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PubMed1982

Drug-pyridoxal phosphate interactions.

In this review it has been pointed out that vitamin B6 and its vitamers can be involved in many interactions with a number of drugs, as well as with the actions of various endocrines and neurotransmitters. Nutritional deficiencies, especially of vitamins and proteins, can affect the manner in which drugs undergo biotransformation, and thereby may also modify the therapeutic efficacy of certain drugs. The differences between nutritional vitamin B6 deficiency and the hereditary disorder producing pyridoxine dependency are discussed. In addition to a pyridoxine deficiency being able to adversely affect drug actions, the improper supplementation with vitamin B6 can in some instances also adversely affect drug efficacy. A decrease by pyridoxine in the efficacy of levodopa used in the treatment of Parkinsonism is an example. The interrelationships and enzymatic interconversions among pyridoxine vitamers, both phosphorylated and non-phosphorylated, are briefly discussed, particularly regarding their pharmacokinetic properties. The ways in which the normal biochemical functions of vitamin B6 may be interfered with by various drugs are reviewed. (1) The chronic administration of isoniazid for the prevention or treatment of tuberculosis can produce peripheral neuropathy which can be prevented by the concurrent administration of pyridoxine. An acute toxic overdose of isoniazid causes generalized convulsions, and the intravenous administration of pyridoxine hydrochloride will prevent or stop these seizures. (2) The acute ingestion of excessive monosodium glutamate will, in some individuals, cause a group of symptoms including among others headache, weakness, stiffness, and heartburn, collectively known as the 'Chinese Restaurant Syndrome.' These symptoms can be prevented by prior supplementation with vitamin B6. The beneficial effect is ascribed to the correction of a deficiency in the activity of glutamic oxaloacetic transaminase, an enzyme that is dependent on pyridoxal phosphate. Some interesting relationships are pointed out between vitamin B6, picolinic acid, and zinc. It is postulated that the intestinal absorption of zinc is facilitated by picolinic acid, a metabolite of tryptophan. The derivation of picolinic acid from tryptophan depends on the action of the enzyme kynureninase, which is dependent on pyridoxal phosphate; therefore, the adequate absorption of zinc is indirectly dependent on an adequate supply of vitamin B6. The formation of pyridoxal phosphate, on the other hand, appears to be indirectly dependent on Zn2++ which activates pyridoxal kinase.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Evaluations of tyrosine apodecarboxylase assays for pyridoxal phosphate.

The alternate procedures used in the tyrosine apodecarboxylase assays for pyridoxal 5'-phosphate were evaluated to determine optimal conditions. Two preparations of tyrosine apodecarboxylase from Streptococcus faecalis were used: a cell suspension and a partially purified cell-free form. The activity of the decarboxylase was measured in two different assays using [14C]tyrosine or [3H]tyrosine as substrate. The presence of serum proteins caused greater inhibition of the assay for serum pyridoxal phosphate using [14C]tyrosine as substrate than the assay with [3H]tyrosine. In contrast, addition of deproteinized serum extract did not appear to inhibit either assay. The rate of reconstitution of the apodecarboxylase in the cell suspension was at least four times slower than that of the cell-free enzyme. The rate of reconstitution of the cell-free enzyme was faster in acetate than in citrate buffer. Inorganic sulfate or phosphate, at normal plasma concentrations, did not alter either the reconstitution rate of tyrosine decarboxylase or the final activity obtained in the assays using either substrate. The tyrosine apodecarboxylase assay for pyridoxal phosphate can be optimized by using deproteinized sera or plasma and incubating the cell-free apoenzyme with the coenzyme in acetate buffer for a time sufficient to obtain maximum reconstitution.

Acetates↗
PubMed1988

Localization of the pyridoxal phosphate binding site at the COOH-terminal region of erythrocyte band 3 protein.

A human erythrocyte Band 3 peptide, affinity labeled with pyridoxal phosphate, was purified by a combination of gel permeation and reverse-phase high performance liquid chromatography. The amino acid sequence of the transmembrane peptide was determined by sequencing subfragments of the peptide obtained from lysyl endopeptidase and staphylococcal proteinase V8 digestions. When a peptide containing the COOH-terminal of human erythrocyte Band 3 was also purified and sequenced, the affinity-labeled peptide was found to be located close to the COOH-terminal of Band 3, where it could be aligned with amino acid residues 852-927 of a murine erythrocyte Band 3, deduced from a nucleotide sequence of a cDNA clone (Kopito, R. R., and Lodish, H. F. (1985) Nature 316, 234-238). The amino acid sequence of the COOH-terminal region was highly homologous to that of murine Band 3. As a result, the sequence of the COOH-terminal peptide of Band 3 was established as follows. (Formula: see text). The pyridoxal phosphate binding site was identified as Lys-18 which corresponded to Lys-869 of the deduced sequence. It appears that the COOH-terminal region of Band 3 constitutes at least a part of the active center for anion transport in human erythrocyte membranes.

Amino Acid Sequence↗
PubMed1999

Characterization of the heme and pyridoxal phosphate cofactors of human cystathionine beta-synthase reveals nonequivalent active sites.

Cystathionine beta-synthase is an unusual enzyme that requires the cofactors heme and pyridoxal phosphate (PLP) to catalyze the condensation of homocysteine and serine to generate cystathionine. This transsulfuration reaction represents one of two major cellular routes for detoxification of homocysteine, which is a risk factor for atherosclerosis. While the beta-replacement reaction catalyzed by this enzyme suggests a role for the pyridoxal phosphate, the role of the heme is uncertain. In this study we have examined the effect of changing one of the ligands to the heme on the activity of the enzyme. Binding of carbon monooxide results in the displacement of a thiolate ligand to the ferrous heme, and is accompanied by complete loss of cystathionine beta-synthase activity. Furthermore, inhibition by CO is competitive with respect to homocysteine, providing the first indication that the homocysteine binding site is in the proximity of heme. Binding of both CO and cyanide to ferrous cystathionine beta-synthase occurs in two distinct isotherms and indicates that the hemes are nonequivalent. We have employed fluorescence spectroscopy to characterize the bound PLP and its interaction with serine. PLP bound to cystathionine beta-synthase is weakly fluorescent and exists as a mixture of the protonated and unprotonated tautomers. Reaction with hydroxylamine releases the oxime and greatly enhances the associated fluorescence. Binding of serine is accompanied by a shift to the unprotonated tautomer of the external aldimine as well as the appearance of a new fluorescent species at approximately 400 nm that could be due to the aminoacrylate or to a gemdiamine intermediate. These data provide the first characterization of the PLP bound to cystathionine beta-synthase. Treatment of cystathionine beta-synthase with hydroxylamine releases two PLPs after 1 day and results in complete loss of activity. Incubation for an additional 3-4 days results in the release of two more PLPs. These data lead us to revise the PLP stoichiometry to 4 per tetramer, and to the conclusion that the heme and PLP sites in cystathionine beta-synthase are nonequivalent.

Binding Sites↗
PubMed1990

[Pyridoxal phosphate as an agent for normalizing the monoamine oxidase activity of the brain in radiation sickness].

A study was made of the influence of the coenzyme pyridoxal phosphate on the activity of mitochondrial monoaminoxidase (MAO) catalyzing oxidative deamination of serotonin at the exacerbation of acute radiation disease (on the 6th day after radiation exposure) in different parts of the brain (cerebral hemisphere, stem and cerebellum). Experiments were staged on rabbits, irradiated by x-ray at a dose of 4.5 Gy with a dose rate of 0.33 Gy/min. The peak of radiation disease was characterized by considerable changes in MAO activity resulting in catalysis of oxidative deamination of serotonin in different parts of the brain and in different mitochondrial subfractions. Pyridoxal phosphate produced a positive effect on monoaminoxidase activity, catalyzing serotonin deamination, and as a coenzyme it can be incorporated in a complex of drugs used for normalization of metabolism of mediators of the nervous system as well as for therapy of radiation injuries.

Animals↗
PubMed1984

Pyridoxal phosphate, tryptophan, and tyrosine in blood and cerebrospinal fluid in elderly patients.

In a material of 74 elderly patients with cerebral symptoms, most of them on account of atherosclerosis, deficiency of pyridoxal phosphate is uncommon: only ten had extremely low plasma levels. Nine of the patients had rather high levels of serum tryptophan. This might depend upon poor metabolization when pyridoxal phosphate is available in insufficient supply. In addition mean values are given for tryptophan, tyrosin and serotonin in this group of patients.

Adult↗
PubMed1981

Structure-function relationship in Escherichia coli initiation factors. Identification of a lysine residue in the ribosomal binding site of initiation factor by site-specific chemical modification with pyridoxal phosphate.

Incubation of Escherichia coli initiation factor 3 (IF3) with pyridoxal phosphate (PLP) followed by reduction with sodium borohydride resulted in the selective modification and inactivation of this protein. The ribosomal-binding site (RNA-binding site) of IF3 is the target of PLP modification, since (a) the phosphate residue of PLP is required for inactivation; (b) RNA as well as synthetic polynucleotides (especially guanine-containing one) protect IF3 from inactivation; and (c) 30 S, but not 50 S ribosomal subunits, protect IF3 from PLP modification and from inactivation. The incorporation of PLP into IF3 occurred exclusively at lysine residues by reduction of the Schiff bases yielding epsilon-(5'-phosphopyridoxyl)lysine. The PLP-modified lysines were identified by amino acid analysis and sequencing of the PLP-modified peptides. Out of the 20 lysines of the factor, only Lys 2, Lys 5, Lys 99, Lys 112, Lys 166, and an unidentified Lys of the central cluster of the molecule (Lys 86, 87, 90, 91, 96) were found to be modified to varying degrees. The incorporation of 3 to 4 mol of PLP/mol of IF3 is accompanied by a substantial (greater than or equal to 80%) inactivation of this protein; the loss of activity follows apparent first order kinetics, and the inactivation results from the modification of just 1 Lys residue. This essential Lys residue was identified by various criteria to be Lys 112. The identification of an "active region" in the IF3 molecule is emerging from this as well as from other chemical modification studies.

Amino Acids↗
PubMed1975

Seizure susceptibility in the developing mouse and its relationship to glutamate decarboxylase and pyridoxal phosphate in brain.

The relationship between the susceptibility to convulsions, the content of pyridoxal 5'-phosphate and the activity of pyridoxal kinase (EC 2.7.1.35) and glutamate decarboxylase (EC 4.1.1.15) in brain, was studied in the developing mouse. Seizures were induced by pyridoxal phosphate-gamma-glutamyl hydrazone (PLPGH), a drug previously reported to reduce the levels of pyridoxal 5'-phosphate and as a consequence to inhibit the activity of glutamate decarboxylase in brain of adult mice. It was found that the seizure pattern, as well as the time of appearance of convulsions, differed between 2- and 5-day old mice and 10-day old or older mice, indicating a progressive increase in seizure susceptibility during development. In brain, pyridoxal kinase activity and pyridoxal 5'-phosphate levels were decreased by the administration of PLPGH at all ages studied, whereas glutamate decarboxylase activity was inhibited less than 25% in 2- and 5-day old mice, and about 50% thereafter. Parallelly, the activation of glutamate decarboxylase by pyridoxal 5'-phosphate added in vitro to control homogenates was less in 2- and 5-day old mice than in older animals. It is concluded that the increase in the susceptibility to seizures induced by PLPGH during development is probably related to the increase observed in the sensitivity of glutamate decarboxylase in vivo to a decrease of pyridoxal 5'-phosphate levels. The correlation between pyridoxal 5'-phosphate, glutamate decarboxylase, and seizure susceptibility seems to be established at about 10 days of age.

Animals↗
PubMed1978

Effect of pyridoxal phosphate on the DNA binding site of activated hepatic glucocorticoid receptor.

The binding of rat liver glucocorticoid.receptor complexes to DNA-cellulose and nuclei has been studied after activation of the complexes by heating. Subsequent exposure to pyridoxal 5'-phosphate or pyridoxal markedly inhibited this binding. In one system 0.75 mM pyridoxal 5'-phosphate or 6.5 mM pyridoxal gave 50% inhibition. Pyridoxamine 5'-phosphate, pyridoxamine, and pyridoxine did not inhibit significantly. The inhibition by pyridoxal 5'-phosphate is competitive with respect to DNA suggesting that its effect is directly on the DNA binding site of the activated receptor. The inhibition of DNA-cellulose binding by pyridoxal 5'-phosphate can be reversed by treatment with dithiothreitol or by gel filtration, but not if the modified receptor is first reduced using sodium borohydride. These results suggest that pyridoxal 5'-phosphate acts by forming a Schiff base of an epsilon-NH2 of a lysine which may be 1 residue appearing on the surface of the steroid.receptor complex upon activation. However, since pretreatment of the DNA-cellulose with the intercalating drug ethidium bormide also inhibits activated receptor binding, we conclude that the binding of the receptor involves more than electrostatic interactions between receptor positive charges and DNA phosphate groups.

Adrenalectomy↗
PubMed1981

A highly sensitive fluorimetric assay for pyridoxal phosphate phosphatase.

A highly sensitive fluorimetric assay for pyridoxal phosphate phosphatase is described. The assay involves separation of the substrate and product by ion-exchange chromatography followed by treatment of pyridoxal with potassium cyanide under slightly alkaline conditions to form 4-pyridoxolactone, a highly fluorescent compound. Certain kinetic properties of the enzyme activities in human neutrophils are described.

Chromatography, Ion Exchange↗
PubMed1987

Pyridoxal phosphate concentrations determined postmortem as an indication of antemortem vitamin B-6 status.

In anticipation of studies relating vitamin B-6 status determined at autopsy to known pathologic causes of death, the postmortem stability of pyridoxal phosphate (PLP) in the plasma, skeletal muscle, and liver of pigs was assessed. Concentrations of plasma K, Mg, Na, and Ca also were examined for postmortem stability using the pig as an experimental model. At 1 hr after death, the mean plasma PLP concentration was essentially unchanged from that observed prior to death. Thereafter, plasma PLP concentration increased with increasing postmortem time interval and was 2.3 times greater than initial by 6 hr postmortem and 7.6 times greater than initial by 12 hr postmortem (P less than 0.01). Skeletal muscle and liver PLP content were 35% lower than initial by 6 hr postmortem (P less than 0.01). Plasma K and Mg were significantly higher by 1 hr postmortem (P less than 0.01) while plasma Na concentration was significantly lower by 1 hr postmortem (P less than 0.01). Plasma Ca concentration was not significantly different at any measured time point. Knowledge of the postmortem time interval appears to be required in order to evaluate the antemortem vitamin B-6 status using pyridoxal phosphate values derived from autopsy samples.

Animals↗
PubMed1986

A simplified method for determination of pyridoxal phosphate in biological samples.

A new method for the determination of pyridoxal phosphate in plasma and in cerebrospinal fluid is described. It is based on the generally accepted apotyrosine decarboxylase method, but, in stead of following the decarboxylation rate using 14C- och 3H-labelled tyrosine, a high performance liquid chromatography (HPLC) method for separation of tyrosine and tyramine is used. This procedure is recommended as it is less time consuming and avoids utilizing radioactive material.

Carbon Radioisotopes↗
PubMed1975

The effect of pyridoxine hydrochloride on blood serotonin and pyridoxal phosphate contents in hyperactive children.

The contents of serotonin (hydroxytryptamine) and pyridoxal phosphate (PLP) in the blood of 11 hyperactive children and 11 controls were determined on an outpatient basis. A significant decrease in serotonin content was found in blood samples from hyperactive patients as compared with controls. There were no differences in PLP content of blood between the two groups. Four children were selected for a study of the effects of pyridoxine hydrochloride (vitamin B6) on low serotonin levels. Oral doses of pyridoxine resulted in an appreciable increase in the serotonin content and a very large increase in the PLP content of blood in these hyperactive patients.

Adolescent↗
PubMed1980

Subunit interactions of tryptophan synthase from Escherichia coli as revealed by binding studies with pyridoxal phosphate analogues.

An improved purification procedure for the alpha 2 beta 2 complex of tryptophan synthase from Escherichia coli has been developed. It consists of DEAE-Sephacel chromatography, followed by hydrophobic chromatography on Sepharose CL 4B, and leads to material with a higher specific activity than reported previously. Inhibition studies, equilibrium dialysis, and spectrophotometric titration were used to study the binding both of pyridoxal phosphate analogues and of bisubstrate analogues. Pyridoxine 5'-phospate and N-phosphopyridoxyl-L-serine bind to the enzyme, but pyridoxamine 5'-phoshate and N-phosphopridoxyl-L-alanine do not. N-Phosphopyridoxyl-L-tryptophan is bound only weakly, although L-tyrptophan binds strongly to the alpha 2 holo beta 2 complex. It is likely that either differences is protonation or in geometry are responsible for the low affinity of the bisubstrate analogues in comparison to that of the external aldimines of either L-serine or L-tyrptophan with pyridoxal 5'-phosphate. As previously found with pyridoxal 5'-phosphate, pyridoxine 5'-phosphate, and N-phosphopryidoxyl-L-serine bind noncooperatively to two identical binding sites in the alpha 2 apo beta 2 complex. The same ligands bind with positive cooperatively to two binding sites in the apo beta 2 subunit. Because the analogues mimic the binding behavior of pyridoxal 5'-phosphate to both proteins, the internal aldimine of pyridoxal 5'-phosphate to the lysine amino group contributes only to the strength of that binding. The nickel apo beta 2 subunit, which is produced by limited proteolysis with trypsin, binds pyroxine 5'-phosphate noncooperatively to two identical sites. Therefore, the loop of polypeptide chain connecting the two autonomous domains of folding must be intact for enzyme activity, for the binding of the alpha subunit, and for cooperative binding of pyridoxine 5'-phosphate.

Binding Sites↗
PubMed1977

Effect of PCB (polychlorobiphenyls) on on L-ascorbic acid, pyridoxal phosphate and riboflavin contents in various organs and on hepatic metabolism of L-ascorbic acid in the rat.

Effects of continuous oral administration of PCB (polychlorobiphenyls, 10-100 mg/kg/day, 4 weeks) on tissue levels of L-ascorbic acid (vitamin C), pyridoxal phosphate and riboflavin (vitamin B2) in various organs and on hepatic metabolism of L-ascorbic acid were examined in male Wistar rats weighing 150-250 g. Riboflavin contents in the liver, kidney, brain, heart and testis were not altered by PCB treatments, whereas the hepatic level of pyridoxal phosphate, a biologically active form of vitamin B6, was significantly reduced by PCB administration. Under the same experimental conditions, L-ascorbic acid contents in the liver, kidney, lung and testis showed a significant increase. Histochemical studied revealed that in the adrenal gland, increase of L-ascorbic acid was localized in the fasciculate and reticular zones of cortex, respectively. It was found that increase of L-ascorbic acid in the liver is caused predominantly by activation of biosynthesis at the steps of galactose to D-glucuronic acid and is not due to changes in the catabolic processes of L-ascorbic acid per se. Possible significance of these changes in tissue levels and/or metabolism of vitamins in the occurrence of PCB intoxication is briefly discussed.

Administration, Oral↗
PubMed1985

The turnover of skeletal muscle glycogen phosphorylase studied using the cofactor, pyridoxal phosphate, as a specific label.

The turnover of glycogen phosphorylase has been measured using the cofactor, pyridoxal phosphate, as a label specific for this enzyme in skeletal muscle. Radiolabelled pyridoxine administered in vivo is incorporated into a protein-bound fraction in skeletal muscle, shown by several criteria to be equivalent to glycogen phosphorylase. This pool of radiolabel disappears slowly with a half-life of 11.9 days, taken to be a good estimate of the intracellular half-life of the enzyme. The use of the cofactor in this fashion minimises overestimation of half-life that results from reincorporation of the label. Further, premature dissociation of the cofactor from native enzyme, which would lead to underestimation of half-life, is unlikely. At the level of sensitivity given by this method there was little evidence for the appearance of pyridoxal phosphate-labelled degradation intermediates of the enzyme.

Animals↗
PubMed1989

Phenelzine treatment of panic disorder: lack of effect on pyridoxal phosphate levels.

Earlier reports indicated that phenelzine treatment may result in clinically significant reductions of vitamin B6 in some individuals. Sixteen subjects, ages 21-59 years (seven men, nine women) with panic disorder with or without agoraphobia were treated with an average of phenelzine 53.5 mg/day for an average of 10 weeks in an open treatment study. No significant effects on plasma levels of pyridoxal phosphate, the active form of vitamin B6, were discernible in this group, nor was there any clear relationship between pyridoxal phosphate levels and symptoms in the subgroup of five patients who did develop deficiency-type symptoms. Pyridoxine replacement had unclear effects in symptomatic patients.

Adult↗