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Serum B6 vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

ABSTRACT: Vitamin B6 is an important enzymatic cofactor in pathways relevant for the development of pancreatic cancer. In order to evaluate vitamin B6 as a preventive factor for pancreatic cancer, a biomarker approach is needed to overcome the limitations inherent in self-reported dietary information.To determine whether levels of serum B6 vitamers, including pyridoxal 5'-phosphate (PLP), pyridoxal (PL), 4-pyridoxic acid (PA), and the PA/(PLP + PL) ratio (PAr), were associated with risk of pancreatic cancer, two nested case-control studies of 187 incident pancreatic cancer cases and 258 individually matched controls were conducted within two prospective cohorts of 81,501 participants in Shanghai, China, and Singapore. PLP, PL, and PA were quantified in pre-diagnostic serum samples. Odds ratios and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for potential confounders.The median (5th-95th percentiles) concentrations of serum PLP among control subjects of the Shanghai and Singapore cohorts were 25.7 (10.0-91.7) nmol/L and 58.1 (20.8-563.0) nmol/L, respectively. In pooled analyses, high serum PLP was associated with a reduced risk of pancreatic cancer (P for trend = 0.048); the adjusted odds ratio for the highest category of PLP (>52.4 nmol/L) was 0.46 (95% CI 0.23, 0.92) compared to vitamin B6 deficiency (<20 nmol/L). No associations were found for serum PL, PA, or PAr with pancreatic cancer risk.Higher concentrations of PLP may protect against the development of pancreatic cancer. The protective effect may be more apparent in populations with low concentrations of circulating vitamin B6.

SUBMITTER: Huang JY

PROVIDER: S-EPMC5161671 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Serum B<sub>6</sub> vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

Huang Joyce Y JY Butler Lesley M LM Midttun Øivind Ø Koh Woon-Puay WP Ueland Per M PM Wang Renwei R Jin Aizhen A Gao Yu-Tang YT Yuan Jian-Min JM

Cancer causes & control : CCC 20161109 12

<h4>Background</h4>Vitamin B<sub>6</sub> is an important enzymatic cofactor in pathways relevant for the development of pancreatic cancer. In order to evaluate vitamin B<sub>6</sub> as a preventive factor for pancreatic cancer, a biomarker approach is needed to overcome the limitations inherent in self-reported dietary information.<h4>Methods</h4>To determine whether levels of serum B<sub>6</sub> vitamers, including pyridoxal 5'-phosphate (PLP), pyridoxal (PL), 4-pyridoxic acid (PA), and the PA/ ...[more]

PMID: 27830400

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Project description:BACKGROUND: The pyridoxal-5'-phosphate (PLP)-dependent or vitamin B6-dependent enzymes that catalyze manifold reactions in the metabolism of amino acids belong to no fewer than four evolutionarily independent protein families. The multiple evolutionary origin and the essential mechanistic role of PLP in these enzymes argue for the cofactor having arrived on the evolutionary scene before the emergence of the respective apoenzymes and having played a dominant role in the molecular evolution of the B6 enzyme families. Here we report on an attempt to re-enact the emergence of a PLP-dependent protoenzyme. The starting protein was pancreatic ribonuclease A (RNase), in which active-site Lys41 or Lys7 readily form a covalent adduct with PLP. RESULTS: We screened the PLP adduct of wild-type RNase and two variant RNases (K7R and K41R) for catalytic effects toward L- and D-amino acids. RNase(K41R)-PLP, in which the cofactor is bound through an imine linkage to Lys7, qualifies for a model proto-B6 enzyme by the following criteria: (1) covalent linkage of PLP (internal aldimine); (2) catalytic activity toward amino acids that depends on formation of an imine linkage with the substrate (external aldimine); (3) adjoining binding sites for the cofactor and amino acid moiety that facilitate the transimination reaction of the internal to the external aldimine and stabilize the resulting noncovalent complex of the coenzyme-substrate adduct with the protein; (4) reaction specificity, the only detectable reactions being racemization of diverse amino acids and beta-decarboxylation of L-aspartate; (5) acceleration factors for racemization and beta-decarboxylation of >103 over and above that of PLP alone; (6) ribonuclease activity that is 103-fold lower than that of wild-type RNase, attenuation of a pre-existing biological activity being indispensable for the further evolution as a PLP-dependent protoenzyme. CONCLUSION: A single amino acid substitution (Lys41Arg) and covalent binding of PLP to active-site Lys7 suffice to turn pancreatic ribonuclease A into a protein catalyst that complies with all plausible criteria for a proto-B6 enzyme. The study thus retraces in a model system what may be considered the committed step in the molecular evolution of a potential ancestor of a B6 enzyme family.

Project description:Introduction The Vitamin B6-dependent epilepsies are a heterogeneous group of autosomal recessive disorders usually characterized by neonatal onset seizures responsive to treatment with vitamin B6 available as pyridoxine (PN) or as the biologically active form pyridoxal 5-phosphate (PLP). The vitamin B6–dependent epilepsies are caused by mutations in at least five different genes involved in B6 metabolism. A literature review revealed that only 30 patients with vitamin B6-dependent epilepsy caused by PLPBP mutation have been reported worldwide. Presentation of case We report a case of baby boy born to first-cousin Pakistani parents who presented with generalized as well as focal seizures starting a few hours after birth and responsive to PLP. Whole exome sequencing revealed a homozygous pathogenic variant NM_007198.4:c.46_47insCA, NP_009129.1:p.Leu17Hisfs, causing a CA duplication resulting in a frameshift in the PLPBP gene. Discussion Vitamin B6-Dependent Epilepsy due to PLPBP defect is a rare disorder. The developmental outcomes are variable even with early therapy. Few patients are reported to achieve optimal developmental milestones with therapy. PLP has been advocated as the treatment of choice for PLPBP defect, but oral PN has also demonstrated good seizure control in some patients, including ours. Conclusion Vitamin B6-dependent epilepsy due to PLPBP defect is an important differential diagnosis to consider in patients with biochemical features suggestive of pyridoxamine 5?-phosphate Oxidase (PNPO) defect and gene testing can facilitate in reaching the correct diagnosis. Prompt diagnosis and treatment led to excellent seizure control in most patients. Highlights • The Vitamin B6-dependent epilepsies are a heterogeneous group of autosomal recessive disorders.• A literature review revealed that only 30 patients with PLPBP mutation have been reported.• We report a case of baby boy born to first-cousin Pakistani parents responsive to pyridoxal 5-phosphate.

Dataset Information

Serum B6 vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

Publications

Serum B<sub>6</sub> vitamers (pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid) and pancreatic cancer risk: two nested case-control studies in Asian populations.

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