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Influence of Antivitamins Ginkgotoxin 5′-Phosphate and Deoxypyridoxine 5′-Phosphate on Human Pyridoxine 5′-Phosphate Oxidase*

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Influence of Antivitamins Ginkgotoxin 5′-Phosphate and Deoxypyridoxine 5′-Phosphate on Human Pyridoxine 5′-Phosphate Oxidase* Original Paper 563 Influence of Antivitamins Ginkgotoxin 5′-Phosphate and Deoxypyridoxine 5′-Phosphate on Human Pyridoxine 5′-Phosphate Oxidase* Authors Nora Salamon, Cristian Gurgui, Eckhard Leistner, Christel Drewke Affiliation Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany Key words Abstract inhibited in vitro by the synthetic vitamin B6 de- l" Ginkgo biloba ! rivative 4′-deoxypyridoxine 5′-phosphate but not l" Ginkgoaceae The pharmacological effects of leaf extracts (EGb by ginkgotoxin or its 5′-phosphate. l" ′‑ ginkgotoxin 5 phosphate 761) from Ginkgo biloba L. are attributed to gink- l" 4′‑deoxypyridoxine 5′‑phos- golides, bilobalide and biflavonoids. However, be- phate l" pyridoxine 5′‑phosphate oxi- sides these beneficial attributes, ginkgotoxin, a B6 Abbreviations ! dase antivitamin which may cause epileptic convul- l" pyridoxal 5′‑phosphate phos- sions, other severe neuronal disorders and even GABA: γ-aminobutyric acid phatase death, is also found in Ginkgo leaves and leaf-de- GAD: glutamate decarboxylase l" vitamin B6 rived remedies. Because of its structural similar- MPN(P): 4′-O-methylpyridoxine ity to the B6 vitamers, an interaction of ginkgotox- (5′-phosphate), i.e., ginkgotoxin in with enzymes involved in the vitamin B6-de- (5′-phosphate) DPN(P): pendent metabolism of the human brain is possi- 4′-deoxypyridoxine (5′-phosphate) ble. This led us to investigate how the neurotoxic PKH: human pyridoxal kinase ginkgotoxin acts in the brain. To this end the gene PL(P): pyridoxal (5′-phosphate) coding for the human pyridoxine 5′-phosphate PLPP: pyridoxal 5′-phosphate phosphatase oxidase was heterologously overexpressed in E. PM(P): pyridoxamine (5′-phosphate) coli and the homogeneous enzyme was character- PN(P): pyridoxine (5′-phosphate) ized. The investigation showed that the enzyme is PNPO: pyridoxine 5′-phosphate oxidase Introduction metabolism and the synthesis of neurotransmit- ! ters in the brain. Thus, an inhibitory or competi- Downloaded by: University of Washington at Seattle. Copyrighted material. received Dec. 18, 2008 Medications based on Ginkgo extracts are top sell- tive influence of ginkgotoxin on these reactions revised January 28, 2009 ing phytopharmaceuticals. The leaves of Ginkgo in vivo seems plausible. Indeed, it has been shown accepted February 12, 2009 biloba are the source of remedies used in the ther- for animal models that the administration of gink- ′ Bibliography apy for insufficient central and peripheral blood gotoxin and other 4 -substituted vitamin B6 ana- DOI 10.1055/s-0029-1185482 flow [1]. The characteristic ingredients which the logues (e.g., 4′-deoxypyridoxine, DPN, l" Fig. 1) Published online March 13, beneficial effects are attributed to are ginkgolides, results in an impaired amino acid metabolism of 2009 bilobalide and biflavonoids [2–5]. However, be- the brain: the production of the important inhib- Planta Med 2009; 75: 563–567 sides these, the B antivitamin ginkgotoxin (i.e., itory neurotransmitter γ-aminobutyric acid (GA- © Georg Thieme Verlag KG 6 ′ l" Stuttgart · New York · 4 -O-methylpyridoxine, MPN) ( Fig. 1) has been BA) is significantly decreased concomitantly with ISSN 0032‑0943 found in the seeds and leaves of Ginkgo biloba, a reduction in glutamate decarboxylase activity and it is even detectable in leaf-based remedies (GAD) in different regions of the rabbit brain and Correspondence Dr. C. Drewke [6]. Ginkgotoxin is a structural analogue of the in the brain of guinea pigs [7–10]. The effects Institute of Pharmaceutical physiologically active B6 vitamins pyridoxal 5′- caused by ginkgotoxin and 4′-deoxypyridoxine Biology phosphate (PLP) and pyridoxamine 5′-phosphate were alleviated by the addition of vitamin B6 [10, University of Bonn l" Nussallee 6 (PMP) ( Fig. 2), which participate in many enzy- 11]. That is why these latter two vitamin B6 deriv- 53115 Bonn matic reactions including those of the amino acid atives are named antivitamins. Investigations on Germany rats and guinea pigs revealed that administration Phone: + 49228732563 of ginkgotoxin led to convulsions followed by Fax: + 492 28733250 * Dedicated to Dr. Heinz G. Floss on the occasion of his 75th γ [email protected] birthday. death of the animals. Also, the cerebral -amino- Salamon N et al. Influence of Antivitamins… Planta Med 2009; 75: 563–567 564 Original Paper Fig. 1 B6 antivitamins 4′-deoxypyridoxine (DPN), ginkgotoxin (MPN) and their 5′-phosphate esters DPNP and MPNP. Fig. 2 Salvage pathway interconverting the B6 vitamers. PKH: human pyr- idoxal 5′-kinase, PNPO: pyridoxine (pyridoxamine) 5′-phosphate oxidase, butyric acid level was reduced with a simultaneous increase of PLPP: pyridoxal (pyridoxine, pyridoxamine) 5′-phosphate phosphatase, PN ′ ′ glutamine and glutamate concentrations [10,12]. (P): pyridoxine (5 -phosphate), PM(P): pyridoxamine (5 -phosphate), PL(P): pyridoxal (5′-phosphate). Similar symptoms had been described as the result of overcon- sumption of Ginkgo seeds in East Asia in the 1930s and 1940s [13,14]: epileptiformic convulsions, vomiting, unconsciousness and paralysis of extremities were the characteristics of this so- convulsions due to the excessive consumption of Ginkgo seeds called “gin-nan sitotoxism”. Many intoxications (up to 74%) were [17,18]. Thus, these results clearly implicate pyridoxal 5′-kinase observed in children and they were lethal in 27% of the cases as a physiological target for ginkgotoxin and provide a plausible [13]. explanation for the intoxication symptoms caused by the toxin. Since epileptic convulsions may be the result of a glutamate/γ- However, an interaction of ginkgotoxin with further enzymes in- aminobutyric acid imbalance, gin-nan sitotoxism can well be ex- volved in the provision of active cofactor for the amino acid me- plained by inhibition of glutamate decarboxylase (GAD) [14,15], tabolism of the brain cannot be excluded. One of these is pyridox- which converts glutamate to γ-aminoburyric acid using pyridox- ine 5′-phosphate oxidase (PNPO) (EC 1.4.3.5.), another enzyme al 5′-phosphate as a cofactor. Inhibition of this enzyme by re- besides pyridoxal 5′-kinase (PKH) of the salvage pathway placement of pyridoxal 5′-phosphate by ginkgotoxin would cause (l" Fig. 2). The enzyme uses both pyridoxine 5′-phosphate and an accumulation of glutamate and thus could lead to the epilepti- pyridoxamine 5′-phosphate as substrates [19–21]. Because of formic seizures observed during intoxication with ginkgotoxin. the structural similarity to these vitamers, an interference of However, the hypothesis that the direct inhibition of glutamate ginkgotoxin or its 5′-phosphate with pyridoxine 5′-phosphate decarboxylase by ginkgotoxin leads to an impaired amino acid oxidase seemed possible. Furthermore, it has already been metabolism of the brain and as such triggers the symptoms of shown that 4′-deoxypyridoxine 5′-phosphate, a synthetic B6 anti- ginkgotoxin intoxication was disproven by studies of Buss et al. vitamin (l" Fig. 1), inhibits the oxidase from rabbit liver between [15]: indeed an inhibition of the glutamate decarboxylase isoen- 34% to 70.2% in high concentrations (200 µM, 1 mM) [21] de- zyme GAD65 by ginkgotoxin 5′-phosphate was shown in vitro, but pending on the substrate (PNP or PMP) employed. A Ki value has the concentration at which this inhibition took place was physio- not been given. logically not relevant (2.7 mM). Since the highest concentration These considerations led us to investigate the antivitamins of ginkgotoxin determined in the serum of people suffering from shown in l" Fig. 1 with respect to their ability to inhibit human gin-nan sitotoxism did not exceed 6.99 µM [15–17] a significant pyridoxine 5′-phosphate oxidase in vitro. As a result, neither interaction of ginkgotoxin with glutamate decarboxylase in vivo ginkgotoxin nor its 5′-phosphate affect the activity of pyridoxine Downloaded by: University of Washington at Seattle. Copyrighted material. can be excluded. 5′-phosphate oxidase in vitro and thus very probably also not in These results prompted us to investigate the possibility that gink- vivo. We observed, however, that the enzyme is inhibited by the gotoxin interferes with the glutamic acid metabolism in an indi- synthetic 4′-deoxypyridoxine 5′-phosphate. rect way through reduction of the vitamin B6 supply in the hu- man brain. A limitation of the active cofactors pyridoxal 5′-phos- phate and pyridoxamine 5′-phosphate can be caused by inhibi- Materials and Methods tion of pyridoxal 5′-kinase (PKH, i.e., human pyridoxal 5′-kinase) ! or pyridoxine 5′-phosphate oxidase (PNPO) which interconvert Subcloning of human pyridoxine 5′-phosphate oxidase " the B6 vitamers in the “salvage pathway” (l Fig. 2). Indeed, re- An EcoRI and XhoI fragment (788 bp) containing the cDNA se- cently it has been reported that ginkgotoxin is phosphorylated quence coding for human pyridoxine 5′-phosphate oxidase by recombinant human pyridoxal 5′-kinase as an alternate sub- (BC006525) was isolated from a commercially available recombi- strate with a significantly lower Km value compared to pyridoxal nant vector (pOTB-PNPO) (Promochem GmbH; catalog no. MGC- (PL) (4.95 µM vs. 58.7 µM) and thus competitively inhibits the for- 953). For further expression the fragment was amplified by PCR mation of pyridoxal 5′-phosphate, the cofactor of glutamate de- along with the creation of a 5′ NdeI and a 3′ BamHI restriction site carboxylase [18]. Due to the 4′-methoxy group a better passage of the PNPO sequence using Platinium® Pfx DNA polymerase
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