Coenzymes do matter....
VITAMIN B6
by Jon B. Pangborn, PhD, ChE, Syracuse University; fellow of the American
Institute of Chemists; licensed nutrition counselor in the State of Illinois; founder
and president of Bionostics, Incorporated; author or coauthor of nine patents and
more than 200 publications; member of NOHA's Professional Advisory Board;
and recipient of the 1991 Herbert J. Rinkel Award from the American Academy of
Environmental Medicine "in recognition for excellence in teaching the techniques
of environmental medicine."
Vitamin B6 is essential for many metabolic pathways involving protein and its
constituent amino acids. Consequently, vitamin B6 status in each of us is
important in health effects all the way from our childhood physical growth to our
lifelong health and mental acuity.
Food contains three natural forms of vitamin B6: pyridoxine, pyridoxamine, and
pyridoxal. Pyrodoxal, with phosphate added to its molecule, is the form of vitamin
B6 that is used by our bodies as a coenzyme. The commercial vitamin form,
pyridoxine hydrochloride, has the hydrochloride added for stability and increased
shelf life. That form is artificial but is well utilized by most individuals. However,
the body cannot use pyridoxine directly. Two metabolic steps are needed.
First, the pyridoxine must be phosphorylated, that is, phosphate is added to the
ring-structure of the molecule. Pyridoxine, pyridoxal, and pyridoxamine are all
well-absorbed through the mucosa of the small intestine. Inside cells, all these
forms are phosphorylated using the enzyme pyridoxal kinase. Generally
accepted wisdom is that magnesium is needed to activate kinase enzymesenzymes
that phosphorylate. However, there is published experimental work,
showing in vitro, that this particular phosphorylating enzyme in human brain
tissue has higher affinity for zinc and higher activity with zinc than with
magnesium. This was published by McCormick and others in the Journal of
Biological Chemistry, volume 236, in 1961. In spite of this finding, many experts
still credit magnesium with activating this and all kinase enzymes. The
phosphate, by the way, comes from adenosine triphosphate or "ATP," which is a
principal molecule for supplying energy in our bodies.
After phosphorylation, if the cell started with pyridoxal, the biochemistry is
completed. The pyridoxal 5-phosphate coenzyme or P 5-P is ready to go to work.
All it has to do is link up with its apoenzyme to form the complete or holoenzyme.
The reference text, Methods in Enzymology, volume 18A, discusses
phosphorylation of B6 forms on page 618. The statement is made that the
phosphorylating kinase prefers pyridoxal over pyridoxine. That is, the enzyme
phosphorylates pyridoxal faster than it phosphorylates pyridoxine. With
pyridoxine, the vegetable source form of B6, this phosphorylation produces
pyridoxine phosphate. Then next, the pyridoxine phosphate has to be oxidized by
an oxidase enzyme that is assisted by vitamin B2, riboflavin, as flavin
mononucleotide, "FMN." Here's one of the rubs in supplementing with pyridoxine.
If vitamin B2 is low as FMN, then the rate of P 5-P production is typically
decreased by 60%.
To summarize the chemistry, which I hope isn't too complicated, pyridoxine has to
go through two steps to form P 5-P. In the first step, it is phosphorylated, and
remember, pyridoxine is not the preferred form for the kinase. Pyridoxal is
preferred. And in the second step, pyridoxine phosphate needs vitamin B2 as
FMN to efficiently form pyridoxal phosphate.
Now, what happens if we start out with P 5-P in the first place? Well, it can be
absorbed intact, or in pyridoxal form without the phosphate. Pyridoxine and
pyridoxal are known to be synergistic in uptake with magnesium. On the cellular
basis, Abraham and others did a clinical measurement of this in premenopausal
women and found that oral B6 at 100 milligrams twice per day very significantly
raised red blood cell (RBC) magnesium levels after four weeks of
supplementation. Their work is published in Annals of Clinical and Laboratory
Science, volume 11(4), 1981, starting on page 333. Growth effects and
synergism between magnesium and vitamin B6 have also been studied in
animals. A study by Kubena and others in the Journal of the American College of
Nutrition, volume1(4), 1988 came to a similar conclusion-deficiencies of
pyridoxine and magnesium impair growth and physiological functions in a
multiplicative or synergistic fashion.
I've heard criticisms that pyridoxal 5-phosphate is destroyed in the stomach or in
the gut. These criticisms have come, without documentation, from pyridoxine
fans. Actually, it's likely that some of the phosphate is knocked off. That's alkaline
phosphatase's job--to rearrange the phosphate supply. But who cares? We've
still got the pyridoxal--stomach won't make pyridoxine from pyridoxal. And once
absorbed, the pyridoxal is more readily phosphorylated-according to the very
authoritative enzymology reference cited earlier. And, the pyridoxal doesn't need
FMN and another enzyme to reach the coenzyme form.
At the Klaire Laboratories International Symposium in Athens, Greece, in 1995,
Dr. Emar Vogelaar reported on blood analyses of human subjects taking
pyridoxal 5-phosphate. He found a better than 15% average increase in blood
pyridoxal after two weeks of supplementation with 50 milligrams per day. So,
there's no question about bioavailability-it gets in.
Finally, there's the problem of interfering vitamers in pyridoxine (substances that
are similar to pyridoxine). At doses above 500 milligrams per day, peripheral or
sensory neuropathy can occur in some individuals. This was widely reported over
10 years ago. Pyridoxine took the blame, but less publicized research later
focussed the blame on vitamer impurities in the pyridoxine. Nothing is 100%
pure, and pyridoxine is no exception: 4-deoxypyridoxine and methoxy-pyridoxine
are known pyridoxine antagonists. However, when pyridoxine is carefully
processed through several refinements to form pyridoxal 5-phosphate, the
concentration of interfering vitamers drops substantially. Also, less P 5-P is
needed than pyridoxine. No controlled studies have given exact comparisons, but
I've found 50 milligrams per day of P 5-P to do the work of 200 to 500 milligrams
of pyridoxine hydrochloride. Also, some case histories are worthwhile here.
Several individuals presenting sensory neuropathy following high doses of
pyridoxine had their conditions completely relieved by discontinuing the
pyridoxine, taking no B6 in any form for 3 days, then taking 50 milligrams per day
P 5-P for five days with no further symptoms.
To summarize, pyridoxal 5-phosphate has the advantages over pyrodoxine
hydrochloride of:
Being the actual coenzyme form.
Avoiding the need of oxidation to pyridoxal, which requires FMN, which in
turn has to be formed from vitamin B2 (riboflavin), which itself has to be
phosphorylated-something that occurs in the intestinal mucosa and
depends on proper mucosal function. And this phosphorylation of riboflavin
is magnesium dependent.
Pyridoxal phosphate may avoid phosphorylation, which may be zincdependent
or magnesium-dependent in humans and could be a weak step
if there is zinc or magnesium insufficiency.
The P 5-P form is purer, and less is needed to achieve the same cofactor
effects.
To my knowledge no sensory neuropathy has ever been reported with use
of P 5-P.
So, P 5-P has the edge over pyridoxine in magnesium deficiency, in zinc
deficiency, in purity, and in potency.
Now, what does coenzyme P 5-P do?
In body tissues it is necessary for amino group transfer called transamination.
This process balances the quantities of amino and organic acids. The balance
between alanine and pyruvate or aspartic acid and oxaloacetic acid are
examples. P 5-P also is the coenzyme for decarboxylation. That is, taking the
carboxyl group-the COOH or organic acid group-away from amino acids.
Formation of histamine from histidine is an example of this. Finally, pyridoxal
phosphate is a necessary coenzyme for certain molecular marriages or breakups
where two amino acids join or where some are split into two parts. Marrying
homocysteine and serine to form cystathionine is an example. Then, splitting the
cystathionine into cysteine and alpha-ketobutyric acid is an example of its divorce
function. Both of these steps, by the way, are documented metabolic error points
in humans. Homocystinuria, of mild degree, is a relatively common occurrence,
with a frequency of about 1 in 100. Cystathioninuria is much rarer. Both
conditions were early examples of medical use of a vitamin to potentiate the
activity of a genetically weak enzyme.
So, the basic clinical use of pyridoxal 5-phosphate is to potentiate activity of P 5-
P dependent enzymes. There are dozens and dozens of these enzymes in
human metabolism. An amino acid analysis performed on blood or urine at a
clinical laboratory often shows presumptive evidence of P 5-P need. Elevations of
alanine, aspartate, glycine, serine, tyrosine, valine, leucine, isoleucine,
homocysteine, cystathionine, alpha-aminoadipic acid, or beta-alanine, just to
name a dozen B6 sensitive amino acids, can signal increased need for
coenzyme P 5-P.
Also notable are the clinical findings of increased cellular magnesium when
vitamin B6 is administered. Individuals with poor magnesium retention may need
B6. Another finding is reduced edema and swelling when B6 is taken. An early
study in 1954 by Gugginheim published in Endocrinology, volume 54, showed
that B6 deficiency can lead to delayed water excretion. Humans that experience
abdominal bloating or swollen ankles may need B6 and may also need increased
protein in their diets as well as more exercise.
Doctors Karl Folkers and John Ellis have long ago published their clinical findings
on the benefits of vitamin B6 in carpal tunnel syndrome. This syndrome features
morning stiffness in the fingers, impaired finger sensations, weakness of hand
grip, and edema in the hands. Elsewhere in the body there is a frequent
occurrence of rheumatism, bursitis, and edema. Karl Folkers was Director of the
Institute for Biomedical Research at the University of Texas. In 1986, he gave the
Priestly Medal Address on B6 and carpal tunnel syndrome to the American
Chemical Society. His lecture is recorded in the April 21st, 1986 issue of
Chemical and Engineering News. Dr. Folkers did double blind studies with a
control group that showed successful therapy using B6. He measured its effect
as P 5-P on a transaminase enzyme. Doctor John Ellis has reported his findings
of beneficial vitamin B6 effects in carpal tunnel syndrome, childhood diabetes,
tendonitis, edema, and arteriosclerosis. This is in his own publication:
"Meditations on Vitamin B6," dated 1989. The arteriosclerosis finding, no doubt, is
related to the now infamous condition of homocystinuria and occlusive arterial
disease. This is alleviated with vitamin B6 and often folate and B12 as well. In the
last seven or eight years articles on B6, homocystine and cardiovascular disease
have been published in the New England Journal of Medicine and in the Journal
of the American Medical Association several times. and also in NOHA NEWS,
Winter, 1998.
Finally, Dr. Bernard Rimland and others have published on the benefits of vitamin
B6 and magnesium in autism and in developmental disorders in children. In
autism, parents have monitored functional improvement or regression with use of
megadose pyridoxine-usually 250 to 500 milligrams per day. By this measure, the
ratio of improved autistics to worsened autistics is about 10 to 1. No laboratory
test is needed, in my opinion, for trial use of pyridoxine or pyridoxal in autism or
developmental problems. Occasionally, some autistics eventually cease to
benefit from 500 milligrams per day of pyridoxine and a few worsened initially.
Many of those individuals improved after switching to pyridoxal 5-phosphate as
reported to me by Dr. Rimland.
In conclusion, pyridoxal 5-phosphate has specific metabolic applications
determined by amino acid analysis and other medical tests. Additionally,
published studies show benefits in conditions of edema and water retention,
magnesium deficiency, peripheral neuropathy, carpal tunnel syndrome,
tendonitis, rheumatism, cardiovascular occlusions and myocardial infarcts,
learning and developmental disorders, and autism.
Article from NOHA NEWS, Vol. XXIV, No. 2, Spring 1999, pages 3-5.
