[Frontiers in Bioscience E4, 897-913, January 1, 2012]
Biomedical aspects of pyridoxal 5'-phosphate availability
Martino L. di Salvo1, Martin K. Safo2, Roberto Contestabile1
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TABLE OF CONTENTS
1. ABSTRACT
The biologically active form of vitamin B6, pyridoxal 5'-phosphate (PLP), is a cofactor in over 160 enzyme activities involved in a number of metabolic pathways, including neurotransmitter synthesis and degradation. In humans, PLP is recycled from food and from degraded PLP-dependent enzymes in a salvage pathway requiring the action of pyridoxal kinase, pyridoxine 5'-phosphate oxidase and phosphatases. Once pyridoxal 5'-phosphate is made, it is targeted to the dozens different apoenzymes that need it as a cofactor. The regulation of the salvage pathway and the mechanism of addition of PLP to the apoenzymes are poorly understood and represent a very challenging research field. Severe neurological disorders, such as convulsions and epileptic encephalopathy, result from a reduced availability of pyridoxal 5'-phosphate in the cell, due to inborn errors in the enzymes of the salvage pathway or other metabolisms and to interactions of drugs with PLP or pyridoxal kinase. Multifactorial neurological pathologies, such as autism, schizophrenia, Alzheimer's disease, Parkinson's disease and epilepsy have also been correlated to inadequate intracellular levels of PLP.
2. INTRODUCTION
Although the term vitamin B6 is often employed as a synonymous of pyridoxine (PN), it actually refers to an ensemble of six substituted pyridine compounds, which also includes pyridoxal (PL), pyridoxamine (PM) and the related 5'-phosphate derivatives (Figure 1). The biologically active form of the vitamin, pyridoxal 5'-phosphate (PLP), is used as enzyme cofactor in a multitude of biochemical transformations, ranging in complexity from simple isomerizations to elaborate syntheses. Also, pyridoxamine 5'-phosphate (PMP) acts as a cofactor for the aminotransferases and in few other enzymes. Vitamin B6-dependent (or PLP-dependent) enzymes, which are responsible for more than 160 distinct catalytic functions (about 4% of all classified enzyme activities) (1, 2), have a widespread involvement in cell metabolism, being involved in amino acids synthesis, transformation and degradation, one carbon units supply, transsulfuration, synthesis of tetrapyrrolic compounds and polyamines. Recently, PLP and pyridoxine have been shown to have a role in membrane ion transport (3-5), to bind to steroid receptors (6) and to modulate transcription factors (7). An additional function of B6 vitamers as oxygen reactive species (ROS) scavengers and factors able to increase resistance to biotic and abiotic stress has been demonstrated in plants (8, 9). Recently, vitamin B6 has also been described as a new virulence factor in Helicobacter pylori, required for the chronic colonization of mice (10). Considering that mammalian hosts are unable to perform de novo vitamin B6 biosynthesis, this finding is of particular interest for the development of new therapeutic targets against bacterial pathogens.
2.1. Role of PLP-dependent enzymes in brain function
Beside their textbook role in the synthesis and degradation of amino acids, PLP-dependent enzymes are involved in the metabolism of several neurotransmitters such as dopamine, serotonin, glycine, epinephrine, norepinephrine, D-serine, L-glutamate, gamma-aminobutyric acid and histamine, whose levels may be affected by PLP deficiency. One important example is the formation of L-glutamate and its breakdown to gamma-aminobutyric acid (GABA). L-glutamate and GABA are the main excitatory and inhibitory neurotransmitters in the central nervous system (CNS), respectively. A significant amount of the de novo synthesized L-glutamate in the CNS is formed from alpha-ketoglutarate and branched-chain amino acids by the action of branched-chain aminotransferase (11). GABA is formed upon decarboxylation of L-glutamate catalyzed by L-glutamic acid decarboxylase (GAD), and is then consumed in the transamination reaction catalyzed by GABA aminotranferase, regenerating L-glutamate. Histamine is formed from decarboxylation of histidine, acted by histidine decarboxylase. Aromatic L-amino acid decarboxylase is involved in the formation of dopamine and serotonine. Dopamine is a precursor of epinephrine and norepinephrine. D-serine, synthesized by serine racemase from L-serine, serves as neuronal signal by activating N-methyl-D-aspartic acid (NMDA) receptors in the brain. While glycine is the primary inhibitory neurotransmitter of the spinal cord and brainstem, it has excitatory effects in the cerebral cortex owing to its agonism for the glutamatergic NMDA receptor. Glycine is formed from L-serine by serine hydroxymethyltransferase and is degraded by the glycine cleavage system, of which one of the four protein components is glycine decarboxylase, another PLP-dependent enzyme.
PLP-dependent enzymes also take part in the kynurenine oxidative pathway of tryptophan degradation, whose catabolic intermediates (kynurenic acid, 3-hydroxykynurenine and quinolinic acid) are involved in the physiological tuning of the CNS and in the etiogenesis and progression of several human neurodegenerative disorders (12, 13).
2.2. Supply of PLP to the enzymes that require it as a cofactor
Microorganisms and plants are able to synthesize PLP using two different and mutually exclusive routes and can also recycle it from protein degradation. Recycling of PLP from B6 vitamers introduced with food is the only way all other organisms have to obtain PLP. Mammals acquire B6 vitamers via intestinal absorption and convert them all into PLP through a salvage pathway (Figure 2). B6 vitamers are absorbed from food and from the microflora, which normally colonizes the large intestine. In animal-derived foods, vitamin B6 is mainly present as PLP, associated to glycogen phosphorylase, and in smaller amounts as PMP, while in plants it is present as PN and PN-5'-beta-D-glucoside (Figure 1) (14). PN-5'-beta-D-glucoside appears to have reduced availability because of the need for hydrolysis by an intestinal glucosidase (15). In human breast milk, vitamin B6 is present as PLP and PL (16). The form of vitamin B6 that is usually employed to fortify foods is pyridoxine hydrochloride, since this is the most commercially convenient.
Once ingested, PLP, PNP and PMP are dephosphorylated by the ecto-enzyme tissue-specific intestinal phosphatase, prior to absorption from the upper small intestine by a carrier-mediated system (17). The portal circulation delivers PM, PN and PL to the liver, where they are phosphorylated by the ATP-dependent pyridoxal kinase (PLK) to PMP, PNP and PLP, respectively. PNP and PMP are then both oxidized to PLP by the FMN-dependent pyridoxine (pyridoxamine) 5'-phosphate oxidase (PNPOx). PLP must return to the blood stream in order to reach all tissues. Albumin-bound PLP represents about 60% of circulating vitamin B6, with PN, PM and PL making up the remaining part (18). While dephosphorylated B6 vitamers can enter the cells and pass the blood-brain barrier, PLP needs to be dephosphorylated again. Tissue-specific phosphatases, expressed in placenta and germ cells (19), and the tissue-nonspecific alkaline phosphatase (TNAP) are membrane-associated enzymes responsible for this step. PL is the vitamer form that is mainly acquired by neurons; once formed by TNAP at the choroid plexus, PL is transported into the cerebrospinal fluid by an active transport mechanism and crosses the neuron plasma membranes to be rephosphorylated in the cells (18). In the cytoplasm, PL, PN and PM are converted into the 5'-phosphorylated vitamers by PLK, while PNPOx converts PNP and PMP into PLP. Once made available, PLP is somehow targeted to the dozens different apo-B6 enzymes that are being synthesized in the cell.
The expression of mRNA of all three enzymes of the salvage pathway is ubiquitous but is highly regulated at the level of transcription in a tissue-specific manner. While PLK is expressed in all tissues, although with the presence of isoforms (20), the major sites of PNPOx expression are liver, skeletal muscle and kidneys; PNPOx is also present, to a lesser extent, in the brain, in particular in the cerebral cortex (21). PNPOx activity is absent in liver and in neurally derived tumors (22, 23). It is worth of note that the pool of free PLP in vivo must be maintained at a very low level in the body, to prevent toxic buildup. In fact, PLP being a very reactive aldehyde, easily combines with amines and thiols in the cell (24). This characteristic has been related to the neurotoxic effect of excess consumption of vitamin B6 (19-21). In eukaryotic cells, the concentration of free PLP is maintained as low as 1 microM. One mechanism involved in PLP homeostasis is the regulation of its rate of production by PLK and PNPOx. Interestingly, it has been shown that both enzymes are able to bind their reaction product, PLP, and that their activity is finely regulated by it. Inhibition of PNPOx activity by the PLP product was observed in the E. coli enzyme, with a Ki of 8 microM (25). MgATP substrate inhibition of E. coli PLK has been observed in the presence of either PNP or PLP (26). A concurring mechanism for maintaining low levels of free PLP is expected to be its dephosphorylation by phosphatases. Catalytic conversion of pyridoxal to 4-pyridoxic acid by aldehyde oxidases and NAD-dependent dehydrogenases also keeps the level of PLP low (27).
The low free PLP concentration in the cell is not believed to be sufficient to allow for spontaneous formation of holo-B6 enzymes (28, 29) and raises the intriguing question of how PLP is actually delivered to the apoenzymes that use it as a cofactor. The importance of vitamin B6 in several cellular processes and in the onset of different pathologies should also be looked at from this new perspective. Studies on PNPOx and PLK suggested that once PLP is formed by these enzymes, it is unlikely to be released into solution, where it could be sequestered, and that it could be rather directly channeled to apo-B6 enzymes (29-31). We have recently observed that a fraction of human PLK purified after expression in E. coli is complexed with PLP and that the stoichiometric amount of PLP bound to the enzyme increases if MgATP is included in the purification buffers. Our published and ongoing studies showed that the active site of PLK binds ATP and PLP tightly, forming a stable ternary complex, and that this PLP is easily transferred to apo-B6 enzymes to form the active holoenzymes (32). Crystallographic and functional studies have shown PLP to bind to PNPOx at a tight binding site that is distinct from the active site and to be readily transferred to serine hydroxymethyltransferase (30, 33, 34). The formation of specific complexes between the oxidase or kinase and a number of different B6 enzymes (that is a requirement for the channeling mechanism) has been observed recently in our laboratory and previously by other authors (29, 31, 32).
Failing to maintain a correct tuning between PLP biosynthesis and degradation, transport to peripheral tissues and delivering to newly formed B6 enzymes might end up in vitamin B6-associated pathogenesis.
3. REASONS AND CONSEQUENCES OF PLP DEFICIENCY
Several are the causes of a reduced availability of PLP in the cell, which results in the incomplete transformation of the newly synthesized, inactive apoenzymes into their active, holoenzyme form. Dietary deficiency, although rare in the western world, is a cause of insufficient vitamin B6 consumption in developing countries, especially in infants, children, women and HIV-1 seropositive patients (35). One of the main causes of vitamin B6 deficiency in developed countries may be the use of contraceptives. In fact, it has been proposed that the vitamin B6 status may be adversely affected by the use of oral contraceptives (36, 37). A recent large-scale population-based study, in which plasma PLP concentration was measured in samples from nearly 8000 participants in the US National Health and Nutrition Examination Survey conducted between 2003 and 2004, showed a significant lower PLP concentration in oral contraceptive users with respect to women who had never assumed exogenous estrogens (38). The same study also showed that smoking lowers plasma PLP levels. Coeliac disease is thought to lead to a reduced absorption of B6 vitamers (39) while renal dialysis determines their loss from circulation. Alcoholism and diabetes also cause vitamin B6 dietary deficiency (40, 41).
Apart from weakness, irritability, insomnia and difficulty with walking, an insufficient vitamin B6 intake has been observed to cause seizures in infants (42), EEG changes in adults (43) and has been also related to hyperhomocysteinemia (44). MCF-7 cells cultured on vitamin B6-deficient medium have lower intracellular PLP and S-adenosyl methionine levels, and the S-adenosyl methionine to S-adenosyl-L-homocysteine ratio is also lower (45). A strong correlation has been established between high levels of homocysteine in the blood due to vitamin B6 deficiency and cardiovascular disease (46). Dietary deficiency of vitamin B6 has been also implicated in cerebrovascular disease (47) and cancer (48). An investigation on Wistar rat has revealed that vitamin B6 deficiency results in the elevation of liver iron concentration and in the reduction of muscle iron concentration (49). Most probably, these alterations of tissue iron concentration are the result of an impairment of heme synthesis. 5-Aminolevulinate, the universal precursor of tetrapyrrole compounds, is derived from a reaction catalyzed by a PLP-dependent enzyme, aminolevulinate synthase, i.e. the condensation of glycine and succinyl-CoA (50). The liver is one of the highest producers of heme in the body. It was therefore hypothesized that the deficiency of heme biosynthesis caused the build up of excess iron in this organ. Macrocytic and microcytic anemia have been indeed associated with a deficiency of dietary vitamin B6 (51). Decreased plasma PL level, loss of appetite and decreased food intake were other outcomes of vitamin B6 deficiency in Wistar rat. Another investigation on Wistar rat has demonstrated that magnesium deficiency impairs vitamin B6 status by decreasing intracellular Mg2+ concentration and thus inhibiting the activity of alkaline phosphatase, a metalloenzyme required for the uptake of PLP by tissues (52).
Vitamin B6 supplementation has been shown to be beneficial in the management of premenstrual syndrome (53), nausea and vomiting during pregnancy (54) and treatment of carpal tunnel syndrome (55). On the other hand, large doses of vitamin B6 were shown to have detrimental effects in experimental animals and humans. Toxicity is observed usually when the intake exceeds 200 mg/day. The current recommended dietary allowance of vitamin B6 is 2 mg/day. Signs of toxicity occur mostly in the peripheral nervous system and include changes in gait and peripheral sensation (56). Central nervous system abnormalities are less commonly observed with excessive vitamin B6 intake, and it has been suggested that the brain is protected from large doses of vitamin B6 (57, 58).
Apart from dietary deficiency, secondary vitamin B6 deficiency may result from one of the following circumstances: i) the catalytic activity of the salvage pathway enzymes may be affected by inherited mutations; ii) inborn errors in enzymes involved in certain metabolisms may lead to the accumulation of intermediates that react with PLP, reducing its availability; iii) some drugs or natural compounds binding to PLK may lead to its inactivation or reacting with PLP may reduce its availability. In all these cases, the most immediate effects of the insufficient supply of PLP are seen on the central nervous system, in the form of several different but related neurological disorders, including convulsions and epileptic encephalopathy (59, 60).
To our knowledge, none of the reported disorders of vitamin B6 metabolism have been ascribed to the malfunctioning of the hypothesized channeling mechanism of transfer of PLP from either PLK or PNPOx to the apo-B6 enzymes. Of course, several pathologic conditions also occur because of inborn mutations in genes encoding PLP-dependent enzymes, which result in their missed expression, reduce their affinity for PLP or impair their regulation mechanisms and catalytic properties. These occurrences will not be considered in this review.
3.1. Inherited defects in the salvage pathway enzymes
3.1.1 Pyridoxine (pyridoxamine) 5'-phosphate oxidase deficiency
This is a newly recognized, rare disorder mimicking aromatic amino acid decarboxylase deficiency, which is presented as a neonatal epileptic encephalopathy (NEE) with seizures intractable with pyridoxine, but responding to PLP (PLP-dependent seizures). The disease, whose main feature is the onset of severe seizures within hours from a mostly premature birth, has been shown to arise from autosomal recessive mutations of the gene encoding PNPOx (OMIM 6032870) and therefore is now referred to as PNP oxidase deficiency (61). Metabolites alterations in cerebrospinal fluid, plasma and urine of affected subjects clearly indicate a deficient flux through PLP-dependent pathways: in cerebrospinal fluid, raised concentrations of 3-methoxytyrosine (3-O-methyl-dopa) and L-DOPA and lowered levels of homovanillic acid and 5-hydroxyindoleacetic acid; a raised urinary vanillactate; elevated threonine and glycine concentrations in plasma and cerebrospinal fluid; hypoglycemia and lactic acidosis (59). To date, 14 cases of patients from 8 related individuals with mutations in the PNPOx encoding gene have been reported. Surviving children are usually mentally retarded and show an abnormal dependence on vitamin B6 in the form of PLP. At least seven mutations in the gene of PNPOx are known to result in NEE. These include homozygous missense (R95C, R95H, R229W), stop codon (X262Q), nonsense (p.A174X), splice site (IVS3-1g>a) and frameshift (c.del246T) mutations (61-66).
3.1.2. Hypophosphatasia
The indispensable role played by the tissue-nonspecific phosphatase in the cellular uptake of B6 vitamers is evident in the onset of hypophosphatasia, a rare genetic disease whose severe forms are characterized by increased plasma concentration of PLP (67, 68) and reduced plasma concentration of pyridoxal (69). The first occurrence of hypophosphatasia was reported by Rathbun (70), who described the case of a child who died with epilepsy and rickets, with very low levels of alkaline phosphatase activity in blood and tissues. The disease results from mutations in the gene encoding the tissue-non-specific isoenzyme of alkaline phosphatase (ALPL; OMIM 171760). Most described mutations are missense mutations (see http://www. sesep.uvsq.fr/Database.html) that result in variable clinical manifestations. Six clinical subgroups may be distinguished on the basis of the age at diagnosis: perinatal lethal, prenatal benign, infantile, childhood and adult onset forms, and odontohypophosphatasia. Clinical variability has been reported in all subgroups; therefore hypophosphatasia may be regarded as a spectrum disorder (71, 72).
Tissue-nonspecific alkaline phosphatase, which is abundant in osteoblasts e chondrocytes, catalyzes the hydrolysis of inorganic pyrophosphates, which retard the growth of nascent hydroxyapatite crystals (73, 74). The intracellular accumulation of inorganic pyrophosphates, resulting from the lack of TNAP activity, accounts for the impaired skeletal mineralization observed in the subjects affected by hypophosphatasia. On top of this, affected subjects show epileptic encephalopathy and abnormal neurotransmitter metabolism (75). As mentioned above, the PL that reaches the neural cells is obtained from dephosphorylation of PLP by TNAP at the choroid plexus. TNAP deactivation therefore results in a shortage of PL supply to the neural cells and the consequent missed activation of PLP-dependent enzymes. In fact, increased levels of vanillactate are observed in hypophosphatasia patients (75), indicating a functional deficiency of aromatic amino acids decarboxylase, required for dopamine and serotonine production. Reduced GABA levels in the brain were showed in TNAP knockout mice (76), which shortly after birth developed seizures that could be prevented by the administration of pyridoxal. With human infants, good responses to treatment have been recorded also with pyridoxine (68, 69).
3.2. Inherited defects in enzymes involved in other metabolisms
3.2.1 Pyridoxine-dependent epilepsy
This is an autosomal recessive disease of probably underestimated incidence, first described in 1954 (77), that is usually presented with neonatal epileptic encephalopathy. Affected subjects depend on daily pharmacological doses of pyridoxine and if untreated die from status epilepticus. Later onsets of the disease and atypical responses to pyridoxine have been observed (59). The accumulation of pipecolic acid (Figure 3), an intermediate of lysine degradation pathway, in plasma and cerebrospinal fluid is a diagnostic marker of pyridoxine-dependent epilepsy (78, 79). The metabolic defect has been shown to originate from mutations of alpha-aminoadipic aldehyde dehydrogenase (or antiquitin, encoded by the ALDH7A1 gene), which catalyzes the oxidation of apha-aminoadipic semialdehyde, deriving from pipecolic acid, to alpha-aminoadipic acid (80, 81). The secondary PLP deficiency induced by the disease derives from the accumulation of alpha-aminoadipic aldehyde, which upon formation of an intramolecular Schiff base (L- delta1-piperideine-6-carboxylic acid) reacts with PLP in a Knoevenagel condensation (Figure 3).
A few cases of neonatal epileptic encephalopathy have been reported to respond to treatment with folinic acid (5-formyl tetrahydrofolate, also known as leucovorin) (82, 83). These cases have been attributed to a distinct disorder with respect to pyridine-dependent epilepsy, until it was demonstrated that folinic acid-responsive patients also respond to pyridoxine, are antiquitin deficient and have mutations in the ALDH7A1 gene (84). The response to folinic acid, which has been serendipitously discovered, is variable and is accompanied by a variable degree of responsiveness to pyridoxine. In our opinion, this observation, together with the fact that all folinic acid-responsive subjects showed the presence of two unidentified compounds in the cerebrospinal fluid, suggest that folinic acid-responsive seizures, although related to pyridoxine-dependent epilepsy, might not be considered the same condition.
3.2.2 Hyperprolinemia type II. This rare disorder, usually presented in childhood with fits and encephalopathy, is caused by the deficiency of the enzyme delta1-pyrroline-5-carboxylate dehydrogenase, involved in proline degradation and encoded by the ALDH4A1 gene. This deficiency results in the accumulation of proline and L-delta1-pyrroline-5-carboxylic acid in plasma and the consequent excessive excretion of the latter compound in urine (85). L-delta1-Pyrroline-5-carboxylic acid has been shown to react in a Knoevenagel condensation of the activated C4 carbon of the pyrroline ring with the aldehyde carbon of PLP (Figure 4) (86, 87). Seizures, which manifest in approximately half of the affected individuals, respond well to pyridoxine treatment.
3.3. Drugs and natural compounds which affect PLP availability
Interference of several drugs and natural compounds with vitamin B6 metabolism have been largely described in patients and animal studies ((88) and references therein). The effect of this interaction, which modifies the vitamin status and function, might explain some of the neurological side effects of these drugs. On the other hand, a protective effect of vitamin B6 administration against drug toxicity has also been described (89-92).
Two mechanisms could account for B6 hypovitaminosis induced by drugs. The first is a direct effect of compounds containing an amine or hydrazine function, which are able to react with PL or PLP. Examples are penicillamine, cycloserine, dopamine and levodopa (Figure 5). The second mechanism is the inhibition of the B6 salvage enzymes, especially PLK, by drugs and natural compounds, such as methylxanthines, ginkgotoxin, benzodiazepines (Figure 6). Neurologic symptoms noted in severe vitamin B6 deficiency caused by any of these mechanisms include irritability, headache, convulsions, depression, confusion and neuropathy.
3.3.1. Drugs and natural compounds that interact with vitamin B6
Neurotransmitters dopamine, norepinephrine, and epinephrine (collectively known as catecholamines). Aside from its natural and essential biological role, L-DOPA is also used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia. Levodopa is known to induce vitamin B6 deficiency and to have dyskinetic side effects when large doses of pyridoxine are simultaneously administered, abolishing its therapeutic effects. The formation of a Schiff base between the amino function of L-DOPA and the aldehyde group of PLP is largely responsible of these significant side effects
Levodopa (L-DOPA). This compound is the precursor of the.
Dopamine. Contrary to its precursor L-DOPA, dopamine cannot cross the blood-brain barrier and no neurological vitamin B6 deficiency has been linked to dopamine therapy in humans. Nevertheless, in animals intoxicated by dopamine, a rapid depletion of PLP due to the formation of a Schiff base complex between the two compounds was shown (91). This complex might also be responsible for PLK inhibition by binding to the enzyme (93).
Penicillamine. It is a metabolite of penicillin that is deprived of antibiotic properties and shows B6 antagonistic effects. It has been shown to increase xanthurenic acid and kynurenine excretion after tryptophan load, which indicates a B6 deficiency condition (94). This results from the reaction between the amino and sulphydryl groups of penicillamine with PLP to form of a stable thiazolidine derivative, which presents a very low affinity for the active site of PLP-dependent enzymes.
Isoniazid. This is a potent antituberculosis drug, which also has antidepressant effects. It reacts with PLP causing a vitamin B6 deficiency (95). The pyridoxal phosphate hydrazide complex can not act as a cofactor (95) and may also inhibit pyridoxal kinase activity (96). During isoniazid treatment of tuberculosis, symptomatic pyridoxine deficiency tends to occur only in patients who are slow isoniazid inactivators or who have renal insufficiency. The most common effect is peripheral neuropathy; this and other side effects can be prevented by giving pyridoxine in a daily 50-100 mg dose.
Cycloserine. It is a highly neurotoxic compound used as antituberculosis drug in combination with isoniazid. Cycloserine-dependent convulsions can be prevented and treated with pyridoxine (92). Cycloserine reacts with PLP forming PMP, mono- and di-PLP derivatives of beta-aminoxyalanine and other covalent complexes that might also inhibit PLK.
3.3.2. Drugs and natural compounds that interact with PLK
Ginkgotoxin. Products prepared from Ginkgo biloba, a living fossil plant belonging to the Ginkgoaceae family, are top-selling phytopharmaceuticals and major botanical dietary supplements. In European medicine, G. biloba medications are used to treat neuronal disorders, and to improve brain metabolism and peripheral blood flow (97). The best known compounds derived from G. biloba are flavonoids and terpene lactones, but they also include allergenic and toxic compounds such as ginkgotoxin. Consequently, there are reports attributing beneficial as well as adverse effects to G. biloba products. Ginkgotoxin (4′-O-methylpyridoxine) is structurally related to vitamin B6 and occurs in the seed albumen and leaves of Ginkgo biloba. Ginkgotoxin triggers symptoms called gin-nan sitotoxism: epileptic convulsions, leg paralysis, loss of consciousness and other neuronal symptoms (98). There are even reports of death due to overconsumption of Ginkgo seeds. Ingestion of raw seeds is most dangerous, while when seeds are canned or boiled the toxin content drops to only 1% compared to raw seeds. Intoxications by Ginkgotoxin can be counteracted by vitamin B6 supplementation (97). There seems to be a connection between the main symptoms of gin-nan sitotoxism and the dysregulation of gamma-aminobutyric acid metabolism. This dysregulation has been tentatively explained by reduced GAD activity (99), however, 5'-O-phosphate ginkgotoxin has been shown to inhibit human GAD65 only at unphysiologically high concentration, while human GAD67 was not inhibited (100). Actually, the main target of ginkgotoxin seems to be PLK, which uses it as an alternative substrate, with an extremely low KM (101). This reflects the antivitamin character of the compound and explains the in vivo depletion of PLP cofactor in the presence of ginkgotoxin. It also becomes evident why the inhibitory effect of ginkgotoxin on PLP formation by PLK can be alleviated by vitamin B6 (namely PL) supplementation. On the other hand, it has been demonstrated that ginkgotoxin and its 5'-phosphorylated analogue do not inhibit PNPOx or pyridoxal phosphatase (102) (Figure 6).
Theophylline. Also known as dimethylxanthine, theophylline is a methylxanthine used in therapy for respiratory diseases such as chronic obstructive lung disease and asthma. Because of its numerous and poorly understood neurotoxic and pharmacological side effects, the drug is now rarely administered for clinical use. It bears structural and pharmacological similarity to caffeine. It is naturally found in tea and cocoa beans, although in amounts that are significantly lower than therapeutic doses. In a study conducted on healthy patients, theophylline administration resulted in a rapid and significant decline in both plasma and erythrocyte PLP levels, while PLK levels increased significantly. Mean erythrocyte aspartate and alanine aminotransferase activity declined drastically (50% to 70%) indicating that decreased availability of PLP can have widespread metabolic consequences. Although plasma PL levels remained normal, the threefold increase in total erythrocyte PLK activity levels did not normalize PLP levels. The effect of theophylline on vitamin B6 metabolism is not transitory and cannot be overcome by elevated intracellular levels of PLK. However, pyridoxine supplementation (10 mg/d for 1 week) normalized indices of vitamin B6 status and reversed the downward trend in both aspartate and alanine aminotransferase activity levels (103). The depressed vitamin B6 status did not seem to be responsible for the higher erythrocyte PLK activities during theophylline therapy, but rather the drug is directly responsible for elevated enzyme levels through regulation of mRNA translation and de novo synthesis of enzyme (104). Theophylline is a potent inhibitor of PLK competing with PL for enzyme binding (Ki = 8.7 microM; therapeutic theophylline concentration 55-110 microM) (105, 106). This inhibition seems to be the only mechanism responsible for unbalanced vitamin B6 metabolism commonly found in asthmatic patients during theophylline therapy.
Roscovitine. It is a 2,6,9-substituted purine analogue that behaves as a rather selective inhibitor of several cycline-dependent kinases (CDKs), altering the growth phase or state within the cell cycle of treated cells. As a side effects, roscovitine also interacts with the non-protein kinase PLK, showing competitive binding versus ATP and PL, but not versus PLP (107). Inhibition constants are in the low micromolar range. (R)-and (S)- enantiomers of roscovitine bind to PLKs from various organisms with different specificity. Unexpectedly, the crystal structure of sheep brain PLK in complex with roscovitine found the inhibitor at the PL binding site, rather than at the expected ATP site. The comparison of PLK and CDKs binding sites for roscovitine shows a somewhat different binding environment, allowing the design of new CDK inhibitors that do not bind to PLK (108). If red blood cells were incubated with roscovitine at a final concentration of 100 microM, both enantiomers induced a significant decrease in the level of PLP in erythrocytes, whereas overall PL level remained constant. The effect of roscovitine was dose-dependent. Beside its action on vitamin B6 balance, it seems unlike that the interaction between roscovitine and PLK could contribute to the anti-proliferative and pro-apoptotic effects of the given drug (107).
Thiamphenicol. It is the methyl-sulfonyl analogue of chloramphenicol, but is 2.5 to 5 times as potent. It is used in many countries as a veterinary antibiotic, but is available in China and Italy for use in humans. Long-term therapy is believed to cause optic neuritis and sensitive peripheral neuropathy. Besides acting as a weak inhibitor of PLK, thiamphenicol glycinate can react with the aldehyde group of PLP forming a mildly stable intermediate (88).
Benzodiazepines. These are psychoactive drugs that enhance the effect of the neurotransmitter GABA, and are used in treating anxiety, insomnia, agitation, seizures, muscle spasms and alcohol withdrawal. In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and paradoxical effects occasionally occur. Interestingly, mammalian PLK has been first purified on a benzodiazepine-affinity chromatography (109) and at least some benzodiazepine-receptor ligands have been shown to bind to PLK, with inhibition features. For example, 1012-S and ethyl-beta-carboline-3-carboxylate are potent inhibitors of human PLK (IC50 = 2 and 5 microM, respectively), whereas other benzodiazepine-receptor ligands are much less effective (e.g. flunitrazepam and PK-11195) (110).
Antiepileptic drugs. Patients treated with antiepileptic and anticonvulsant drugs, such as progabide, carbamazepine, lamotrigine, phenytoin, phenobarbital and primidone, tend to have high plasma levels of homocysteine and low levels of folates and vitamin B6 (111). At least some of these drugs seem to inhibit PLK activity, with a Ki in the low micromolar range. Other drugs, such as vigabatrin, reduce localized PNPOx expression in the hippocampus of seizure prone gerbils. This is a distinct effect with respect to inhibition of GABA aminotransferase. In this case, PLK is not affected by the drug (112).
4. MULTIFACTORIAL DISEASES RELATED TO PLP AVAILABILITY
In multifactorial diseases, many risk factors operating at different levels have to be taken into consideration, including biological levels (both genetic and metabolic) and societal and individual behavior. As an example, multifactorial neurological pathologies such as autism, schizophrenia, epilepsy, Alzheimer's and Parkinson's disease, have been correlated to inadequate intracellular concentration of PLP. This correlation will be taken into consideration in the next paragraph.
4.1. Autism
Several studies have been carried out on the effect of high-dose supplementation of vitamin B6 on children and adults with autism, reporting positive benefits (113). Autistic children show abnormally high plasma levels of total vitamin B6 (including both phosphorylated and unphosphorylated forms) compared to controls (medians of 56 versus 32 ng/ml). On the other end, levels of PLP are much lower than in control subjects. It has been found that in autistic children PLK has an increased value of KM for pyridoxine. Thus, it appears that the reduced conversion of pyridoxal to its phosphorylated analogue results in the low levels of PLP (113). Moreover, low plasma levels of methionine, cysteine and glutathione were found in children with prototypic autistic disorder.
Normalization of PLP levels would be expected to improve mental and physical functions, and may explain many reports of improvement in autistic patients upon treatment with high-dose vitamin B6. It could be questioned whether similar improvements would occur by simply giving PLP. However, the phosphate group being removed during digestion, PLP would likely have no additional benefits over pyridoxal. A compared study treatment with PLP or PN in autistic children had found adverse effects (worsening of behaviors) in 10% of the children receiving PLP versus none in those receiving PN. Therefore, it appears that vitamin B6 should be given as pyridoxal HCl or pyridoxine HCl, not as PLP (113).
4.2. Schizophrenia
High serum homocysteine levels have been reported in schizophrenic patients with low folate levels (114), supporting the hypothesis that a subtle genetic defect in homocysteine metabolism may play an etiologic role in schizophrenia. A meta-analysis of eight studies has provided evidence for an association of elevated homocysteine serum levels with schizophrenia. Moreover, the elevated risk of schizophrenia has been also associated with the homozygous genotype of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism, providing support for causality between a disturbed homocysteine metabolism and risk of schizophrenia (115). In fact, strategies that reduce homocysteine levels, such as oral administration of folic acid, vitamin B12 and pyridoxine, may alleviate the symptoms experienced by chronic schizophrenic patients with hyperhomocysteinemia (116). Considering that PLP is required as a cofactor for enzymes involved in homocysteine metabolism, it has been hypothesized that polymorphisms of the PNPOx encoding gene may contribute to overall genetic risk for schizophrenia. In a Japanese population study, eight single nucleotide polymorphisms (SNPs) were examined in PNPOx gene and its 5'-flanking regions in 359 schizophrenia patients and 582 control subjects. Four marker regions of PNPOx showed significant levels of allelic associations with schizophrenia (the highest was rs2325751, P=0.004). In addition, the haplotype case-control study revealed a significant association (permutation P<0.00001) between PNPOx polymorphisms and schizophrenia (117).
In another study, schizophrenic patients had lower plasma folate concentrations and elevated red blood cells levels compared to controls. Vitamin B6, vitamin B12 and homocysteine levels did not differ from control. A significant dose-response relation between plasma folate concentration and risk for schizophrenia suggested a protective effect by high plasma folate concentrations. At least in this case, homocysteine levels and MTHFR 677C-T mutation did not seem to be associated with an increased risk of schizophrenia (118).
4.3. Epilepsy
Besides the obvious finding that vitamin B6 deficiency reduces GABA concentration (promoting the onset of seizures), it has been also reported that intracerebroventricular injection of PLP causes epileptic episodes (119). Therefore, the role of PLP in the prevention, as well as in the production of convulsive seizures has still to be defined. In a Mongolian gerbil model, it was shown that PNPOx and PLK immunoreactivity was stronger in a preseizure group of seizure-sensitive animals, compared to a seizure-resistant group (120, 121). The density of both enzymes' immunoreactivity would significantly decrease 30 min after a seizure event and go back to normal in the next 12 hr. The overexpression of PNPOx and PLK may then be responsible of an excessive PLP concentration, which may enhance seizure susceptibility by diminishing the GABA levels through several mechanisms, e.g. the modification of GABAA receptors (leading to a degeneration of GABAergic neurotransmission (122)), or the enhancement of GABA uptake by neurons (123). Therefore, the excitability of the neurons in the hippocampus of seizure-sensitive animals may be unusually elevated and the salvage pathway enzymes may play an important role in this modulation. In addition, the change in PNPOx and PLK immunoreactivity following a seizure event may represent a compensatory response for reducing epileptic activity, at least in gerbils. In the same animal model, PNPOx expression and specific activity were found to be reduced in the hippocampus upon vigabatrin treatment. Vigabatrin then, besides increasing GABA concentration through its action as GABA aminotransferase inhibitor, may indirectly downregulate the expression of PNPOx in neurons, protecting the system from seizure onset. In contrast, in this case the expression of PLK was unaltered by vigabatrin treatment (112).
4.4. Alzheimer's disease, cognition, dementia, ageing
Alzheimer's disease, a neurodegenerative disorder with memory loss and progressive decline on cognitive function is the most common form of dementia. Half of the population over 85 suffers from the disease. Vascular dementia is the second most frequent type of dementia, with stroke as its major cause. Genetic and non-genetic factors, such trauma, education, stress, and nutrition, all play a role in the development of dementia. Nutrition is indeed a modifiable lifestyle factor, which may be relevant to the onset of dementia conditions. Low vitamin B6 and elevated plasma homocysteine status is prevalent in patients with Alzheimer's disease, although it is not known if elevated plasma homocysteine or low vitamin B6 status directly influences Alzheimer's pathogenesis or progression. It has been reported that patients with Alzheimer's disease are more likely than controls to have low plasma PLP concentrations (124).
Pharmacological doses of vitamin B6 have been used in the hope of improving speech and language functions in children with learning difficulties. An inverse relationship between plasma pyridoxal concentration and age has been documented in several studies. Poor vitamin B6 status and low dietary vitamin B6 intakes and other necessary nutrients have been observed in older people, with approximately 20% of aged people having inadequate vitamin B6 status (44). The prevailing hypothesis for the possible downward trend of vitamin B6 status in later life involves low intake, less efficient retention, and increased catabolism of the vitamin. Also, a correlation between blood levels of B vitamins and cognitive function has been documented, and high vitamin B6 concentration has been correlated with better performance in memorization tests (125).
There is some evidence that 20 mg of vitamin B6 daily has an impact on vitamin B6 levels as measured biochemically in healthy older men. Although at present there is no evidence to support the use of vitamin B6 supplements for improving cognitive function or mood of older people, supplementation is known to improve biochemical indices of vitamin B6 status in older men, suggesting that some may be deficient in the vitamin (126). On the other hand, vitamin B6 was inferred to be positively related to multiple cognitive domains and evidence was found that B6 supplementation may improve cognitive performance in elderly men (127). It has been hypothesized that folate and vitamins B6 and B12 are related to cognitive performance because homocysteine metabolism requires these vitamins, and disruption of methylation pathways may lead to cognitive impairment via the accumulation of S-adenosyl homocysteine, a strong inhibitor of the majority of methyltransferases. Clearly, vitamin B6 emerged as a good predictor of cognitive performance across cognitive domains, but whether B6 supplementation can improve cognitive performance is still to be demonstrated through ongoing longitudinal clinical trials (128).
4.5. Parkinson's disease (PD)
This is a degenerative disorder of the central nervous system that impairs motor skills, cognitive processes, and other functions. Dopamine deficiency is normally responsible for the occurring of primary Parkinson's symptoms. Current treatments are effective at managing the early motor symptoms of the disease, through the use of levodopa (L-DOPA), dopamine agonists and monoamine oxidase inhibitors. Diet also has shown some effectiveness at mitigating symptoms. However, the majority of people suffer from idiopathic PD. In a recent study, whole-genome expression profiling of isolated substantia nigra neurons from PD patients, followed by association analysis of single-nucleotide polymorphisms in differentially regulated genes, identified four differentially expressed genes, among them PLK. Intronic and 3'-untranslated region variants of PLK gene were associated with PD risk, and the up-regulation of PLK was linked to PD patients (129). Emphasis was also put on the impact of vitamin B6 status and metabolism on Parkinson's disease risk and therapy. Successive examination of other independent patient-control series showed no significant association between PLK variants and an increased risk of disease, suggesting careful interpretation of genetic association studies (130, 131).
4.6. Malaria
It was shown many years ago that African-American people have a high frequency of low-activity PLK in red cells, compared to individuals with European ancestry. This genetic variant appears to be inherited as a single autosomal allele, and confers decreased in vivo stability on the red-cell PLK. Moreover, this racial difference was found to be tissue-specific, with leukocyte and skin fibroblast PLK activities being the same in both ethnic groups (132). Two antimalarial drugs used in the study, chloroquine and pyrimethamine, did not seem to increase PLK activity. It was suggested that the selective pressure of malaria was the cause of the lowered erythrocyte enzyme activities (133). Diet also was shown to influence PLK activity, although this alone is not enough to explain the difference seen between African-Americans and Caucasians.
A number of polymorphisms were discovered by sequencing PLK genes; among these an insertion event in the promoter region which had a significantly lower frequency in African-Americans than in either Caucasian or Asian subjects. The insert introduced a putative core promoter binding protein (CPBP) binding site adjacent to a binding site for an erythrocyte specific transcription factor. The presence of the insert was found to correlate with increased erythrocyte PLK enzyme activity, both in vivo and in vitro, and could account for the observed ethnic variation in erythrocyte PLK activity (134).
5. ACKNOWLEDGEMENTS
This work was supported by grants from the Ministero dell'Università e della Ricerca and from Istituto Pasteur - Fondazione Cenci Bolognetti to MLDS and RC, and by the AD Williams Fund (VCU) and the Jeffress Research Memorial Grant Award to MKS.
6. REFERENCES
1. R. Percudani and A. Peracchi: A genomic overview of pyridoxal-phosphate-dependent enzymes. EMBO Rep, 4(9), 850-4 (2003) doi:10.1038/sj.embor.embor914 embor914 (pii)
2. R. Percudani and A. Peracchi: The B6 database: a tool for the description and classification of vitamin B6-dependent enzymatic activities and of the corresponding protein families. BMC Bioinformatics, 10, 273 (2009) doi:1471-2105-10-273 (pii) 10.1186/1471-2105-10-273
3. G. Lambrecht, K. Braun, M. Damer, M. Ganso, C. Hildebrandt, H. Ullmann, M. U. Kassack and P. Nickel: Structure-activity relationships of suramin and pyridoxal-5'-phosphate derivatives as P2 receptor antagonists. Curr Pharm Des, 8(26), 2371-99 (2002)
doi:10.2174/1381612023392973
PMid:12369951
4. K. Dakshinamurti, K. J. Lal and P. K. Ganguly: Hypertension, calcium channel and pyridoxine (vitamin B6). Mol Cell Biochem, 188(1-2), 137-48 (1998)
doi:10.1023/A:1006832810292
PMid:9823019
5. J. M. Salhany, P. B. Rauenbuehler and R. L. Sloan: Characterization of pyridoxal 5'-phosphate affinity labeling of band 3 protein. Evidence for allosterically interacting transport inhibitory subdomains. J Biol Chem, 262(33), 15965-73 (1987)
PMid:3680237
6. T. Oka: Modulation of gene expression by vitamin B6. Nutr Res Rev, 14(2), 257-66 (2001)
PMid:19087426
7. M. D. Huq, N. P. Tsai, Y. P. Lin, L. Higgins and L. N. Wei: Vitamin B6 conjugation to nuclear corepressor RIP140 and its role in gene regulation. Nat Chem Biol, 3(3), 161-5 (2007)
doi:10.1038/nchembio861
PMid:17277785
8. P. Bilski, M. Y. Li, M. Ehrenshaft, M. E. Daub and C. F. Chignell: Vitamin B6 (pyridoxine) and its derivatives are efficient singlet oxygen quenchers and potential fungal antioxidants. Photochem Photobiol, 71(2), 129-34 (2000)
doi:10.1562/0031-8655(2000)071<0129:SIPVBP>2.0.CO;2
9. M. Ehrenshaft, P. Bilski, M. Y. Li, C. F. Chignell and M. E. Daub: A highly conserved sequence is a novel gene involved in de novo vitamin B6 biosynthesis. Proc Natl Acad Sci U S A, 96(16), 9374-8 (1999)
doi:10.1073/pnas.96.16.9374
10. A. Grubman, A. Phillips, M. Thibonnier, M. Kaparakis-Liaskos, C. Johnson, J. M. Thiberge, F. J. Radcliff, C. Ecobichon, A. Labigne, H. de Reuse, G. L. Mendz and R. L. Ferrero: Vitamin B(6) Is Required for Full Motility and Virulence in Helicobacter pylori. MBio, 1(3) (2010) doi:10.1128/mBio.00112-10
doi:10.1128/mBio.00112-10
PMid:21151756 PMCid:3000542
11. M. A. Garcia-Espinosa, R. Wallin, S. M. Hutson and A. J. Sweatt: Widespread neuronal expression of branched-chain aminotransferase in the CNS: implications for leucine/glutamate metabolism and for signaling by amino acids. J Neurochem, 100(6), 1458-68 (2007) doi:JNC4332 (pii) 10.1111/j.1471-4159.2006.04332.x
12. R. Schwarcz and R. Pellicciari: Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther, 303(1), 1-10 (2002)
doi:10.1124/jpet.102.034439
PMid:12235226
13. T. W. Stone, G. M. Mackay, C. M. Forrest, C. J. Clark and L. G. Darlington: Tryptophan metabolites and brain disorders. Clin Chem Lab Med, 41(7), 852-9 (2003)
doi:10.1515/CCLM.2003.129
PMid:12940508
14. D. B. McCormick: Two interconnected B vitamins: riboflavin and pyridoxine. Physiol Rev, 69(4), 1170-98 (1989)
PMid:2678166
15. A. D. Mackey, S. O. Lieu, C. Carman and J. F. Gregory, 3rd: Hydrolytic activity toward pyridoxine-5'-beta-D-glucoside in rat intestinal mucosa is not increased by vitamin B-6 deficiency: effect of basal diet composition and pyridoxine intake. J Nutr, 133(5), 1362-7 (2003)
PMid:12730423
16. L. A. Morrison and J. A. Driskell: Quantities of B6 vitamers in human milk by high-performance liquid chromatography. Influence of maternal vitamin B6 status. J Chromatogr, 337(2), 249-58 (1985)
17. H. M. Said: Recent advances in carrier-mediated intestinal absorption of water-soluble vitamins. Annu Rev Physiol, 66, 419-46 (2004) doi:10.1146/annurev.physiol.66.032102.144611
doi:10.1146/annurev.physiol.66.032102.144611
PMid:14977409
18. R. A. Surtees, P. B. Mills and P. Clayton: Inborn errors affecting vitamin B6 metabolism. Future Medicine, 1(5), 615-620 (2006)
19. J. L. Millán: Mammalian alkaline phosphatases : from biology to applications in medicine and biotechnology. Wiley-VCH, Weinheim (2006)
doi:10.1002/3527608060
20. X. Fang, Z. M. Zhou, L. Lu, L. L. Yin, J. M. Li, Y. Zhen, H. Wang and J. H. Sha: Expression of a novel pyridoxal kinase mRNA splice variant, PKH-T, in human testis. Asian J Androl, 6(2), 83-91 (2004)
PMid:15154080
21. J. H. Kang, M. L. Hong, D. W. Kim, J. Park, T. C. Kang, M. H. Won, N. I. Baek, B. J. Moon, S. Y. Choi and O. S. Kwon: Genomic organization, tissue distribution and deletion mutation of human pyridoxine 5'-phosphate oxidase. Eur J Biochem, 271(12), 2452-61 (2004) doi:10.1111/j.1432-1033.2004.04175.x
doi:10.1111/j.1432-1033.2004.04175.x
PMid:15182361
EJB4175 (pii)
22. N. T. Meisler and J. W. Thanassi: Vitamin B6 metabolism in McA-RH7777 cells. Cancer Res, 48(5), 1080-5 (1988)
PMid:3342390
23. E. O. Ngo, G. R. LePage, J. W. Thanassi, N. Meisler and L. M. Nutter: Absence of pyridoxine-5'-phosphate oxidase (PNPO) activity in neoplastic cells: isolation, characterization, and expression of PNPO cDNA. Biochemistry, 37(21), 7741-8 (1998) doi:10.1021/bi972983r bi972983r (pii)
24. T. F. Fu, M. di Salvo and V. Schirch: Distribution of B6 vitamers in Escherichia coli as determined by enzymatic assay. Anal Biochem, 298(2), 314-21 (2001)
doi:10.1006/abio.2001.5401
PMid:11700988
25. G. Zhao and M. E. Winkler: Kinetic limitation and cellular amount of pyridoxine (pyridoxamine) 5'-phosphate oxidase of Escherichia coli K-12. J Bacteriol, 177(4), 883-91 (1995)
PMid:7860596 PMCid:176679
26. M. K. Safo, F. N. Musayev, M. L. di Salvo, S. Hunt, J. B. Claude and V. Schirch: Crystal structure of pyridoxal kinase from the Escherichia coli pdxK gene: implications for the classification of pyridoxal kinases. J Bacteriol, 188(12), 4542-52 (2006)
doi:10.1128/JB.00122-06
PMid:16740960 PMCid:1482971
27. M. Stanulovic, V. Jeremic, V. Leskovac and S. Chaykin: New pathway of conversion of pyridoxal to 4-pyridoxic acid. Enzyme, 21(4), 357-69 (1976)
PMid:939227
28. T. K. Li, L. Lumeng and R. L. Veitch: Regulation of pyridoxal 5'-phosphate metabolism in liver. Biochem Biophys Res Commun, 61(2), 677-84 (1974)
doi:10.1016/0006-291X(74)91010-9
29. Y. T. Kim, F. Kwok and J. E. Churchich: Interactions of pyridoxal kinase and aspartate aminotransferase emission anisotropy and compartmentation studies. J Biol Chem, 263(27), 13712-7 (1988)
PMid:2843532
30. E. S. Yang and V. Schirch: Tight binding of pyridoxal 5'-phosphate to recombinant Escherichia coli pyridoxine 5'-phosphate oxidase. Arch Biochem Biophys, 377(1), 109-14 (2000)
doi:10.1006/abbi.2000.1737
PMid:10775448
31. P. Y. Cheung, C. C. Fong, K. T. Ng, W. C. Lam, Y. C. Leung, C. W. Tsang, M. Yang and M. S. Wong: Interaction between pyridoxal kinase and pyridoxal-5-phosphate-dependent enzymes. J Biochem, 134(5), 731-8 (2003)
doi:10.1093/jb/mvg201
PMid:14688239
32. M. L. di Salvo, R. Contestabile and M. K. Safo: Vitamin B(6) salvage enzymes: Mechanism, structure and regulation. Biochim Biophys Acta (2010) doi:S1570-9639(10)00317-1 (pii) 10.1016/j.bbapap.2010.12.006
33. M. K. Safo, F. N. Musayev, M. L. di Salvo and V. Schirch: X-ray structure of Escherichia coli pyridoxine 5'-phosphate oxidase complexed with pyridoxal 5'-phosphate at 2.0 A resolution. J Mol Biol, 310(4), 817-26 (2001)
doi:10.1006/jmbi.2001.4734
PMid:11453690
34. F. N. Musayev, M. L. Di Salvo, T. P. Ko, V. Schirch and M. K. Safo: Structure and properties of recombinant human pyridoxine 5'-phosphate oxidase. Protein Sci, 12(7), 1455-63 (2003)
doi:10.1110/ps.0356203
PMid:12824491 PMCid:2323923
35. A. Dannhauser, A. M. van Staden, E. van der Ryst, M. Nel, N. Marais, E. Erasmus, E. M. Attwood, H. C. Barnard and G. D. le Roux: Nutritional status of HIV-1 seropositive patients in the Free State Province of South Africa: anthropometric and dietary profile. Eur J Clin Nutr, 53(3), 165-73 (1999)
doi:10.1038/sj.ejcn.1600691
PMid:10201796
36. L. Lumeng, R. E. Cleary and T. K. Li: Effect of oral contraceptives on the plasma concentration of pyridoxal phosphate. Am J Clin Nutr, 27(4), 326-33 (1974)
PMid:4206322
37. F. Lussana, M. L. Zighetti, P. Bucciarelli, M. Cugno and M. Cattaneo: Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users. Thromb Res, 112(1-2), 37-41 (2003) doi:10.1016/j.thromres.2003.11.007S0049384803006157 (pii)
doi:10.1016/j.thromres.2003.11.007
PMid:15013271
38. M. S. Morris, M. F. Picciano, P. F. Jacques and J. Selhub: Plasma pyridoxal 5'-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004. Am J Clin Nutr, 87(5), 1446-54 (2008) doi:87/5/1446 (pii)
39. O. D. Kowlessar, L. J. Haeffner and G. D. Benson: Abnormal Tryptophan Metabolism in Patients with Adult Celiac Disease, with Evidence for Deficiency of Vitamin B6. J Clin Invest, 43, 894-903 (1964) doi:10.1172/JCI104975
doi:10.1172/JCI104975
PMid:14169518 PMCid:289568
40. M. L. Cravo and M. E. Camilo: Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B(6) and B(12) status. Nutrition, 16(4), 296-302 (2000) doi:S089990079900297X (pii)
41. M. Okada, M. Shibuya, E. Yamamoto and Y. Murakami: Effect of diabetes on vitamin B6 requirement in experimental animals. Diabetes Obes Metab, 1(4), 221-5 (1999)
doi:10.1046/j.1463-1326.1999.00028.x
42. D. B. Coursin: Convulsive seizures in infants with pyridoxine-deficient diet. J Am Med Assoc, 154(5), 406-8 (1954)
PMid:13117629
43. M. J. Kretsch, H. E. Sauberlich and E. Newbrun: Electroencephalographic changes and periodontal status during short-term vitamin B-6 depletion of young, nonpregnant women. Am J Clin Nutr, 53(5), 1266-74 (1991)
PMid:2021133
44. J. Selhub, P. F. Jacques, P. W. Wilson, D. Rush and I. H. Rosenberg: Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA, 270(22), 2693-8 (1993)
PMid:9129252
45. C. Perry, S. Yu, J. Chen, K. S. Matharu and P. J. Stover: Effect of vitamin B6 availability on serine hydroxymethyltransferase in MCF-7 cells. Arch Biochem Biophys, 462(1), 21-7 (2007) doi:S0003-9861(07)00186-5 (pii) 10.1016/j.abb.2007.04.005
46. I. M. Graham and P. O'Callaghan: Vitamins, homocysteine and cardiovascular risk. Cardiovasc Drugs Ther, 16(5), 383-9 (2002) doi:5114385 (pii)
47. P. J. Kelly, V. E. Shih, J. P. Kistler, M. Barron, H. Lee, R. Mandell and K. L. Furie: Low vitamin B6 but not homocyst(e)ine is associated with increased risk of stroke and transient ischemic attack in the era of folic acid grain fortification. Stroke, 34(6), e51-4 (2003) doi:10.1161/01.STR.0000071109.23410.AB 01.STR.0000071109.23410.AB (pii)
48. B. N. Ames and P. Wakimoto: Are vitamin and mineral deficiencies a major cancer risk? Nat Rev Cancer, 2(9), 694-704 (2002) doi:10.1038/nrc886 nrc886 (pii)
49. I. Mackraj, M. L. Channa, F. J. Burger, J. B. Ubbink and P. Smyth: Zinc, copper and iron levels in tissues of the vitamin B6 deficient rat. Int J Vitam Nutr Res, 67(2), 102-5 (1997)
PMid:9866426
50. G. A. Hunter and G. C. Ferreira: 5-aminolevulinate synthase: catalysis of the first step of heme biosynthesis. Cell Mol Biol (Noisy-le-grand), 55(1), 102-10 (2009) doi:102 (pii)
51. H. Iwama, O. Iwase, S. Hayashi, M. Nakano and K. Toyama: (Macrocytic anemia with anisocytosis due to alcohol abuse and vitamin B6 deficiency). Rinsho Ketsueki, 39(11), 1127-30 (1998)
PMid:9263185
52. E. Planells, A. Lerma, N. Sanchez-Morito, P. Aranda and L. L. J: Effect of magnesium deficiency on vitamin B2 and B6 status in the rat. J Am Coll Nutr, 16(4), 352-6 (1997)
53. A. M. Whelan, T. M. Jurgens and H. Naylor: Herbs, vitamins and minerals in the treatment of premenstrual syndrome: a systematic review. Can J Clin Pharmacol, 16(3), e407-29 (2009)
PMid:21151729 PMCid:2990891
54. N. Ebrahimi, C. Maltepe and A. Einarson: Optimal management of nausea and vomiting of pregnancy. Int J Womens Health, 2, 241-8 (2010)
doi:10.2147/IJWH.S6794
PMid:6308447
55. M. Ryan-Harshman and W. Aldoori: Carpal tunnel syndrome and vitamin B6. Can Fam Physician, 53(7), 1161-2 (2007) doi:53/7/1161 (pii)
56. G. J. Krinke and R. E. Fitzgerald: The pattern of pyridoxine-induced lesion: difference between the high and the low toxic level. Toxicology, 49(1), 171-8 (1988) doi:0300-483X(88)90190-4 (pii)
57. H. Schaumburg, J. Kaplan, A. Windebank, N. Vick, S. Rasmus, D. Pleasure and M. J. Brown: Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med, 309(8), 445-8 (1983) doi:10.1056/NEJM198308253090801
doi:10.1056/NEJM198308253090801
PMid:6308448
58. D. Rudman and P. J. Williams: Megadose vitamins. Use and misuse. N Engl J Med, 309(8), 488-90 (1983) doi:10.1056/NEJM198308253090808
doi:10.1056/NEJM198308253090808
PMid:16763894
59. S. M. Gospe, Jr.: Neonatal vitamin-responsive epileptic encephalopathies. Chang Gung Med J, 33(1), 1-12 (2010) doi:3301/330101 (pii)
60. P. T. Clayton: B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis, 29(2-3), 317-26 (2006) doi:10.1007/s10545-005-0243-2
doi:10.1007/s10545-005-0243-2
PMid:17216302
61. P. B. Mills, R. A. Surtees, M. P. Champion, C. E. Beesley, N. Dalton, P. J. Scambler, S. J. Heales, A. Briddon, I. Scheimberg, G. F. Hoffmann, J. Zschocke and P. T. Clayton: Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. Hum Mol Genet, 14(8), 1077-86 (2005) doi:ddi120 (pii) 10.1093/hmg/ddi120
62. M. Khayat, S. H. Korman, P. Frankel, Z. Weintraub, S. Hershckowitz, V. F. Sheffer, M. Ben Elisha, R. A. Wevers and T. C. Falik-Zaccai: PNPO deficiency: an under diagnosed inborn error of pyridoxine metabolism. Mol Genet Metab, 94(4), 431-4 (2008) doi:S1096-7192(08)00120-0 (pii) 10.1016/j.ymgme.2008.04.008
63. S. Bagci, J. Zschocke, G. F. Hoffmann, T. Bast, J. Klepper, A. Muller, A. Heep, P. Bartmann and A. R. Franz: Pyridoxal phosphate-dependent neonatal epileptic encephalopathy. Arch Dis Child Fetal Neonatal Ed, 93(2), F151-2 (2008) doi:93/2/F151 (pii) 10.1136/adc.2006.115162
64. A. Ruiz, J. Garcia-Villoria, A. Ormazabal, J. Zschocke, M. Fiol, A. Navarro-Sastre, R. Artuch, M. A. Vilaseca and A. Ribes: A new fatal case of pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency. Mol Genet Metab, 93(2), 216-8 (2008) doi:S1096-7192(07)00443-X (pii) 10.1016/j.ymgme.2007.10.003
65. G. F. Hoffmann, B. Schmitt, M. Windfuhr, N. Wagner, H. Strehl, S. Bagci, A. R. Franz, P. B. Mills, P. T. Clayton, M. R. Baumgartner, B. Steinmann, T. Bast, N. I. Wolf and J. Zschocke: Pyridoxal 5'-phosphate may be curative in early-onset epileptic encephalopathy. J Inherit Metab Dis, 30(1), 96-9 (2007) doi:10.1007/s10545-006-0508-4
doi:10.1007/s10545-006-0508-4
66. F. N. Musayev, M. L. Di Salvo, M. A. Saavedra, R. Contestabile, M. S. Ghatge, A. Haynes, V. Schirch and M. K. Safo: Molecular basis of reduced pyridoxine 5'-phosphate oxidase catalytic activity in neonatal epileptic encephalopathy disorder. J Biol Chem, 284(45), 30949-56 (2009) doi:M109.038372 (pii) 10.1074/jbc.M109.038372
67. S. J. Iqbal, A. Brain, T. M. Reynolds, M. Penny and S. Holland: Relationship between serum alkaline phosphatase and pyridoxal-5'-phosphate levels in hypophosphatasia. Clin Sci (Lond), 94(2), 203-6 (1998)
PMid:11999978
68. Litmanovitz, O. Reish, T. Dolfin, S. Arnon, R. Regev, G. Grinshpan, M. Yamazaki and K. Ozono: Glu274Lys/Gly309Arg mutation of the tissue-nonspecific alkaline phosphatase gene in neonatal hypophosphatasia associated with convulsions. J Inherit Metab Dis, 25(1), 35-40 (2002)
doi:10.1023/A:1015121414782
PMid:3350970 PMCid:329654
69. M. P. Whyte, J. D. Mahuren, K. N. Fedde, F. S. Cole, E. R. McCabe and S. P. Coburn: Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5'-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase. J Clin Invest, 81(4), 1234-9 (1988) doi:10.1172/JCI113440
doi:10.1172/JCI113440
PMid:18110134
70. J. C. Rathbun: Hypophosphatasia; a new developmental anomaly. Am J Dis Child, 75(6), 822-31 (1948)
71. M. P. Whyte, D. A. Walkenhorst, K. N. Fedde, P. S. Henthorn and C. S. Hill: Hypophosphatasia: levels of bone alkaline phosphatase immunoreactivity in serum reflect disease severity. J Clin Endocrinol Metab, 81(6), 2142-8 (1996)
doi:10.1210/jc.81.6.2142
72. K. N. Fedde, M. P. Michell, P. S. Henthorn and M. P. Whyte: Aberrant properties of alkaline phosphatase in patient fibroblasts correlate with clinical expressivity in severe forms of hypophosphatasia. J Clin Endocrinol Metab, 81(7), 2587-94 (1996)
doi:10.1210/jc.81.7.2587
PMid:1647780
73. A. M. Caswell, M. P. Whyte and R. G. Russell: Hypophosphatasia and the extracellular metabolism of inorganic pyrophosphate: clinical and laboratory aspects. Crit Rev Clin Lab Sci, 28(3), 175-232 (1991) doi:10.3109/10408369109106862
doi:10.3109/10408369109106862
PMid:8133587
74. J. K. Heinonen: Biological role of inorganic pyrophosphate. Kluwer Academic Publishers, Boston (2001)
75. S. Balasubramaniam, F. Bowling, K. Carpenter, J. Earl, J. Chaitow, J. Pitt, E. Mornet, D. Sillence and C. Ellaway: Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5'-phosphate availability. J Inherit Metab Dis (2010) doi:10.1007/s10545-009-9012-y
doi:10.1007/s10545-009-9012-y
76. K. G. Waymire, J. D. Mahuren, J. M. Jaje, T. R. Guilarte, S. P. Coburn and G. R. MacGregor: Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Nat Genet, 11(1), 45-51 (1995) doi:10.1038/ng0995-45
doi:10.1038/ng0995-45
77. A. D. Hunt, Jr., J. Stokes, Jr., C. W. Mc and H. H. Stroud: Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics, 13(2), 140-5 (1954)
78. B. Plecko, C. Hikel, G. C. Korenke, B. Schmitt, M. Baumgartner, F. Baumeister, C. Jakobs, E. Struys, W. Erwa and S. Stockler-Ipsiroglu: Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics, 36(3), 200-5 (2005) doi:10.1055/s-2005-865727
doi:10.1055/s-2005-865727
79. B. Plecko, S. Stockler-Ipsiroglu, E. Paschke, W. Erwa, E. A. Struys and C. Jakobs: Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy. Ann Neurol, 48(1), 121-5 (2000)
doi:10.1002/1531-8249(200007)48:1<121::AID-ANA20>3.0.CO;2-V
80. P. B. Mills, E. Struys, C. Jakobs, B. Plecko, P. Baxter, M. Baumgartner, M. A. Willemsen, H. Omran, U. Tacke, B. Uhlenberg, B. Weschke and P. T. Clayton: Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med, 12(3), 307-9 (2006) doi:nm1366 (pii) 10.1038/nm1366
81. G. Scharer, C. Brocker, V. Vasiliou, G. Creadon-Swindell, R. C. Gallagher, E. Spector and J. L. Van Hove: The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1. J Inherit Metab Dis, 33(5), 571-81 (2010) doi:10.1007/s10545-010-9187-2
doi:10.1007/s10545-010-9187-2
82. K. Hyland, N. R. Buist, B. R. Powell, G. F. Hoffman, D. Rating, J. McGrath and I. N. Acworth: Folinic acid responsive seizures: a new syndrome? J Inherit Metab Dis, 18(2), 177-81 (1995)
doi:10.1007/BF00711760
83. J. Nicolai, V. H. van Kranen-Mastenbroek, R. A. Wevers, W. A. Hurkx and J. S. Vles: Folinic acid-responsive seizures initially responsive to pyridoxine. Pediatr Neurol, 34(2), 164-7 (2006) doi:S0887-8994(05)00496-0 (pii) 10.1016/j.pediatrneurol.2005.08.019
84. R. C. Gallagher, J. L. Van Hove, G. Scharer, K. Hyland, B. Plecko, P. J. Waters, S. Mercimek-Mahmutoglu, S. Stockler-Ipsiroglu, G. S. Salomons, E. H. Rosenberg, E. A. Struys and C. Jakobs: Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol, 65(5), 550-6 (2009) doi:10.1002/ana.21568
doi:10.1002/ana.21568
85. V. Walker, G. A. Mills, S. A. Peters and W. L. Merton: Fits, pyridoxine, and hyperprolinaemia type II. Arch Dis Child, 82(3), 236-7 (2000)
doi:10.1136/adc.82.3.236
86. R. D. Farrant, V. Walker, G. A. Mills, J. M. Mellor and G. J. Langley: Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. J Biol Chem, 276(18), 15107-16 (2001) doi:10.1074/jbc.M010860200
doi:10.1074/jbc.M010860200
M010860200 (pii)
87. V. Walker, G. A. Mills, J. M. Mellor, G. J. Langley and R. D. Farrant: A novel pyrroline-5-carboxylic acid and acetoacetic acid adduct in hyperprolinaemia type II. Clin Chim Acta, 331(1-2), 7-17 (2003) doi:S0009898103000779 (pii)
88. P. Laine-Cessac, A. Cailleux and P. Allain: Mechanisms of the inhibition of human erythrocyte pyridoxal kinase by drugs. Biochem Pharmacol, 54(8), 863-70 (1997) doi:S0006-2952(97)00252-9 (pii)
89. Z. Desta and M. Steingruber: Pharmacodynamic interactions between isoniazid and theophylline in mice and rats, and the influence of pyridoxine. Pharmazie, 47(7), 525-8 (1992)
90. S. Smetana, S. Khalef, G. Kopolovic, Y. Bar-Khayim, Y. Birk and S. Kacew: Effect of interaction between gentamicin and pyridoxal-5-phosphate on functional and metabolic parameters in kidneys of female Sprague-Dawley rats. Ren Fail, 14(2), 147-53 (1992)
doi:10.3109/08860229209039124
91. R. C. Keniston, S. Cabellon, Jr. and K. S. Yarbrough: Pyridoxal 5'-phosphate as an antidote for cyanide, spermine, gentamicin, and dopamine toxicity: an in vivo rat study. Toxicol Appl Pharmacol, 88(3), 433-41 (1987)
doi:10.1016/0041-008X(87)90217-1
92. A. C. Cohen: Pyridoxine in the prevention and treatment of convulsions and neurotoxicity due to cycloserine. Ann N Y Acad Sci, 166(1), 346-9 (1969)
doi:10.1111/j.1749-6632.1969.tb54286.x
93. T. Asakura, N. Takahashi, T. Hirakawa, K. Ohkawa and N. Hibi: Regulation of pyridoxal-5'-phosphate level by biogenic amines in mouse brain. Neurochem Res, 21(1), 47-50 (1996)
doi:10.1007/BF02527671
94. I. A. Jaffe: Antivitamin B6 effect of D-penicillamine. Ann N Y Acad Sci, 166(1), 57-60 (1969)
doi:10.1111/j.1749-6632.1969.tb54255.x
95. J. P. Biehl and R. W. Vilter: Effects of isoniazid on pyridoxine metabolism. J Am Med Assoc, 156(17), 1549-52 (1954)
96. D. B. McCormick and E. E. Snell: Pyridoxal phosphokinases. II. Effects of inhibitors. J Biol Chem, 236, 2085-8 (1961)
97. E. Leistner and C. Drewke: Ginkgo biloba and ginkgotoxin. J Nat Prod, 73(1), 86-92 (2010) doi:10.1021/np9005019
doi:10.1021/np9005019
98. K. Wada, S. Ishigaki, K. Ueda, M. Sakata and M. Haga: An antivitamin B6, 4'-methoxypyridoxine, from the seed of Ginkgo biloba L. Chem Pharm Bull (Tokyo), 33(8), 3555-7 (1985)
99. C. Nitsch and Y. Okada: Differential decrease of GABA in the substantia nigra and other discrete regions of the rabbit brain during the preictal period of methoxypyridoxine-induced seizures. Brain Res, 105(1), 173-8 (1976) doi:0006-8993(76)90934-3 (pii)
100. K. Buss, C. Drewke, S. Lohmann, A. Piwonska and E. Leistner: Properties and interaction of heterologously expressed glutamate decarboxylase isoenzymes GAD(65kDa) and GAD(67kDa) from human brain with ginkgotoxin and its 5'-phosphate. J Med Chem, 44(19), 3166-74 (2001) doi:jm010868f (pii)
101. U. Kastner, C. Hallmen, M. Wiese, E. Leistner and C. Drewke: The human pyridoxal kinase, a plausible target for ginkgotoxin from Ginkgo biloba. FEBS J, 274(4), 1036-45 (2007) doi:EJB5654 (pii) 10.1111/j.1742-4658.2007.05654.x
102. N. Salamon, C. Gurgui, E. Leistner and C. Drewke: Influence of antivitamins ginkgotoxin 5'-phosphate and deoxypyridoxine 5'-phosphate on human pyridoxine 5'-phosphate oxidase. Planta Med, 75(6), 563-7 (2009) doi:10.1055/s-0029-1185482
doi:10.1055/s-0029-1185482
103. J. B. Ubbink, R. Delport, S. Bissbort, W. J. Vermaak and P. J. Becker: Relationship between vitamin B-6 status and elevated pyridoxal kinase levels induced by theophylline therapy in humans. J Nutr, 120(11), 1352-9 (1990)
104. R. Delport, J. B. Ubbink, W. J. Vermaak and P. J. Becker: Theophylline increases pyridoxal kinase activity independently from vitamin B6 nutritional status. Res Commun Chem Pathol Pharmacol, 79(3), 325-33 (1993)
105. J. B. Ubbink, R. Delport, P. J. Becker and S. Bissbort: Evidence of a theophylline-induced vitamin B6 deficiency caused by noncompetitive inhibition of pyridoxal kinase. J Lab Clin Med, 113(1), 15-22 (1989) doi:0022-2143(89)90070-X (pii)
106. J. B. Ubbink, S. Bissbort, W. J. Vermaak and R. Delport: Inhibition of pyridoxal kinase by methylxanthines. Enzyme, 43(2), 72-9 (1990)
107. S. Bach, M. Knockaert, J. Reinhardt, O. Lozach, S. Schmitt, B. Baratte, M. Koken, S. P. Coburn, L. Tang, T. Jiang, D. C. Liang, H. Galons, J. F. Dierick, L. A. Pinna, F. Meggio, F. Totzke, C. Schachtele, A. S. Lerman, A. Carnero, Y. Wan, N. Gray and L. Meijer: Roscovitine targets, protein kinases and pyridoxal kinase. J Biol Chem, 280(35), 31208-19 (2005) doi:M500806200 (pii) 10.1074/jbc.M500806200
108. L. Tang, M. H. Li, P. Cao, F. Wang, W. R. Chang, S. Bach, J. Reinhardt, Y. Ferandin, H. Galons, Y. Wan, N. Gray, L. Meijer, T. Jiang and D. C. Liang: Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. J Biol Chem, 280(35), 31220-9 (2005) doi:M500805200 (pii) 10.1074/jbc.M500805200
109. E. F. Kirkness and A. J. Turner: Characterization of a cytosolic protein (P36) isolated from pig brain by benzodiazepine-affinity chromatography. J Neurochem, 50(2), 356-65 (1988)
doi:10.1111/j.1471-4159.1988.tb02920.x
110. M. C. Hanna, A. J. Turner and E. F. Kirkness: Human pyridoxal kinase. cDNA cloning, expression, and modulation by ligands of the benzodiazepine receptor. J Biol Chem, 272(16), 10756-60 (1997)
doi:10.1074/jbc.272.16.10756
111. T. Apeland, M. A. Mansoor, K. Pentieva, H. McNulty, I. Seljeflot and R. E. Strandjord: The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs. Epilepsy Res, 51(3), 237-47 (2002) doi:S0920121102001535 (pii)
112. S. J. An, S. K. Park, I. K. Hwang, S. Y. Choi, O. S. Kwon, M. H. Won and T. C. Kang: Vigabatrin inhibits pyridoxine-5'-phosphate oxidase, not pyridoxal kinase in the hippocampus of seizure prone gerbils. Neurochem Int, 44(3), 133-7 (2004) doi:S0197018603001359 (pii)
113. J. B. Adams, F. George and T. Audhya: Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements. J Altern Complement Med, 12(1), 59-63 (2006) doi:10.1089/acm.2006.12.59
doi:10.1089/acm.2006.12.59
114. A. S. Brown and E. S. Susser: Homocysteine and schizophrenia: from prenatal to adult life. Prog Neuropsychopharmacol Biol Psychiatry, 29(7), 1175-80 (2005) doi:S0278-5846(05)00225-3 (pii) 10.1016/j.pnpbp.2005.06.028
115. J. W. Muntjewerff, R. S. Kahn, H. J. Blom and M. den Heijer: Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry, 11(2), 143-9 (2006) doi:4001746 (pii) 10.1038/sj.mp.4001746
116. J. Levine, Z. Stahl, B. A. Sela, V. Ruderman, O. Shumaico, I. Babushkin, Y. Osher, Y. Bersudsky and R. H. Belmaker: Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry, 60(3), 265-9 (2006) doi:S0006-3223(05)01274-6 (pii) 10.1016/j.biopsych.2005.10.009
117. H. Song, S. Ueno, S. Numata, J. Iga, S. Shibuya-Tayoshi, M. Nakataki, S. Tayoshi, K. Yamauchi, S. Sumitani, T. Tomotake, T. Tada, T. Tanahashi, M. Itakura and T. Ohmori: Association between PNPO and schizophrenia in the Japanese population. Schizophr Res, 97(1-3), 264-70 (2007) doi:S0920-9964(07)00336-2 (pii) 10.1016/j.schres.2007.08.004
118. J. W. Muntjewerff, N. van der Put, T. Eskes, B. Ellenbroek, E. Steegers, H. Blom and F. Zitman: Homocysteine metabolism and B-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schizophrenia. Psychiatry Res, 121(1), 1-9 (2003) doi:S0165178103002002 (pii)
119. J. C. Kouyoumdjian and M. Ebadi: Anticonvulsant activity of muscimol and gamma-aminobutyric acid against pyridoxal phosphate-induced epileptic seizures. J Neurochem, 36(1), 251-7 (1981)
doi:10.1111/j.1471-4159.1981.tb02401.x
120. T. C. Kang, S. K. Park, I. K. Hwang, S. J. An, J. H. Bahn, A. Y. Kim, S. Y. Choi, O. S. Kwon, N. I. Baek, H. Y. Lee and M. H. Won: Chronological changes in pyridoxine-5'-phosphate oxidase immunoreactivity in the seizure-sensitive gerbil hippocampus. J Neurosci Res, 68(6), 785-91 (2002) doi:10.1002/jnr.10280
doi:10.1002/jnr.10280
121. T. C. Kang, S. K. Park, I. K. Hwang, S. J. An, J. H. Bahn, D. W. Kim, S. Y. Choi, O. S. Kwon, N. I. Baek, H. Y. Lee and M. H. Won: Changes in pyridoxal kinase immunoreactivity in the gerbil hippocampus following spontaneous seizure. Brain Res, 957(2), 242-50 (2002) doi:S0006899302035667 (pii)
122. N. Ishioka, J. Sato, J. Nakamura, T. Ohkubo, A. Takeda and S. Kurioka: In vivo modification of GABAA receptor with a high dose of pyridoxal phosphate induces tonic-clonic convulsion in immature mice. Neurochem Int, 26(4), 369-73 (1995) doi:019701869400145K (pii)
123. M. Ebadi and B. Klangkalya: On the mechanism of pyridoxal phosphate-related convulsions as implicated in enhanced transport of GABA. Neuropharmacology, 18(3), 301-7 (1979)
doi:10.1016/0028-3908(79)90130-8
124. J. W. Miller, R. Green, D. M. Mungas, B. R. Reed and W. J. Jagust: Homocysteine, vitamin B6, and vascular disease in AD patients. Neurology, 58(10), 1471-5 (2002)
125. K. M. Riggs, A. Spiro, 3rd, K. Tucker and D. Rush: Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr, 63(3), 306-14 (1996)
126. R. Malouf and J. Grimley Evans: The effect of vitamin B6 on cognition. Cochrane Database Syst Rev(4), CD004393 (2003) doi:10.1002/14651858.CD004393
127. J. B. Deijen, E. J. van der Beek, J. F. Orlebeke and H. van den Berg: Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. Psychopharmacology (Berl), 109(4), 489-96 (1992)
doi:10.1007/BF02247729
128. M. F. Elias, M. A. Robbins, M. M. Budge, P. K. Elias, S. L. Brennan, C. Johnston, Z. Nagy and C. J. Bates: Homocysteine, folate, and vitamins B6 and B12 blood levels in relation to cognitive performance: the Maine-Syracuse study. Psychosom Med, 68(4), 547-54 (2006) doi:68/4/547 (pii) 10.1097/01.psy.0000221380.92521.51
129. M. Elstner, C. M. Morris, K. Heim, P. Lichtner, A. Bender, D. Mehta, C. Schulte, M. Sharma, G. Hudson, S. Goldwurm, A. Giovanetti, M. Zeviani, D. J. Burn, I. G. McKeith, R. H. Perry, E. Jaros, R. Kruger, H. E. Wichmann, S. Schreiber, H. Campbell, J. F. Wilson, A. F. Wright, M. Dunlop, G. Pistis, D. Toniolo, P. F. Chinnery, T. Gasser, T. Klopstock, T. Meitinger, H. Prokisch and D. M. Turnbull: Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene. Ann Neurol, 66(6), 792-8 (2009) doi:10.1002/ana.21780
doi:10.1002/ana.21780
130. C. Vilarino-Guell, C. Wider, J. O. Aasly, L. R. White, A. Rajput, A. H. Rajput, T. Lynch, A. Krygowska-Wajs, B. Jasinska-Myga, G. Opala, M. Barcikowska, K. Czyzewski, R. M. Wu, R. J. Uitti, Z. K. Wszolek, M. J. Farrer and O. A. Ross: Association of pyridoxal kinase and Parkinson disease. Ann Neurol, 67(3), 409-11 (2010) doi:10.1002/ana.21962
doi:10.1002/ana.21962
131. I. Guella, R. Asselta, S. Tesei, M. Zini, G. Pezzoli and S. Duga: The PDXK rs2010795 variant is not associated with Parkinson disease in Italy. Ann Neurol, 67(3), 411-2; author reply 412 (2010) doi:10.1002/ana.21964
doi:10.1002/ana.21964
132. C. J. Chern and E. Beutler: Pyridoxal kinase: decreased activity in red blood cells of Afro-Americans. Science, 187(4181), 1084-6 (1975)
doi:10.1126/science.1114336
133. S. K. Martin, L. H. Miller, J. A. Kark, C. U. Hicks, M. J. Haut, V. C. Okoye and G. J. Esan: Low erythrocyte pyridoxal-kinase activity in Blacks: Its possible relation to falciparum malaria. Lancet, 1(8062), 466-8 (1978) doi:S0140-6736(78)90133-2 (pii)
134. J. M. Flanagan and E. Beutler: The genetic basis of human erythrocyte pyridoxal kinase activity variation. Haematologica, 91(6), 801-4 (2006) doi:03906078_9451 (pii)
Abbreviations: CDK: cycline-dependent kinase, CNS: central nervous system, GABA: gamma-aminobutyric acid, MTHFR: 5,10-methylenetetrahydrofolate reductase, NEE: neonatal epileptic encephalopathy, PL: pyridoxal, PLK: pyridoxal kinase, PLP: pyridoxal 5'-phosphate, PN: pyridoxine, PNP: pyridoxine 5'-phosphate, PNPOx: pyridoxine (pyridoxamine) 5'-phosphate oxidase, PM: pyridoxamine, PMP: pyridoxamine 5'-phosphate, TNAP: tissue-nonspecific alkaline phosphatase.
Key Words: Vitamin B6, Pyridoxal 5'-Phosphate, Salvage Pathway, Pyridoxal Kinase, Pyridoxine 5'-Phosphate Oxidase, Plp Deficiency, Neurological Disorders, Review
Send correspondence to: Roberto Contestabile, Dipartimento di Scienze Biochimiche A. Rossi Fanelli, Sapienza Universita di Roma, Via degli Apuli 9, 00185 Roma, Italy, Tel: 39 06 49917575, Fax: 39 06 49917566, E-mail:roberto.contestabile@uniroma1.it