Vitamin B6

Overview
Vitamin B6 is a water-soluble vitamin. Pyridoxal phosphate (PLP) is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. PLP also is necessary for the enzymatic reaction governing the release of glucose from glycogen.

History
Vitamin B6 is a water-soluble compound that was discovered in the 1930s during nutrition studies on rats. The vitamin was named pyridoxine to indicate its structural homology to pyridine. Later it was shown that vitamin B6 could exist in two other, slightly different, chemical forms, termed pyridoxal and pyridoxamine. All three forms of vitamin B6 are precursors of an activated compound known as pyridoxal 5'-phosphate (PLP), which plays a vital role as the cofactor of a large number of essential enzymes in the human body.

Enzymes dependent on PLP focus a wide variety of chemical reactions mainly involving amino acids. The reactions carried out by the PLP-dependent enzymes that act on amino acids include transfer of the amino group, decarboxylation, racemization, and beta- or gamma-elimination or replacement. Such versatility arises from the ability of PLP to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

Overall, the Enzyme Commission (EC; http://www.chem.qmul.ac.uk/iubmb/enzyme/ ) has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities.

In the early 1990s, it was suggested in megadoses as treatment for PMS and clinical depression, but this is no longer considered effective.

Forms
Seven forms of this vitamin are known:


 * pyridoxine (PN). PN is the form that is given as vitamin B6 supplement.
 * pyridoxine 5'-phosphate (PNP).
 * pyridoxal (PL).
 * pyridoxal 5'-phosphate (PLP). PLP is the metabolically active form.
 * pyridoxamine (PM).
 * pyridoxamine 5'-phosphate (PMP).
 * 4-pyridoxic acid (PA). PA is the catabolite which is excreted in the urine.

All forms except PA can be interconverted.

Functions
Pyridoxal phosphate, the metabolically active form of vitamin B6, is involved in many aspects of macronutrient metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function and gene expression. Pyridoxal phosphate generally serves as a coenzyme for many reactions and can help facilitate decarboxylation, transamination, racemization, elimination, replacement and beta-group interconversion reactions.

Amino Acid Metabolism
Pyridoxal phosphate (PLP) is a cofactor in transaminases that can catabolize amino acids. PLP is also an essential component of two enzymes that converts methionine to cysteine via two reactions. Low vitamin B6 status will result in decreased activity of these enzymes. PLP is also an essential cofactor for enzymes involved in the metabolism of selenomethionine to selenohomocysteine and then from selenohomocysteine to hydrogen selenide. Vitamin B6 is also required for the conversion of tryptophan to niacin and low vitamin B6 status will impair this conversion. PLP is also used to create physiologically active amines by decarboxylation of amino acids. Some notable examples of this include: histadine to histamine, tryptophan to serotonin, glutamate to GABA (gamma-aminobutyric acid), and dihydroxyphenylalanine to dopamine.

Gluconeogenesis
Vitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze transamination reactions that are essential for the providing amino acids as a substrate for gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen phosphorylase<, the enzyme that is necessary for glycogenolysis to occur.

Lipid Metabolism
Vitamin B6 is an essential component of enzymes that facilitate the biosynthesis of sphingolipids. Particularly, the synthesis of ceramide requires PLP. In this reaction serine is decarboxylated and combined with palmitoyl-CoA to form sphinganine which is combined with a fatty acyl CoA to form ceramide.

Metabolic Functions
The primary role of vitamin B6 is to act as a coenzyme to many other enzymes in the body that are involved predominately in metabolism. This role is performed by the active form, pyridoxal phosphate. This active form is converted from the two other natural forms founds in food: pyridoxal, pyridoxine and pyridoxamine.

Vitamin B6 is involved in the following metabolic processes:
 * Amino acid, glucose and lipid metabolism
 * neurotransmitter synthesis
 * histamine synthesis
 * hemoglobin synthesis and function
 * gene expression

Amino Acid Metabolism
Pyridoxal phosphate is involved in almost all amino acid metabolism, from synthesis to breakdown.

1. Transamination: transaminase enzymes needed to breakdown amino acids are dependent on the presence of pyridoxal phosphate. The proper activity of these enzymes are crucial for the process of moving amine groups from one amino acid to another.

2. Transsulfuration: Pyridoxal phosphate is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes work to transform methionine into cysteine.

3. Selenoamino acid metabolism: Selenomethionine is the primary dietary form of selenium. Pyridoxal phosphate is needed as a cofactor for the enzymes that allow selenium to be used from the dietary form. Pyridoxal phosphate also plays a cofactor role in releasing selenium from selenohomocysteine to produce hydrogen selenide. This hydrogen selenide can then be used to incorporate selenium into selenoproteins<.

4. Vitamin B6 is also required for the conversion of tryptophan to niacin and low vitamin B6 status will impair this conversion.

Gluconeogenesis
Vitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen phosphorylase, the enzyme that is necessary for glycogenolysis to occur.

Neurotransmitter Synthesis
Pyridoxal phosphate-dependent enzymes play a role in the biosynthesis of four important neurotranmsitters: serotonin, epinephrine, norepinephrine and gamma-aminobutyric acid.

Histamine Synthesis
Pyridoxal phosphate is involved in the metabolism of histamine.

Hemoglobin Synthesis and Function
Pyridoxal phosphate aids in the synthesis of heme and can also bind to two sites on hemoglobin to enhance the oxygen binding of hemoglobin.

Gene Expression
Pyridoxal phosphate has been implicated in increasing or decreasing the expression of certain genes. Increased intracellular levels of the vitamin will lead to a decrease in the transcription of glucocorticoid hormones. Also, vitamin B6 deficiency will lead to the increased expression of albumin mRNA. Also, pyridoxal phosphate will influence gene expression of glycoprotein IIb by interacting with various transcription factors. The result is inhibition of platelet aggregation.

Dietary Reference Intakes
The Institute of Medicine notes that "No adverse effects associated with Vitamin B6 from food have been reported. This does not mean that there is no potential for adverse effects resulting from high intakes.  Because data on the adverse effects of Vitamin B6 are limited, caution may be warranted.  Sensory neuropathy has occurred from high intakes of supplemental forms." Click on the pdf at the end of this sentence to see the Institute of Medicine's Dietary Reference Intake tables for vitamins.

Absorption
Vitamin B6 is absorbed in the jejunum and ileum via passive diffusion. With the capacity for absorption being so great, animals are able to absorb quantities much greater than what is needed for physiological demands. The absorption of pyridoxal phosphate and pyridoxamine phosphate involves their phosphorylation catalyzed by a membrane-bound alkaline phosphatase. Those products and non-phosphorylated vitamers in the digestive tract are absorbed by diffusion, which is driven by trapping of the vitamin as 5'-phosphates through the action of phosphorylation (by a pyridoxal kinase) in the jejunal mucosa. The trapped pyridoxine and pyridoxamine are oxidized to pyridoxal phosphate in the tissue.

Excretion
The products of vitamin B6 metabolism are excreted in the urine; the major product of which is 4-pyridoxic acid. It has been estimated that 40-60% of ingested vitamin B6is oxidized to 4-pyridoxic acid. Several studies have shown that 4-pyridoxic acid is undetectable in the urine of vitamin B6 deficient subjects, making it a useful clinical marker to assess the vitamin B6 status of an individual. Other products of vitamin B6metabolism that are excreted in the urine when high doses of the vitamin have been given include pyridoxal, pyridoxamine, and pyridoxine and their phosphates.

Deficiencies
The classic clinical syndrome for B6 deficiency is a seborrheic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, and neurologic symptoms of somnolence, confusion, and neuropathy.

While severe vitamin B6 deficiency results in dermatologic and neurologic changes, less severe cases present with metabolic lesions associated with insufficient acitivities of the coenzyme pyridoxal phosphate. The most prominent of the lesions is due to impaired tryptophan-niacin conversion. This can be detected based on urinary excretion of xanthurenic acid after an oral tryptophan load. Vitamin B6 deficiency can also result from impaired transsulfuration of methionine to cysteine. The pyridoxal phosphate-dependent transaminases and glycogen phosphorylase provide the vitamin with its role in gluconeogenesis, so deprivation of vitamin B6 results in impaired glucose tolerance.

A deficiency of vitamin B6 alone is relatively uncommon and often occurs in association with other vitamins of the B complex. The elderly and alcoholics have an increased risk of vitamin B6 deficiency, as well as other micronutrient deficiencies.

Toxicity
An overdose of pyridoxine can cause a temporary deadening of certain nerves such as the proprioceptory nerves; causing a feeling of disembodiment common with the loss of proprioception. This condition is reversible when supplementation is stopped.

Because adverse effects have only been documented from vitamin B6 supplements and never from food sources, this article only discusses the safety of the supplemental form of vitamin B6 (pyridoxine). Although vitamin B6 is a water-soluble vitamin and is excreted in the urine, very high doses of pyridoxine over long periods of time may result in painful neurological symptoms known as sensory neuropathy. Symptoms include pain and numbness of the extremities, and in severe cases difficulty walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day. However, there have been a few case reports of individuals who developed sensory neuropathies at doses of less than 500 mg daily over a period of months. None of the studies, in which an objective neurological examination was performed, found evidence of sensory nerve damage at intakes of pyridoxine below 200 mg/day. In order to prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults. Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the UL of 100 mg/day. Studies have shown, however, that in the case of individuals diagnosed with autism, high doses of vitamin B6 given with magnesium have been found to be beneficial.

Preventive roles and therapeutic uses
At least one preliminary study has found that this vitamin may increase dream vividness or the ability to recall dreams. It is thought that this effect may be due to the role this vitamin plays in the conversion of tryptophan to serotonin.

The intake of vitamin B6, from either diet or supplements, could cut the risk of Parkinson’s disease by half according to a prospective study from the Netherlands. "Stratified analyses showed that this association was restricted to smokers," wrote the authors.

Nutritional supplementation with high dose vitamin B6 and magnesium is claimed to alleviate the symptoms of autism and is one of the most popular complementary and alternative medicine choices for autism. Three small randomized controlled trials have studied this therapy; the smallest one (with 8 individuals) found improved verbal IQ in the treatment group and the other two (with 10 and 15 individuals, respectively) found no significant difference. The short-term side effects seem to be mild, but there may be significant long-term side effects of peripheral neuropathy. Some studies suggest that the B6-magnesium combination can also help attention deficit disorder, citing improvements in hyperactivity, hyperemotivity/aggressiveness and improved school attention.

It is also suggested that ingestion of vitamin B6 can alleviate some of the many symptoms of an alcoholic hangover and morning sickness from pregnancy. This might be due to B6's mild diuretic effect.