-
Clinica Chimica Acta; International... Mar 2017We quantified pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) in the cerebrospinal fluid (CSF) of children and to investigate the effect of age,...
BACKGROUND
We quantified pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) in the cerebrospinal fluid (CSF) of children and to investigate the effect of age, sex, epilepsy, and anti-epileptic drug (AED) therapy on these vitamers.
METHODS
CSF samples prospectively collected from 116 pediatric patients were analyzed. PLP, PL, and PA were measured using high-performance liquid chromatography with fluorescence detection, using pre-column derivatization by semicarbazide. Effects of age, sex, epilepsy, and AEDs on these vitamers and the PLP/PL ratio were evaluated using multiple linear regression models.
RESULTS
The PLP, PL, and PA concentrations were correlated negatively with age and the PLP/PL ratio was correlated positively with age. Multiple regression analysis revealed that the presence of epilepsy was associated with lower PLP concentrations and PLP/PL ratios but sex and AED therapy had no influence on these values. The observed ranges of these vitamers in epileptic and non-epileptic patients were demonstrated.
CONCLUSIONS
We showed the age dependence of PLP and PL in CSF from pediatric patients. Epileptic patients had lower PLP concentrations and PLP/PL ratios than non-epileptic patients, but it is unknown whether this is the cause, or a result, of epilepsy.
Topics: Age Factors; Child; Chromatography, High Pressure Liquid; Epilepsy; Female; Humans; Linear Models; Male; Prospective Studies; Pyridoxal; Pyridoxal Phosphate; Pyridoxic Acid; Sex Factors
PubMed: 28040557
DOI: 10.1016/j.cca.2016.12.027 -
International Journal of Molecular... Aug 2020The chemical processes taking place in humans intersects the myriad of metabolic pathways occurring in commensal microorganisms that colonize the body to generate a... (Review)
Review
The chemical processes taking place in humans intersects the myriad of metabolic pathways occurring in commensal microorganisms that colonize the body to generate a complex biochemical network that regulates multiple aspects of human life. The role of tryptophan (Trp) metabolism at the intersection between the host and microbes is increasingly being recognized, and multiple pathways of Trp utilization in either direction have been identified with the production of a wide range of bioactive products. It comes that a dysregulation of Trp metabolism in either the host or the microbes may unbalance the production of metabolites with potential pathological consequences. The ability to redirect the Trp flux to restore a homeostatic production of Trp metabolites may represent a valid therapeutic strategy for a variety of pathological conditions, but identifying metabolic checkpoints that could be exploited to manipulate the Trp metabolic network is still an unmet need. In this review, we put forward the hypothesis that pyridoxal 5'-phosphate (PLP)-dependent enzymes, which regulate multiple pathways of Trp metabolism in both the host and in microbes, might represent critical nodes and that modulating the levels of vitamin B6, from which PLP is derived, might represent a metabolic checkpoint to re-orienteer Trp flux for therapeutic purposes.
Topics: Animals; Bacteria; Host-Pathogen Interactions; Humans; Mammals; Pyridoxal Phosphate; Tryptophan; Vitamin B 6
PubMed: 32823705
DOI: 10.3390/ijms21165823 -
Bone Oct 2022We investigated the utility of urine phosphoethanolamine (PEA) as a marker to aid in diagnosing and/or confirming hypophosphatasia (HPP) in adults and for monitoring...
OBJECTIVES
We investigated the utility of urine phosphoethanolamine (PEA) as a marker to aid in diagnosing and/or confirming hypophosphatasia (HPP) in adults and for monitoring patients on enzyme replacement therapy (ERT).
METHODS
Data was collected from seventy-eight adults who were referred to the Vanderbilt Program for Metabolic Bone Disease for evaluation of a possible or confirmatory HPP diagnosis between July 2014 through December 2019. Fifty-nine patients were diagnosed with HPP and nineteen were excluded from a diagnosis of HPP. The urine PEA results of those patients with a confirmed diagnosis of HPP and those patients with a diagnosis of HPP excluded were captured and compared to other laboratory and clinical parameters consistent with HPP, including alkaline phosphatase (ALP) activity, plasma pyridoxal 5'-phosphate (PLP), the presence of musculoskeletal abnormalities, and genetic testing for pathogenic mutations in ALPL.
RESULTS
Initial urine PEA values in patients in our HPP cohort and not on ERT were significantly higher (median = 150.0 nmol/mg creatinine, IQR = 82.0-202.0) compared patients in our HPP negative group (median 18.0 nmol/mg creatinine, IQR = 14.0-30.0, p < 0.0001) and higher than patients on ERT (median 65.0 nmol/mg creatinine, IQR = 45.3-79.8). Patients who began ERT had a decline in urine PEA levels after treatment with a mean decrease of 68.1 %. Plasma ALP levels were significantly lower in the group of patients with HPP and not on ERT group (median = 24.0 U/L, IQR = 15.0-29.50) compared to the patients without HPP (median = 45.50 U/L, IQR = 34.0-62.0;) and plasma PLP levels were significantly higher in the HPP non-ERT group (median = 284.0 nmol/L, IQR = 141.0-469.4) compared to the patients without HPP (median = 97.5 nmol/L, IQR = 43.7-206.0;). The area under the curve (AUC) of urine PEA, ALP, and PLP to distinguish between HPP and non-HPP patients is 0.968, 0.927 and 0.781, respectively, in our cohort. Urine PEA had 100 % specificity (95 % CI of 83.2 % to 100.0 %) for diagnosing HPP at a value >53.50 nmol/mg creatinine with a sensitivity of 88.4 %; 95%CI 75.5 to 94.9 %. ALP had a 100 % specificity (95 % CI of 82.4 % to 100.0 %) for diagnosing HPP at a value <30.5 U/L with a sensitivity of 77.2 %; (95%CI 64.8 to 86.2 %). PLP had a 100 % specificity (95 % CI of 81.6 % to 100.0 %) for diagnosing HPP at a value >436 nmol/L with a sensitivity of 26.9 %; (95%CI 16.8 to 40.3 %). The most common pathogenic or likely pathogenic mutations in our cohort were c.1250A>G (p.Asn417Ser), c.1133A>T (p.Asp378Val), c.881A>C (p.Asp294Ala), c.1171C>T (p.Arg391Cys), and c.571G>A, (p.Glu191Lys).
CONCLUSIONS
Urine PEA is a promising diagnostic and confirmatory marker for HPP in patients undergoing investigation for HPP. Urine PEA also has potential use as a marker to monitor ERT compliance. Future studies are necessary to evaluate the association between PEA levels and clinical outcomes.
Topics: Adult; Alkaline Phosphatase; Biomarkers; Creatinine; Ethanolamines; Humans; Hypophosphatasia; Pyridoxal Phosphate
PubMed: 35878747
DOI: 10.1016/j.bone.2022.116504 -
Biochimica Et Biophysica Acta Sep 2015The present review focuses on a subfamily of pyridoxal phosphate (PLP)-dependent enzymes, belonging to the broader fold-type I structural group and whose archetypes can... (Review)
Review
The present review focuses on a subfamily of pyridoxal phosphate (PLP)-dependent enzymes, belonging to the broader fold-type I structural group and whose archetypes can be considered ornithine δ-transaminase and γ-aminobutyrate transaminase. These proteins were originally christened "subgroup-II aminotransferases" (AT-II) but are very often referred to as "class-III aminotransferases". As names suggest, the subgroup includes mainly transaminases, with just a few interesting exceptions. However, at variance with most other PLP-dependent enzymes, catalysts in this subfamily seem specialized at utilizing substrates whose amino function is not adjacent to a carboxylate group. AT-II enzymes are widespread in biology and play mostly catabolic roles. Furthermore, today several transaminases in this group are being used as bioorganic tools for the asymmetric synthesis of chiral amines. We present an overview of the biochemical and structural features of these enzymes, illustrating how they are distinctive and how they compare with those of the other fold-type I enzymes. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio-applications.
Topics: Amines; Binding Sites; Catalysis; Pyridoxal Phosphate; Substrate Specificity; Transaminases
PubMed: 25770684
DOI: 10.1016/j.bbapap.2015.02.023 -
The Cochrane Database of Systematic... Apr 2015Tardive dyskinesia is a chronic and disabling abnormal movement disorder affecting the muscles of the face, neck, tongue and the limbs. It is a common side effect of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tardive dyskinesia is a chronic and disabling abnormal movement disorder affecting the muscles of the face, neck, tongue and the limbs. It is a common side effect of long-term antipsychotic medication use in individuals with schizophrenia and other related psychotic disorders. While there are no known effective treatments for tardive dyskinesia to date, some reports suggest that pyridoxal 5 phosphate may be effective in reducing the severity of tardive dyskinesia symptoms.
OBJECTIVES
To determine the effectiveness of pyridoxal 5 phosphate (vitamin B6 or Pyridoxine or Pyridoxal phosphate) in the treatment of neuroleptic-induced tardive dyskinesia among people with schizophrenia and other related psychotic disorders.
SEARCH METHODS
The Cochrane schizophrenia group's register of clinical trials was searched (January 2013) using the phrase: [*Pyridoxal* OR *Pyridoxine* OR *P5P* OR *PLP* OR *tardoxal* OR *Vitamin B6* O *Vitamin B 6* R in title, abstract or index terms of REFERENCE, or interventions of STUDY. References of relevant identified studies were handsearched and where necessary, the first authors of relevant studies were contacted.
SELECTION CRITERIA
Studies described as randomised controlled trials comparing the effectiveness pyridoxal 5 phosphate with placebo in the treatment of neuroleptic-induced tardive dyskinesia among patients with schizophrenia.
DATA COLLECTION AND ANALYSIS
The review authors independently extracted data from each selected study. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CIs) on an intention-to-treat basis based on a fixed-effect model. For continuous data, we calculated mean differences (MD) with 95% CIs, again based on a fixed-effect model. We assessed risk of bias for each included study and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to rate quality of evidence.
MAIN RESULTS
Of the 12 records retrieved by the search, three trials published in 2001, 2003 and 2007, involving 80 inpatients with schizophrenia, aged 18 to 71 years, admitted in a psychiatric facility and followed up for a period nine weeks to 26 weeks, were included. Overall, pyridoxal 5 phosphate produced a significant improvement in tardive dyskinesia symptoms when compared with placebo, assessed by a change in Extrapyramidal Symptoms Rating Scale (ESRS) scores from baseline to the end of the first phase of the included studies (2 RCTs n = 65, RR 19.97, CI 2.87 to 139.19, low quality evidence). The endpoint tardive dyskinesia score (a measure of its severity) assessed with the ESRS, was significantly lower among participants on pyridoxal 5 phosphate compared to those on placebo (2 RCTs n = 60, MD -4.07, CI -6.36 to -1.79, low quality evidence).It was unclear whether pyridoxal 5 phosphate led to more side effects (n = 65, 2 RCTs, RR 3.97, CI 0.20 to 78.59, low quality evidence) or caused deterioration in tardive dyskinesia symptoms when compared to placebo (n = 65, 2 RCTs, RR 0.16, CI 0.01 to 3.14, low quality evidence). Five participants taking pyridoxal 5 phosphate withdrew from the study because they were not willing to take more medications while none of the participants taking placebo discontinued their medications (n = 65, 2 RCTs, RR 8.72, CI 0.51 to 149.75, low quality evidence).There was no significant difference in the endpoint positive and negative psychiatric symptoms scores, measured using the Positive and Negative symptoms Scale (PANSS) between participants taking pyridoxal 5 phosphate and those taking placebo. For the positive symptoms: (n = 15, 1 RCT, MD -1.50, CI -4.80 to 1.80, low quality evidence). For negative the symptoms: (n = 15, 1 RCT, MD -1.10, CI -5.92 to 3.72, low quality evidence).
AUTHORS' CONCLUSIONS
Pyridoxal 5 phosphate may have some benefits in reducing the severity of tardive dyskinesia symptoms among individuals with schizophrenia. However, the quality of evidence supporting the effectiveness of pyridoxal 5 phosphate in treating tardive dyskinesia is low, based on few studies, short follow-up periods, small sample sizes and inadequate adherence to standardised reporting guidelines for randomised controlled trials among the included studies.
Topics: Adult; Aged; Antipsychotic Agents; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; Pyridoxal Phosphate; Randomized Controlled Trials as Topic; Schizophrenia; Vitamin B Complex
PubMed: 25866243
DOI: 10.1002/14651858.CD010501.pub2 -
International Journal of Biological... Apr 2023Pyridoxal 5'-phosphate (PLP), an essential cofactor for multiple enzymes, was used as a protein decoy to prompt enzyme expression and activity for the first time. The...
Pyridoxal 5'-phosphate (PLP), an essential cofactor for multiple enzymes, was used as a protein decoy to prompt enzyme expression and activity for the first time. The best chassis, denoted as WJK, was developed using a pyridoxal kinase (PdxK) and integrated at the HK022 phage attack site of Escherichia coli W3110. When compared with the original strain, the amount and activity of lysine decarboxylase (CadA) in WJK were significantly increased by 100 % and 120 %, respectively. When supplementary nineteen amino acids as second carbon source, cell growth and protein trade-off were observed. The transcriptional levels of genes from glycolysis to TCA cycle, adhE, argH and gdhA were dominating and redirected more flux into α-ketoglutarate, thus facilitated cell growth. Stepwise improvement was conducted with pyridoxal and nitrogen-rich medium; hence, CadA activity was increased to 60 g-cadaverine/g-dry cell weight/h. By reutilizing the whole-cell biocatalysts in two repeated reactions with the supplementation of fresh cells, a total cadaverine of 576 g/L was obtained even without additional PLP. Notably, PLP decoy augment the enzymatic activities of 5-aminolevulinic acid synthase and glutamate/lysine/arginine decarboxylases by over 100 %. Finally, a conserved PLP-binding pocket, Ser-His-Lys, was identified as a vital PLP sponge site that simultaneously improved protein quality and quantity.
Topics: Escherichia coli; Pyridoxal Phosphate; Carboxy-Lyases; Transformation, Genetic; Cadaverine; Pyridoxal Kinase; Metabolic Engineering
PubMed: 36841388
DOI: 10.1016/j.ijbiomac.2023.123814 -
Preparative Biochemistry & Biotechnology 2022Pyridoxal 5'-phosphate (PLP) is the coenzyme of more than 140 enzymes and is widely used in various fields. In this study, to enhance the production of PLP in BL21, the...
Pyridoxal 5'-phosphate (PLP) is the coenzyme of more than 140 enzymes and is widely used in various fields. In this study, to enhance the production of PLP in BL21, the recombinant strain BL21/pETDuet-1-pdxj-zwf-dxs was constructed. The concentration of PLP in this strain was 82.69 mg/L, which was increased by 1.38-fold as compared to that in BL21. Glucose, yeast extract, and pH had an obvious impact on the concentration of PLP, and their optimal levels were 34.89 g/L, 31.17 g/L, and 10.07, respectively. The concentration of PLP under the optimal condition reached 2.23 g/L. The time-course analysis showed that the highest concentration of PLP was 2.32 g/L in recombinant strain after the induction for 12 h by 0.1 mM IPTG in a 1 L shake flask, which was increased by 38.76-fold as compared to that in BL21. This study provides a good basis for the efficient production of PLP in BL21.
Topics: Escherichia coli; Escherichia coli Proteins; Ligases; Phosphates; Pyridoxal Phosphate
PubMed: 34431758
DOI: 10.1080/10826068.2021.1966801 -
Journal of the National Cancer Institute Mar 2017Vitamin B6 is involved in many biochemical reactions and might play a role in carcinogenesis. We summarized the evidence linking vitamin B6 to cancer risk. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Vitamin B6 is involved in many biochemical reactions and might play a role in carcinogenesis. We summarized the evidence linking vitamin B6 to cancer risk.
METHODS
We conducted a systematic review of both observational and intervention studies investigating the relationship between vitamin B6 intake or blood levels of its bioactive form pyridoxal-5'-phosphate (PLP) and the risk of any type of cancer. Random-effects meta-analysis was used to calculate pooled relative risks (RRs) and their 95% confidence intervals (CIs) across studies for high vs low categories of vitamin intake or PLP levels. We also performed a random-effects dose-response meta-analysis.
RESULTS
We identified 121 observational studies (participants, n = 1 924 506; cases, n = 96 , 436) and nine randomized controlled trials (RCTs; participants, n = 34 911; cases, n = 2539) considering 19 tumor sites. High intake of dietary (food only) vitamin B6 was statistically significantly associated with lower risk of all cancers (relative risk [RR] = 0.78, 95% CI = 0.73 to 0.84) and specific tumors, with special regard to gastrointestinal carcinomas (RR = 0.68, 95% CI = 0.61 to 0.75). An inverse association was also observed between high PLP levels and the risk of all cancers (RR = 0.66, 95% CI = 0.58 to 0.76) and single tumor sites, the most consistent results being those for gastrointestinal tumors (RR = 0.56, 95% CI = 0.48 to 0.65). There was a statistically significant inverse linear relationship between cancer risk and both vitamin B6 dietary intake and PLP levels. When total (food and supplements) intake was considered, the associations were weaker or null. Findings from RCTs did not support a protective effect of vitamin B6 against cancer, although this evidence was graded as low level.
CONCLUSIONS
Epidemiological evidence supports the potential of vitamin B6 as a cancer risk reduction agent and the role of PLP as a cancer screening biomarker, especially for gastrointestinal tumors. However, inconsistent findings from total intake and intervention studies suggest that vitamin B6 might also be an indicator of other dietary protective micronutrients.
Topics: Diet; Dose-Response Relationship, Drug; Humans; Neoplasms; Observational Studies as Topic; Protective Factors; Pyridoxal Phosphate; Randomized Controlled Trials as Topic; Risk Assessment; Vitamin B 6
PubMed: 28376200
DOI: 10.1093/jnci/djw230 -
The Journal of Pharmacy and Pharmacology Apr 2017To assess the pyridoxal 5'-phosphate (PLP) content and stability of extemporaneous PLP liquids prepared from dietary supplements used for the treatment of vitamin B...
OBJECTIVES
To assess the pyridoxal 5'-phosphate (PLP) content and stability of extemporaneous PLP liquids prepared from dietary supplements used for the treatment of vitamin B -dependent epilepsy.
METHODS
Pyridoxal 5'-phosphate liquids were prepared in accordance with the guidelines given to patients from marketed 50 mg PLP dietary capsules and tablets. The PLP content and its stability were evaluated under conditions resembling the clinical setting using reverse phase HPLC and mass spectrometry.
KEY FINDINGS
Pyridoxal 5'-phosphate content in most of the extemporaneously prepared liquids from dietary supplements was found to be different from the expected amount (~16-60 mg). Most of these PLP extemporaneous liquids were stable at room temperature (protected from light) after 24 h but unstable after 4 h when exposed to light. A key photodegradation product of PLP in water was confirmed as 4-pyridoxic acid 5'-phosphate (PAP).
CONCLUSION
Pyridoxal 5'-phosphate tablets from Solgar were found to be the most reliable product for the preparation of extemporaneous PLP liquids. This work highlighted the difference between the marketed PLP dietary supplements quality and the importance of proper storage of aqueous PLP. There is a need to develop pharmaceutical forms of PLP that ensure dose accuracy and avoid potentially unsafe impurities with the aim of enhancing safety and compliance.
Topics: Dietary Supplements; Dosage Forms; Drug Stability; Drug Storage; Epilepsy; Pharmaceutical Solutions; Photolysis; Pyridoxal Phosphate; Quality Control; Vitamin B Complex
PubMed: 28220480
DOI: 10.1111/jphp.12701 -
Proceedings of the National Academy of... Oct 2021The mechanism by which molecular oxygen is activated by the organic cofactor pyridoxal phosphate (PLP) for oxidation reactions remains poorly understood. Recent work has...
The mechanism by which molecular oxygen is activated by the organic cofactor pyridoxal phosphate (PLP) for oxidation reactions remains poorly understood. Recent work has identified arginine oxidases that catalyze desaturation or hydroxylation reactions. Here, we investigate a desaturase from the indolmycin pathway. Our work, combining X-ray crystallographic, biochemical, spectroscopic, and computational studies, supports a shared mechanism with arginine hydroxylases, involving two rounds of single-electron transfer to oxygen and superoxide rebound at the 4' carbon of the PLP cofactor. The precise positioning of a water molecule in the active site is proposed to control the final reaction outcome. This proposed mechanism provides a unified framework to understand how oxygen can be activated by PLP-dependent enzymes for oxidation of arginine and elucidates a shared mechanistic pathway and intertwined evolutionary history for arginine desaturases and hydroxylases.
Topics: Amino Acid Oxidoreductases; Catalytic Domain; Crystallography, X-Ray; Evolution, Chemical; Mixed Function Oxygenases; Protein Conformation; Pyridoxal Phosphate
PubMed: 34580201
DOI: 10.1073/pnas.2012591118