Vitamin B6

Vitamin B6 has a central role in the metabolism of amino acids: in transaminase reactions (and hence the interconversion and catabolism of amino acids and the synthesis of nonessential amino acids), in decarboxylation to yield biologically active amines, and in a variety of elimination and replacement reactions. It is also the cofactor for glycogen phosphorylase and a variety of other enzymes. In addition, pyridoxal phosphate, the metabolically active vitamer, has a role in the modulation of steroid hormone action and the regulation of gene expression.

The vitamin is widely distributed in foods, and clinical deficiency is virtually unknown, apart from an outbreak during the 1950s, which resulted from overheating of infant milk formula.

Marginal inadequacy, affecting amino acid metabolism and possibly also steroid hormone responsiveness, may be relatively common. A number of vitamin B6 dependency syndromes have been reported - inborn errors of metabolism in which the defect is in the coenzyme binding site of the affected enzyme.

Estrogens cause abnormalities of tryptophan metabolism that resemble those seen in vitamin B6 deficiency, and the vitamin is widely used to treat the side effects of estrogen administration and estrogen-associated symptoms of the premenstrual syndrome, although there is little evidence of its efficacy. High doses of the vitamin, of the order of 100 times requirements, cause peripheral sensory neuropathy.

In a number of enzymes that catalyze reactions that might be assumed to be pyridoxal phosphate-dependent, pyruvate provides the reactive car-bonyl group (Section 9.8.1). Other enzymes have reactive carbonyl groups provided by a variety of quinones. One of these quinones, pyrrolidone quino-linequinone, may be a dietary essential, although no mammalian enzymes have been demonstrated to use it; the other catalytic quinones are covalently bound to the enzyme and are formed by postsynthetic modification of amino acid residues in a precursor protein, so are unlikely to be nutritionally relevant (Section 9.8.3).


The generic descriptor vitamin B6 includes six vitamers: the alcohol pyridox-ine, the aldehyde pyridoxal, the amine pyridoxamine, and their 5-phosphates. There is some confusion in the older literature, because at one time pyridoxine was used as a generic descriptor, with pyridoxol as the specific name for the alcohol. As shown in Figure 9.1, the vitamers are metabolically interconvertible and, as far as is known, they have equal biological activity.

A significant proportion (in some cases up to 75%) of the vitamin B6 in plant foods is present as glycosides, mainly to the 5 -hydroxyl group, although 4-glycosides also occur. There may be some hydrolysis of glycosides in the

Estrogen Metabolism Vitamin

Figure 9.1. Interconversion of the vitamin B6 vitamers. Pyridoxal kinase, EC; pyridoxine oxidase, EC; pyridoxamine phosphate oxidase, EC; and pyridoxal oxidase, EC Relative molecular masses (Mr): pyridoxine, 168.3 (hydrochloride, 205.6); pyridoxal, 167.2; pyridoxamine, 168.3 (dihydrochloride, 241.1); pyridoxal phosphate, 247.1; pyridoxamine phosphate, 248.2; and 4-pyridoxic acid, 183.2.

CH3 pyridoxamine

Figure 9.1. Interconversion of the vitamin B6 vitamers. Pyridoxal kinase, EC; pyridoxine oxidase, EC; pyridoxamine phosphate oxidase, EC; and pyridoxal oxidase, EC Relative molecular masses (Mr): pyridoxine, 168.3 (hydrochloride, 205.6); pyridoxal, 167.2; pyridoxamine, 168.3 (dihydrochloride, 241.1); pyridoxal phosphate, 247.1; pyridoxamine phosphate, 248.2; and 4-pyridoxic acid, 183.2.

gastrointestinal tract, and about half the vitamin present in foods as glycosides may be biologically available. However, pyridoxine glycosides are also absorbed intact (and excreted unchanged in the urine), and may compete for intestinal absorption and tissue uptake with the vitamin, thus having antivitamin activity (Gregory, 1998).

A proportion of the vitamin B6 in foods may be biologically unavailable alter heating, as a result of the formation of (phospho)pyridoxyllysine by reduction of the aldimine (Schiff base) by which pyridoxal and the phosphate are bound to the e-amino groups of lysine residues in proteins. A proportion of this pyridoxyllysine may be useable, because it is a substrate for pyridoxamine phosphate oxidase to form pyridoxal and pyridoxal phosphate. However, it is also a vitamin B6 antimetabolite, and even at relatively low concentrations can accelerate the development of deficiency in experimental animals maintained on vitamin B6-deficient diets (Gregory, 1980a, 1980b).


The phosphorylated vitamers are dephosphorylated by membrane-bound alkaline phosphatase in the intestinal mucosa; pyridoxal, pyridoxamine, and pyridoxine are all absorbed rapidly by carrier-mediated diffusion. Intestinal mucosal cells have pyridoxine kinase and pyridoxine phosphate oxidase (see Figure 9.1), so that there is net accumulation of pyridoxal phosphate by metabolic trapping. Much of the ingested pyridoxine is released into the portal circulation as pyridoxal, after dephosphorylation at the serosal surface.

Tissue uptake of vitamin B6 is again by carrier-mediated diffusion of pyridoxal (and other unphosphorylated vitamers), followed by metabolic trapping by phosphorylation. Circulating pyridoxal and pyridoxamine phosphates are hydrolyzed by extracellular alkaline phosphatase. All tissues have pyridoxine kinase activity, but pyridoxine phosphate oxidase is found mainly in the liver, kidney, and brain.

Pyridoxine phosphate oxidase is a flavoprotein, and activation of the erythrocyte apoenzyme by riboflavin 5'-phosphate in vitro can be used as an index of riboflavin nutritional status (Section 7.4.3). However, even in riboflavin deficiency, there is sufficient residual activity of pyridoxine phosphate oxidase to permit normal metabolism of vitamin B6 (Lakshmi and Bamji, 1974). Pyridoxine phosphate oxidase is inhibited by its product, pyridoxal phosphate, which binds a specific lysine residue in the enzyme. In the brain, the Kj of pyridoxal phosphate is of the order of 2 ^mol per L - the same as the brain concentration of free and loosely bound pyridoxal phosphate, suggesting that this inhibition may be a physiologically important mechanism in the control of tissue pyridoxal phosphate (Choi et al., 1987).

Pyridoxine is rapidly converted to pyridoxal phosphate in the liver and other tissues. Pyridoxal phosphate does not cross cell membranes, and efflux of the vitamin from most tissues is as pyridoxal. Pyridoxal phosphate is exported from the liver bound to albumin by formation of a Schiff base to lysine (Zhang et al., 1999). Much of the free pyridoxal phosphate in the liver (i.e., that which is not protein bound) is hydrolyzed to pyridoxal, which is also exported, and circulates bound to both albumin and hemoglobin in erythrocytes.

Extrahepatic tissues take up both pyridoxal and pyridoxal phosphate from the plasma. Pyridoxal phosphate is hydrolyzed to pyridoxal, which can cross cell membranes, by extracellular alkaline phosphatase, which is then trapped intracellularly by phosphorylation.

In subjects with hypophosphatasia, the rare genetic lack of extracellular alkaline phosphatase, plasma concentrations of pyridoxal phosphate are very much higher than normal (up to 4 ^mol per L, compared with a normal range of about 100 nmol per L), and intracellular concentrations of pyridoxal phosphate are lower than normal (Narisawa et al., 2001).

Tissue concentrations of pyridoxal phosphate are controlled by the balance between phosphorylation and dephosphorylation. The activity of phos-phatases acting on pyridoxal phosphate is greater than that of the kinase in most tissues, although this may be an artifact of determining alkaline phosphatase activity at its pH optimum rather than at a more physiological pH, when the two activities are approximately equal. This means that pyridoxal phosphate that is not bound to enzymes is readily dephosphorylated.

Free pyridoxal either leaves the cells or is oxidized to 4-pyridoxic acid by aldehyde dehydrogenase (which is present in all tissues) and also by hepatic and renal aldehyde oxidases. 4-Pyridoxic acid is actively secreted by the renal tubules, so measurement of the plasma concentration provides an index of renal function (Coburn et al., 2002). There is some evidence that oxidation to 4-pyridoxic acid increases with increasing age; in elderly people, the plasma concentration of pyridoxal phosphate is lower, and that of 4-pyridoxic acid higher, than in younger subjects even when there is no evidence of impaired renal function (Bates et al., 1999b). Small amounts of pyridoxal and pyridox-amine are also excreted in the urine, although much of the active vitamin B6 that is filtered in the glomerulus is reabsorbed in the kidney tubules.

Although pyridoxine is taken up and phosphorylated by muscle (and other tissues), the resultant pyridoxine phosphate is not oxidized to pyridoxal phosphate. It has been suggested that the neurotoxicity of high intakes of pyridoxine (Section may be caused by the uptake and trapping of pyridoxine, and hence competition with pyridoxal, resulting in depletion of tissue pyridoxal phosphate and a deficiency of the metabolically active form of the vitamin.

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