Metabolic functions of pyridoxine

Metabolic functions of pyridoxine

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.
Generalmechanismsare:
●Decarboxylations
●Transamination, racemization,
elimination andreplacement reactions
●β-group interconversions
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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3. Metabolism of amino acids
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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B6
Pyridoxalphosphate
The metabolically
active form of
vitamin B6.
Decarboxylations
β-group
interconversions
Transamination,
racemization,
elimination and
replacement reactions

4. Mechanisms of action
•In each of these reactions the cofactor
remainstightly bound to the enzyme,
pyridoxal phosphatemore so than
pyridoxaminephosphate.
•Bindingoccurs by the formation of a Schiff
base betweenthe keto-carbon of the
coenzyme and the ε-aminogroup of a
specific lysylresidue of the apoenzyme.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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5. Mechanisms of action
VitaminB6-dependent enzymes tend to
havestructural similarities in the
coenzyme-bindingregion.
The mechanisms of the reactions catalyzed
by the vitamin B6-dependent enzymes also
tend tobe similar.
Each involves the binding of an α-carbonof
an α-amino acid substrate to the pyridine
nitrogen of pyridoxal phosphate.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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6. Mechanisms of action
•The delocalization ofthe electrons from
the α-carbon by the action ofthe
protonated pyridine nitrogen as an electron
sinkresultsin the conversion of the
α-carbon to a carbanion at the α-carbon
and the labilizationof its bonds.
•This results in the heterolyticcleavage of
one of thethree bonds to the α-carbon.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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7. Mechanisms of action
The particular bond to be cleaved is
determinedby the particular pyridoxal
phosphate-dependentenzyme.
Each involves the loss of the cationic
ligandof an amino acid.
April 17, 2018
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8. Metabolic roles
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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9. April 17, 2018
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Amino acid metabolism

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.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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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).
April 17, 2018
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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.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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13. Selenoamino acid metabolism
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14. April 17, 2018
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Tryptophan-niacin conversion

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 tryptophanto the branch-
point intermediate α-amino-β-
carboxymuconic-ε-semialdehyde in the
tryptophan-niacin conversion pathway.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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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
3-hydroxykynurenine, yielding kynurenic
and xanthurenic acids.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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17. Tryptophan-niacin conversion
•Transaminaseshave much greater binding
affinitiesfor pyridoxal phosphate than does
kynureninase.
•VitaminB6 deprivation usually reduces the latter
activity preferentially to the former ones.
•The resultis a blockage in the tryptophan-niacin
pathway, withan accumulation of
3-hydroxykynurenine that continues to be
transaminated, resulting in increased production
of xanthurenicacid.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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18. Tryptophan-niacin conversion
Vitamin B6 deficiencyimpairs the metabolic conversion
of tryptophan to niacin, diverting it instead to
xanthurenicacid, which appears in the urine:
•Assessmentof vitamin B6 status-deficiency
is indicated by urinary excretion of
xanthurenicacid after a tryptophan load.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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19. April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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Gluconeogenesis

20. Gluconeogenesis
Transaminations
Amino acid catabolism
depends on pyridoxal
phosphate and is acofactor
for transaminases.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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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.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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22. Gluconeogenesis
Gycogen utilization
Coenzyme’sphosphate groupis
catalytically important, participating
in thetransfer of inorganic phosphate
to the glucoseunits of glycogen to
produce glucose-1-phosphate, which
is released.
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Nutrition and Health. Elsevier Inc. 2008.
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23. April 17, 2018
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Neurotransmitter synthesis

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
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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25. April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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Histamine synthesis

26. Histamine synthesis
Pyridoxal phosphate functions
in the metabolism ofthe
vasodilator and gastric
secretagoguehistamine:
cofactor for histidine
decarboxylase.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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27. April 17, 2018
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Hemoglobin synthesis and function

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
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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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 O
2-binding
capacity of hemoglobin and inhibits
sickling in sickle-cell hemoglobin.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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30. Hemoglobin synthesis and function
The catalytic properties of other
enzymes are alsoaffected (some
stimulated,others inhibited) by
interactions with pyridoxal
phosphate, usually viavaline,
histidine or lysine residues.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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31. April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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Lipid metabolism

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.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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33. April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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Gene expression

34. 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 causedby the formation of Schiff base
linkages ofthe vitamin to the DNA-binding site of the
receptor-steroid complex.
•This inhibits theligand binding to the glucocorticoid-
responsiveelement in the regulatory region of the gene.
April 17, 2018
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Nutrition and Health. Elsevier Inc. 2008.
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35. Gene expression
Serum albumin
Vitamin B6 deficiency increasesthe expression of albumin
mRNA sevenfold.
The effect appears due to the action of pyridoxalphosphate
inactivating tissue-specific transcription factors by directly
interacting with DNAligand-binding sites.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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37. Gene expression
Other proteins
•Pyridoxal phosphate has beenshown 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.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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38. Health effects
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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40. Vascular disease
•Low plasma pyridoxal phosphate levels have
been associated with increased risk to
vascular diseaseindependent of plasma
homocysteine level.
•Treatmentwith high doses of vitamin B6 and
folic acid might be helpfulin reducing both
plasma homocysteine and the incidence of
abnormalexercise ECGtests, suggesting
reductions in risk of atherosclerotic disease.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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41. Neurologic function
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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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
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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43. Cancer
Epidemiological studies
have demonstrated inverse
associations of projected
vitamin B6 intake and
coloncancer risk.
April 17, 2018
Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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44. Literature
•Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
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