1. Metabolic functions of pyridoxine
Domina Petric, MD

2. Mechanisms of action
The metabolically active form of vitamin B6 is pyridoxal phosphate, which serves as a coenzyme of numerous enzymes, most of which are involved in the metabolism of amino acids.
General mechanisms are: ● Decarboxylations ● Transamination, racemization, elimination and replacement reactions ● β-group interconversions
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

3. Metabolism of amino acids
Pyridoxal phosphate
The metabolically active form of vitamin B6. B6
Decarboxylations
β-group interconversions
Transamination, racemization, elimination and replacement reactions
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

4. Mechanisms of action
In each of these reactions the cofactor remains tightly bound to the enzyme, pyridoxal phosphate more so than pyridoxamine phosphate.
Binding occurs by the formation of a Schiff base between the keto-carbon of the coenzyme and the ε-amino group of a specific lysyl residue of the apoenzyme.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

5. Mechanisms of action
Vitamin B6-dependent enzymes tend to have structural similarities in the coenzyme-binding region.
The mechanisms of the reactions catalyzed by the vitamin B6-dependent enzymes also tend to be similar.
Each involves the binding of an α-carbon of an α-amino acid substrate to the pyridine nitrogen of pyridoxal phosphate.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

6. Mechanisms of action
The delocalization of the electrons from the α-carbon by the action of the protonated pyridine nitrogen as an electron sink results in the conversion of the α-carbon to a carbanion at the α-carbon and the labilization of its bonds.
This results in the heterolytic cleavage of one of the three bonds to the α-carbon.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

7. Mechanisms of action
The particular bond to be cleaved is determined by the particular pyridoxal phosphate-dependent enzyme.
Each involves the loss of the cationic ligand of an amino acid.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

8. Metabolic roles
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

9. Amino acid metabolism
Pyridoxal phosphate is involved in practically all amino acid metabolism reactions, in both their biosynthesis and their catabolism.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

10. Transaminations
Pyridoxal phosphate-dependent transaminases catabolize most amino acids.
The response of erythrocyte aspartate aminotransferase (EAAT) to in vitro additions of pyridoxal phosphate has been used as a biochemical maker of vitamin B6 status.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

11. Transsulfuration
Pyridoxal phosphate-dependent enzymes cystathionine synthase and cystathionase catalyze the transsulfuration of methionine to cysteine.
Vitamin B6 deprivation reduces the activities of these enzymes.
Affected individuals show homocysteinuria (due to the impaired conversion to cystathionine) and cystathionuria (due to the impaired cleavage of cystathionine to cysteine and α-ketobutyrate).
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

12. Selenoamino acid metabolism
Vitamin B6 is essential for the utilization of selenium from the major dietary form, selenomethionine.
After that selenium is transferred to selenohomocysteine.
Pyridoxal phosphate is a cofactor for two enzymes, selenocysteine β-lyase and selenocysteine γ-lyase, which catalyze the elimination of the selenium atom from selenohomocysteine to yield hydrogen selenide.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

13. Selenoamino acid metabolism
Selenide is the obligate precursor for the incorporation of selenium into selenoproteins in the form of selenocysteinyl residues produced during translation.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

14. Tryptophan-niacin conversion
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

15. Tryptophan-niacin conversion
Vitamin B6 is required, as a cofactor for kynureninase, for the removal of an alanyl residue from 3-hydroxykynurenine in the metabolism of tryptophan to the branch-point intermediate α-amino-β-carboxymuconic-ε-semialdehyde in the tryptophan-niacin conversion pathway.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

16. Tryptophan-niacin conversion
Kynureninase catalyzes the analogous reaction (removal of alanine) using nonhydroxylated kynurenine as substrate and yielding the nonhydroxylated analog of 3-hydroxykynurenine, anthranilic acid.
Vitamin B6-dependent transaminases are also able to metabolize kynurenine and hydroxykynurenine, yielding kynurenic and xanthurenic acids.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

17. Tryptophan-niacin conversion
Transaminases have much greater binding affinities for pyridoxal phosphate than does kynureninase.
Vitamin B6 deprivation usually reduces the latter activity preferentially to the former ones.
The result is a blockage in the tryptophan-niacin pathway, with an accumulation of hydroxykynurenine that continues to be transaminated, resulting in increased production of xanthurenic acid.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

18. Tryptophan-niacin conversion
Vitamin B6 deficiency impairs the metabolic conversion of tryptophan to niacin, diverting it instead to xanthurenic acid, which appears in the urine:
Assessment of vitamin B6 status-deficiency is indicated by urinary excretion of xanthurenic acid after a tryptophan load.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

19. Gluconeogenesis
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

20. Gluconeogenesis
Transaminations
Amino acid catabolism depends on pyridoxal phosphate and is a cofactor for transaminases.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

21. Gluconeogenesis
Gycogen utilization
Vitamin B6 is required for the utilization of glycogen to release glucose by serving as a coenzyme of glycogen phosphorylase, to which it is bound (as pyridoxal phosphate) via a Schiff base linkage to a peptidyllysine residue.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

22. Gluconeogenesis
Gycogen utilization
Coenzyme’s phosphate group is catalytically important, participating in the transfer of inorganic phosphate to the glucose units of glycogen to produce glucose-1-phosphate, which is released.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

23. Neurotransmitter synthesis
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

24. Neurotransmitter synthesis
Pyridoxal phosphate-dependent enzymes function in the biosynthesis of the neurotransmitters:
Serotonin-cofactor for tryptophan decarboxylase
Epinephrine and norepinephrine-cofactor for tyrosine carboxylase
Source of energy for the brain γ-aminobutyric acid (GABA)
Cofactor for glutamate decarboxylase
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

25. Histamine synthesis
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

26. Histamine synthesis
Pyridoxal phosphate functions in the metabolism of the vasodilator and gastric secretagogue histamine: cofactor for histidine decarboxylase.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

27. Hemoglobin synthesis and function
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

28. Hemoglobin synthesis and function
Pyridoxal phosphate functions in the synthesis of heme from porphyrin precursors as a cofactor for δ-aminolevulinic acid synthase.
The vitamin also binds to hemoglobin at two sites on the β chains:
N-terminal valine
Lys-82 residues
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

29. Hemoglobin synthesis and function
Pyridoxal also binds at the N-terminal valine residues of the α-chains.
The binding of pyridoxal and pyridoxal phosphate enhances the O2-binding capacity of hemoglobin and inhibits sickling in sickle-cell hemoglobin.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

30. Hemoglobin synthesis and function
The catalytic properties of other enzymes are also affected (some stimulated, others inhibited) by interactions with pyridoxal phosphate, usually via valine, histidine or lysine residues.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

31. Lipid metabolism
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

32. Lipid metabolism
Changes in lipid metabolism have been reported in response to vitamin B6 deprivation.
Vitamin B6 is required for the biosynthesis of sphingolipids via the pyridoxal phosphate-dependent serine palmitoyltransferase and other enzymes in phospholipid synthesis.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

33. Gene expression
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

34. Steroid hormone receptor-induced enzymes
Gene expression
Steroid hormone receptor-induced enzymes
Elevated intracellular levels of the vitamin are associated with decreased transcription in responses to glucocorticoid hormones: progesterone, androgens, estrogens.
Inhibition is caused by the formation of Schiff base linkages of the vitamin to the DNA-binding site of the receptor-steroid complex.
This inhibits the ligand binding to the glucocorticoid-responsive element in the regulatory region of the gene.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

35. Gene expression Serum albumin
Vitamin B6 deficiency increases the expression of albumin mRNA sevenfold.
The effect appears due to the action of pyridoxal phosphate inactivating tissue-specific transcription factors by directly interacting with DNA ligand-binding sites.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

36. Gene expression
Glycoprotein IIb
Pyridoxal phosphate appears to modulate glycoprotein IIb gene expression by interacting directly with tissue-specific transcription factors.
This results in inhibition of platelet aggregation due to impaired binding of fibrinogen or other adhesion proteins to glycoprotein complexes.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

37. Gene expression
Other proteins
Pyridoxal phosphate has been shown to suppress mRNA levels for glycogen phosphorylase, apolipoprotein A-1, phenylalanine hydroxylase, glyceraldehyde-3-phosphate dehydrogenase and ß-actin.
And to decrease mRNA levels for RNA polymerases I and II in the rat model.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

38. Health effects
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

39. Vascular disease
Low vitamin B6 status results in homocysteinemia as a result of lost capacity to convert that metabolite to cystathionine due to impaired activities of the pyridoxal phosphate-dependent enzyme cystathionine ß-synthase.
Homocysteinemia has been associated with increased risks to occlusive vascular disease, total and cardiovascular disease-related mortality, stroke, dementia, Alzheimer’s disease, fracture and chronic heart failure.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

40. Vascular disease
Low plasma pyridoxal phosphate levels have been associated with increased risk to vascular disease independent of plasma homocysteine level.
Treatment with high doses of vitamin B6 and folic acid might be helpful in reducing both plasma homocysteine and the incidence of abnormal exercise ECG tests, suggesting reductions in risk of atherosclerotic disease.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

41. Neurologic function
Vitamin B6 has been shown to affect the postnatal development of a glutamate receptor in the brain: an important role in learning.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

42. Immune function
Human studies have demonstrated effects of vitamin B6 deprivation on
Humoral-mediated immune responses: diminished antibody production
Cell-mediated immune responses: increased lymphocyte proliferation, reduced delayed-type hypersensitivity responses, reduced T cell mediated cytotoxicity, reduced cytokine production
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

43. Cancer
Epidemiological studies have demonstrated inverse associations of projected vitamin B6 intake and colon cancer risk.
November 16, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

44. Literature
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc
November 16, 2018