Competitive inhibition between 4'-substituted pyridoxine analogues and pyridoxal for pyridoxal kinase from mouse brain.

Mizuno, Nobuyasu; Kawakami, Kimihiro; Morita, Emiko

doi:10.3177/jnsv.26.535

Cited by 18 publications

(23 citation statements)

References 5 publications

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“…These drugs include the vitamin B6 analog 4-deoxypyridoxine (4-DP), isoniazid (tuberculosis treatment, antidepressant), penicillamine (antirheumatic), and cycloserine (tuberculosis treatment, antidepressant) [32], [33]. Brains from wild type larvae incubated for 4 hours in the presence of 4-DP, isoniazid or penicillamine (protocol 2, Figure 1B) showed higher levels of CABs than untreated controls (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Sugar and Chromosome Stability: Clastogenic Effects of Sugars in Vitamin B6-Deficient Cells

et al. 2014

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Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, has been implicated in preventing human pathologies, such as diabetes and cancer. However, the mechanisms underlying the beneficial effects of PLP are still unclear. Using Drosophila as a model system, we show that PLP deficiency, caused either by mutations in the pyridoxal kinase-coding gene (dPdxk) or by vitamin B6 antagonists, results in chromosome aberrations (CABs). The CAB frequency in PLP-depleted cells was strongly enhanced by sucrose, glucose or fructose treatments, and dPdxk mutant cells consistently displayed higher glucose contents than their wild type counterparts, an effect that is at least in part a consequence of an acquired insulin resistance. Together, our results indicate that a high intracellular level of glucose has a dramatic clastogenic effect if combined with PLP deficiency. This is likely due to an elevated level of Advanced Glycation End-products (AGE) formation. Treatment of dPdxk mutant cells with α-lipoic acid (ALA) lowered both AGE formation and CAB frequency, suggesting a possible AGE-CAB cause-effect relationship. The clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. RNAi-mediated silencing of PDXK in human cells or treatments with PLP inhibitors resulted in chromosome breakage, which was potentiated by glucose and reduced by ALA. These results suggest that patients with concomitant hyperglycemia and vitamin B6 deficiency may suffer chromosome damage. This might impact cancer risk, as CABs are a well-known tumorigenic factor.

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Section: Resultsmentioning

confidence: 99%

Sugar and Chromosome Stability: Clastogenic Effects of Sugars in Vitamin B6-Deficient Cells

et al. 2014

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“…We next examined the role of Pdxk on the genome integrity of human cells by employing the well-characterized vitamin B6 analog 4-deoxypyridoxine (4-DP) [44]. First, we determined whether inhibition of human Pdxk leads to DNA damage, particularly DSBs.…”

Section: Resultsmentioning

confidence: 99%

A Screen for Suppressors of Gross Chromosomal Rearrangements Identifies a Conserved Role for PLP in Preventing DNA Lesions

Kanellis

Gagliardi

Banáth³

et al. 2007

PLoS Genet

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Genome instability is a hallmark of cancer cells. One class of genome aberrations prevalent in tumor cells is termed gross chromosomal rearrangements (GCRs). GCRs comprise chromosome translocations, amplifications, inversions, deletion of whole chromosome arms, and interstitial deletions. Here, we report the results of a genome-wide screen in Saccharomyces cerevisiae aimed at identifying novel suppressors of GCR formation. The most potent novel GCR suppressor identified is BUD16, the gene coding for yeast pyridoxal kinase (Pdxk), a key enzyme in the metabolism of pyridoxal 5′ phosphate (PLP), the biologically active form of vitamin B6. We show that Pdxk potently suppresses GCR events by curtailing the appearance of DNA lesions during the cell cycle. We also show that pharmacological inhibition of Pdxk in human cells leads to the production of DSBs and activation of the DNA damage checkpoint. Finally, our evidence suggests that PLP deficiency threatens genome integrity, most likely via its role in dTMP biosynthesis, as Pdxk-deficient cells accumulate uracil in their nuclear DNA and are sensitive to inhibition of ribonucleotide reductase. Since Pdxk links diet to genome stability, our work supports the hypothesis that dietary micronutrients reduce cancer risk by curtailing the accumulation of DNA damage and suggests that micronutrient depletion could be part of a defense mechanism against hyperproliferation.

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“…To date, the effect of ginkgotoxin on pyridoxal kinase had been studied only with a partially purified homogenate from mouse brain [5]. Detailed experiments on the mode of inhibition of the human enzyme by ginkgotoxin are lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Ginkgotoxin is structurally related to vitamin B 6 and likely interferes with its biosynthesis, metabolism or function. It is for this reason that ginkgotoxin is considered to be a B 6 ‘antivitamin’, as is 4′‐deoxypyridoxine (DPN) [5] (Fig. 1), a synthetic analogue of the B 6 vitamers pyridoxal (PL), pyridoxamine (PM) and pyridoxine (PN).…”

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confidence: 99%

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

Kästner

Hallmen²,

Wiese³

et al. 2007

The FEBS Journal

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Ginkgotoxin (4′‐O‐methylpyridoxine) occurring in the seeds and leaves of Ginkgo biloba, is an antivitamin structurally related to vitamin B6. Ingestion of ginkgotoxin triggers epileptic convulsions and other neuronal symptoms. Here we report on studies on the impact of B6 antivitamins including ginkgotoxin on recombinant homogeneous human pyridoxal kinase (EC 2.7.1.35). It is shown that ginkgotoxin serves as an alternate substrate for this enzyme with a lower Km value than pyridoxal, pyridoxamine or pyridoxine. Thus, the presence of ginkgotoxin leads to temporarily reduced pyridoxal phosphate formation in vitro and possibly also in vivo. Our observations are discussed in light of Ginkgo medications used as nootropics.

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Competitive inhibition between 4'-substituted pyridoxine analogues and pyridoxal for pyridoxal kinase from mouse brain.

Cited by 18 publications

References 5 publications

Sugar and Chromosome Stability: Clastogenic Effects of Sugars in Vitamin B6-Deficient Cells

Sugar and Chromosome Stability: Clastogenic Effects of Sugars in Vitamin B6-Deficient Cells

A Screen for Suppressors of Gross Chromosomal Rearrangements Identifies a Conserved Role for PLP in Preventing DNA Lesions

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

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