel food colourings (E 150c). Feeding experiments with rodents have revealed a significant lymphopenic effect that has been linked to the presence of THI in these food colourings. Pyridoxal kinase inhibition by THI has been suggested, but not demonstrated, as a mode of action as it leads to lowered levels of pyridoxal-5 0 -phosphate, which are known to cause lymphopenia. Recently, THI was also shown to inhibit sphingosine-1-phosphate lyase causing comparable immunosuppressive effects and derivatives of THI are being developed for the treatment of rheumatoid arthritis in humans. Interestingly, sphingosine-1-phosphate lyase activity depends on pyridoxal-5 0 -phosphate, which in turn is provided by pyridoxal kinase. This report shows that THI does inhibit pyridoxal kinase with competitive and mixed-type non-competitive behaviour towards its two substrates, pyridoxal and ATP, respectively. The corresponding inhibition constants are in the low millimolar range.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

Elsinghorst

Salvo

Parroni

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…Various supplements from Ginkgo biloba are available over the counter and widely used in alleviating medical conditions including bronchial asthma, irritable bladder, depression, dizziness and tinnitus (Kajiyama et al, 2002; Kastner et al, 2007; Leistner and Drewke, 2010; Wada et al, 1985). However, use or accidental ingestion of Ginkgo biloba resulting in an overdose of ginkgotoxin is reported to cause poisoning, characterized by epileptic convulsions, vomiting, unconsciousness and irritability.…”

Section: Introductionmentioning

confidence: 99%

Zebrafish larvae exposed to ginkgotoxin exhibit seizure-like behavior that is relieved by pyridoxal-5′-phosphate, GABA and anti-epileptic drugs

Lee

Sung

Chang

et al. 2012

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

SUMMARYThe etiology of epilepsy is a very complicated, multifactorial process that is not completely understood. Therefore, the availability of epilepsy animal models induced by different mechanisms is crucial in advancing our knowledge and developing new therapeutic regimens for this disorder. Considering the advantages of zebrafish, we have developed a seizure model in zebrafish larvae using ginkgotoxin, a neurotoxin naturally occurring in Ginkgo biloba and hypothesized to inhibit the formation of the neurotransmitter γ-aminobutyric acid (GABA). We found that a 2-hour exposure to ginkgotoxin induced a seizure-like behavior in zebrafish larvae. This seizure-like swimming pattern was alleviated by the addition of either pyridoxal-5′-phosphate (PLP) or GABA and responded quickly to the anti-convulsing activity of gabapentin and phenytoin, two commonly prescribed anti-epileptic drugs (AEDs). Unexpectedly, the ginkgotoxin-induced PLP depletion in our experimental setting did not affect the homeostasis of folate-mediated one-carbon metabolism, another metabolic pathway playing a crucial role in neural function that also relies on the availability of PLP. This ginkgotoxin-induced seizure behavior was also relieved by primidone, which had been tested on a pentylenetetrazole-induced zebrafish seizure model but failed to rescue the seizure phenotype, highlighting the potential use and complementarity of this ginkgotoxin-induced seizure model for AED development. Structural and morphological characterization showed that a 2-hour ginkgotoxin exposure did not cause appreciable changes in larval morphology and tissues development. In conclusion, our data suggests that this ginkgotoxin-induced seizure in zebrafish larvae could serve as an in vivo model for epileptic seizure research and potential AED screening.

show abstract

“…[56] The assay determines phosphorylation of pyridoxal by PDXK by measuring pyridoxal 5'-phosphate at its absorption maximum of 388 nm. Test compounds dissolved in DMSO were pipetted into the wells of a UV/vis-transparent 96-well microtiter plate (BD Biosciences Europe, Erembodegem, Belgium) that contained assay buffer (250 mL; 70 mm potassium phosphate, pH 6.2, 0.1 mm ZnCl 2 , 2.5 mm ATP, 2.5 mg mL À1 PDXK).…”

Section: Enzymatic Assaysmentioning

confidence: 99%

“…[56] The recombinant strain BL21 (DE3)-pET11a-PDXK was grown in LB medium that contained ampicillin (200 mg mL…”

Section: Immobilization Of Pyridoxalmentioning

confidence: 99%

Off‐Target Decoding of a Multitarget Kinase Inhibitor by Chemical Proteomics

et al. 2009

View full text Add to dashboard Cite

Unbiased: Chemical proteomics was used to profile compound interactions in an unbiased fashion. We present here the application of different compound-immobilization routes for decoding nonprotein kinase off-targets of the multitarget kinase inhibitor C1, which interacts with distinct compound moieties. Since the approval of the first selective tyrosine kinase inhibitor, imatinib, various drugs have been developed to target protein kinases. However, due to a high degree of structural conservation of the ATP binding site, off-target effects have been reported for several drugs. Here, we report on off-target decoding for a multitarget protein kinase inhibitor by chemical proteomics, by focusing on interactions with nonprotein kinases. We tested two different routes for the immobilization of the inhibitor on a carrier matrix, and thus identified off-targets that interact with distinct compound moieties. Besides several of the kinases known to bind to the compound, the pyridoxal kinase (PDXK), which has been described to interact with the CDK inhibitor (R)-roscovitine, was captured. The PDXK-inhibitor interaction was shown to occur at the substrate binding site rather than at the ATP binding site. In addition, carbonic anhydrase 2 (CA2) binding was demonstrated, and the determination of the IC(50) revealed an enzyme inhibition in the submicromolar range. The data demonstrate that different compound immobilization routes for chemical proteomics approaches are a valuable method to improve the knowledge about the off-target profile of a compound.

show abstract

The human pyridoxal kinase, a plausible target for ginkgotoxin from Ginkgo biloba

Cited by 63 publications

References 28 publications

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

Inhibition of human pyridoxal kinase by 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI)

Zebrafish larvae exposed to ginkgotoxin exhibit seizure-like behavior that is relieved by pyridoxal-5′-phosphate, GABA and anti-epileptic drugs

Off‐Target Decoding of a Multitarget Kinase Inhibitor by Chemical Proteomics

Contact Info

Product

Resources

About