Methionine Synthase, Methylmalonyl

Methionine Synthase, Methylmalonyl-CoA Mutase and Vitamin B12
Deficiency
by Mark J. Donohue
Vitamin B12 (cobalamin)
Vitamin B12 is the largest and most complex vitamin known. The central core of the B12 molecule
contains cobalt; thus, the chemical name for this vitamin is cobalamin. Vitamin B12 is water soluble and
is not destroyed by extreme heat; however, significant destruction can result when it is exposed to
intense ultraviolet and visible light.
Vitamin B12 serves as a coenzyme in two important enzymatic reactions. The enzymes methionine
synthase and methylmalonyl-CoA mutase both require the coenzyme B12, which are involved in several
metabolic functions within the body. Some of these metabolic functions are involved in:
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Manufacture of red blood cells to carry oxygen.
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Help maintain normal energy levels by
supporting normal metabolism of
carbohydrates & fats.
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Produce and maintain the myelin sheath that
surrounds nerve cells.
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Promote healthy neurological activity, including
mental alertness.
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Manufacture and maintain DNA for healthy cell
growth and repair.
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Support normal homocysteine levels for
healthy cardiac function.
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Help ease occasional stress and sleeplessness.
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Promote normal immune function.
Figure: Vitamin B12 - Cobalamin
Forms of B12/Cobalamin
What we know as vitamin B-12 is actually a collection of four related but different cobalt-containing
molecules. Each of these forms plays a distinct role in the body which is noted through this report and
will be described in detail at the end of this report. But for now the four major forms of cobalamin are:
1.
2.
3.
4.
Cyano-cobalamin
Hydroxo-cobalamin
Methyl-cobalamin
Adenosyl-cobalamin
Sources of Vitamin B12
The only dietary sources of B12 for humans are animal products, which have derived their cobalamins
from microorganisms (bacteria) inhabiting their digestive tract. All naturally occurring B12 is produced
by microorganisms, therefore, humans can obtain small amounts of B12 from their gut flora.
“The normal flora synthesizes and excretes vitamins in excess of their own needs,
which can be absorbed as nutrients by their host. For example, in humans, enteric
bacteria secrete Vitamin K and Vitamin B12, and lactic acid bacteria produce certain
B-vitamins.” (Todar 2012)
However, this issue is being debate. This is due to the fact that most of the production of B12 takes
place “down” in the large intestine, while absorption of B12 takes place further “up” in the ileum.
“The human gut also contains B12synthesizing bacteria, living from the
mouth to the anus. The colon contains
the greatest number of bacteria and here
most of our intestinal B12 is
produced. However, because B12 is
absorbed in the ileum, which lies
upstream of the colon, this plentiful
source of B12 is not immediately
available for absorption—unless people
eat feces (don’t gasp). Feces of cows,
chickens, sheep and people contain large
amounts of active B12. Until recently
most people lived in close contact with
their farm animals, and all people consumed B12 left as residues
by bacteria living on their un-sanitized vegetable foods.” (McDougall 2007)
Also, despite the fact that B12 is not found in plant foods, synthetic forms are widely available and are
added to many foods (i.e. cereals). The top 10 foods highest in naturally occurring vitamin B12 are:
FOODS
1. Shellfish (clams, oysters, mussels)
Per 100 gram serving
99mcg
2. Liver (lamb, beef, veal, turkey, duck)
85mcg
3. Caviar (fish eggs)
20 – 56mcg
4. Octopus
36mcg
5. Fish (mackerel, herring, salmon, tuna, etc.)
6-19mcg
6. Crab & Lobster
4-11mcg
7. Beef
5-6mcg
8. Lamb
3mcg
9. Cheese (swiss, mozzarella, parmesan, feta)
1.5-3mcg
10. Eggs (yoke)
2-4mcg
 U.S. RDA for adults for B12 is 2.4mcg/day
 The primary forms of B12 in food are hydroxo& adensoyl- cobalamin.
Absorption of B12
Vitamin B12 in foods is generally bound to proteins. Cooking food will release some of the vitamin while
pepsin in the stomach juice will free the remaining protein bound B12.
Once B12 is released it now must go through several steps to be absorbed. The first step is for B12 to
bind with proteins in the mouth and stomach called R-proteins. The purpose of R-proteins is to protect
the degradation of B12 as it passes through the stomach and into the small intestine. In the duodenum
(upper part of small intestine) B12 is released from R-proteins, at which point the B12 will now bind to
another protein called intrinsic factor (IF). Though intrinsic factor is produced and released by the gastric
parietal cells in the stomach it does not bind with B12 until entry into the duodenum.
The newly formed Cobalamin-IF complex moves through the small intestine to the terminal ileum. The
Cobalamin-IF complex then binds to specific receptors on the mucosal brush border. Intrinsic factor (IF)
is degraded and B12 is absorbed into the mucosal cells.
Once absorbed into the mucosal cells B12 is transferred to one of three transcobalamins (TCI, TCII, TCIII).
Up to 80% of B12 is bound to TCI, which may function as a circulating storage. TCII is the main protein
that carries newly absorbed B12 to the body’s tissues. TCIII may function in the delivery of B12 to the
liver for storage.
Following the absorption of B12, the vitamin appears in circulation about 3 to 4 hours later. Peak levels
of the vitamin in the blood typically are not reached for another 4 to 8 hours. In the blood,
methycobalamin comprises about 60% - 80% and adenosylcobalamin perhaps up to 20% of total plasma
B12. Overall absorption of B12 from the diet ranges from about 11% to 65%.
Enterohepatic circulation is important for the long biological half-life of B12. About 1.4mcg per day is
thought to be secreted by the liver into the bile. Once bile enters the small intestines B12 will once again
bind with intrinsic factor and be reabsorbed in the ileum. Thus malabsorption syndromes not only cause
a decrease in absorption of ingested B12 but also interfere with enterohepatic circulation.
Storage of B12 in the Body
Vitamin B12 is stored in the liver for use when intake is scarce with the total content in the liver being
about 4-5 milligrams. The major form of B12 in the liver is adenosylcobalamin. Though
hydroxocobalamin and methylcobalamin are also stored, but to a lesser extent. Other tissues such as the
brain, kidney, bone, spleen and muscle also present relatively higher concentrations.
The storage of B12 in the liver and other organs can be retained for long periods of time – up to 3 to 6
years. Vitamin B12 ingested in excess of the livers storage capacity is generally eliminated via the bile
into the stool. But because of enterohepatic circulation most of the B12 in the intestines will be
reabsorbed. Therefore, less than 0.1% of B12 is eliminated per day via the stool.
NOTE: There is conflicting information about the elimination of B12 via the urine. Some sources indicate
excess B12 is eliminated in the urine while other sources claim little B12 is eliminated in the urine… ???
Biochemistry of a Vitamin B12 Deficiency
As mentioned there are two enzymatic reactions within the body that require B12 as a coenzyme:
1. Methionine synthase requires methylcobalamin
2. Methylmalonyl-CoA mutase requires adenosylcobalamin
“Three hours after absorption, cobalamin is transported in the blood from the ileum
to the brain bound to transcobalamin II (TCII). The cobalamin-TCII complex crosses
the blood brain barrier and enters the brain cells by a process of absorptive
endocytosis using a specific high affinity cell surface receptor. TCII is degraded by
lysosomal proteases and the released cobalamins are converted to their methyl and
adenosyl forms. Mehtylcobalamin is bound to methionine synthase in the cytosol,
while adenosylcobalamin is bound to methyl malonyl-CoA mutase in the
mitochondria. The synthase and mutase enzymes are the only mammalian enzymes,
which are known to be cobalamin dependent. (Weir 1999)
Figure: Simplified chart showing the two metabolic pathways of vitamin B12
There are several disorders and symptoms which occur as a result of a B12 deficiency. These disorders
and symptoms occur due to abnormalities in the metabolic pathways in which B12 is a cofactor. Or to
put another way, a B12 deficiency results in either a build-up and /or a deficiency of a particular
compound which are directly associated with the B12 enzymes – methionine synthase and
methylmalonyl CoA mutase.
B12 Deficiency in Methionine Synthase
The methylcobalamin requiring enzyme – methionine synthase - serves a dual role. In the methylation
cycle it converts homocysteine to methionine, while simultaneously converting
5’-methyltetrahydrofolate (5-MTHF) to tetrahydrofolate (THF) in the folate cycle. These enzymatic
reactions take place in the cytosol of the cell.
Methylcobalamin is formed when the cobalamin in methionine synthase picks up a methyl group from
5-MTHF. Next, the newly formed methycobalamin, bound to methionine synthase, releases the methyl
group for transfer to homocysteine thereby producing methionine. Methionine subsequently is
converted to S-adenosylmethionine (SAMe) - the body’s main methyl group donor - which is involved in
numerous biochemical pathways. The release and transfer of the methyl group also causes 5-MTHF to
now become THF.
Because the formation of 5-MTHF is irreversible, a B12 deficiency in the folate cycle will cause a build-up
of 5-MTHF in what is known as the methyl-folate trap. This prevents 5-MTHF from being converted to
THF that is needed for nucleic acid (DNA, RNA) metabolism. Such a block is responsible for disorders and
symptoms such as
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Megaloblastic anemia
Anemia
Macrocytosis
Pancytopenia
Thrombocytopenia
Leukopenia
Lowered resistance to infection
Decreased anti-body formation
Poor wound healing
Pallor
Shortness of breath
Weakness
Fatigue
A B12 deficiency in methionine synthase will also prevent the conversion of homocysteine to
methionine in the methylation cycle. This will obviously cause a buildup in homocysteine and a condition
known as hyperhomocysteinemia. High levels of homocysteine are a well-known risk factor for:
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Cardiovascular diseases
Arterial Plaque
Stroke
Exacerbation of angina, palpitations
Folate Cycle
Methylation Cycle
This impaired conversion also results in reduced levels of methionine and therefore reduced levels of
SAMe, which is vital for the methylation of numerous biochemical reactions. These biochemical
reactions are responsible for maintaining brain chemistry and synthesizing neurotransmitters like
dopamine, serotonin and epinephrine. Reduced levels of methionine and SAMe manifest as:
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Mood changes – angry/moody/snappy/irritable
Insomnia – B12 stimulates melatonin from pineal gland
Poor appetite,
Lack of motivation, drive, movement
Depression, Withdrawal
Anxiety
Mental Lethargy
Psychosis-paranoia
B12 Deficiency in Methylmalonyl CoA Mutase
Methylmalonyl-CoA mutase is the other enzyme which is greatly affected by a B12 deficiency. Needing
vitamin B12 in the adenosylcobalamin form, methylmalonyl-CoA mutase is responsible for the
conversion of L-methylmalonyl CoA into succinyl CoA. This conversion takes place in the mitochondria.
L-methylmalonyl CoA arises from the oxidation of the amino acids -methionine, isoleucine, valine, and
threonine. L-methylmalonyl CoA also arises via beta-oxidation of odd-chain fatty acids. Though most
fatty acids found in nature are even-numbered fatty acids, there are some odd-numbered fatty acids.
“Odd-numbered fatty acids such as pentadecanoic acid and heptadecanoic acid are
characteristically found in ruminants and fish. Thus, dairy products
characteristically contain odd-numbered fatty acids. The odd-numbered fatty acids
in ruminants are derived from bacterial flora in the rumen. In contrast, those in fish
are derived from an organism, i.e., the amphipod at the bottom of the marine food
chain.” (Gotoh 2008)
Fatty acid chains with an odd-number of carbons are oxidized in the same manner as even-numbered
chains (through beta-oxidation), but the final product is propionyl-CoA instead of acetyl-CoA. PropionylCoA is subsequently converted into methylmalonyl-CoA.
Therefore, the B12 requiring enzyme – methylmalonyl CoA mutase – also serves a dual purpose as well.
It converts both specific amino acids as well as odd-chain fatty acids into succinyl CoA. Succinyl-CoA is a
Krebs cycle intermediate and thereby functions as an integral part in the formation of ATP. Therefore,
impairment in the conversion of this metabolic pathway will manifest as:
 Lethargy/Fatigue
What also occurs when the conversion of methylmalonyl-CoA to succinyl-CoA is impaired is a build-up of
methylmalonyl-CoA. The accumulation of methylmalonyl-CoA interferes with the formation of the
myelin sheath, and does this in two ways. First, methylmalonyl-CoA is a competitive inhibitor of
malonyl-CoA in fatty acid biosynthesis. The myelin sheath is turning over continually, and a decrease in
fatty acid synthesis can lead to its eventual degeneration.
Second, the accumulated methylmalonyl-CoA can be converted back to propionyl-CoA (a three-carbon
compound) that can substitute for acetyl-CoA (a two-carbon compound) as a primer for fatty acid
synthesis. The resulting odd-chain fatty acids are incorporated into membrane lipids where they disrupt
membrane function possibly because of their unusual physical properties.
The build-up of methylmalonyl-CoA eventually results in neurological features of demyelination, axonal
degeneration, and neuronal death. These features manifest as neurological symptoms and disorders
such as:
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Neuropathy
Multiple Sclerosis
ALS/Lou Gehrig’s Disease
Bell’s palsy
Myopathy
Memory loss
Poor concentration
Confusion
Dementia
Dizziness - vertigo
Tremor
Visual disturbances
Tinnitus
Numbing & tingling
Headaches
Restless leg
Burning Feet
Increased sensitivity to pain
Balance problems
Weakness
Impotence
Incontinence
Cramps
Stiffness
NOTE: The accumulation of methylmalonyl-CoA also causes a build-up of methylmalonic acid (formed
from the hydrolysis of methylmalonyl CoA) which accumulates in body fluids. High levels of
methylmalonic acid in the blood or urine are indications of a possible B12 deficiency. It should also be
noted that long term B12 deficiencies can result in permanent impairment of the nervous system.
Oxidation of
Odd-Chain
Fatty Acids
Methionine
Threonine
Isoleucine
Valine
Figure: Pathways involved in L-methylmalonyl-CoA mutase B12 deficiency
A B12 deficiency also affects the gastro-intestinal tract and causes a variety of GI disorders and
symptoms such as:
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Pernicious anemia
Gastritis
Irritable Bowel Syndrome
Crohn’s Disease
Mouth ulcers, bleeding gums
Diarrhea
Constipation
Abdominal pain
Causes of a B12 Deficiency
Because the daily requirement for B12 is small and the body is able to adequately store it, clinical
deficiency typically takes years to develop. Deficiency of B12 may arise due to several reasons:
 Decreased B12 dietary intake – due to chronic malnutrition or strict vegetarianism.
 Inadequate absorption caused by:
o
Atrophic gastritis – is a process of chronic inflammation of the stomach mucosa, leading to the
loss of gastric glandular cells. As a result, the stomach secretions are impaired.
o
Pernicious anemia - is the loss of gastric parietal cells responsible for secretion of intrinsic factor.
o
Small Intestinal Bacterial Overgrowth (SIBO) – is a disorder of excessive bacterial growth in the
small intestine, unlike the colon which is rich with bacteria.
o
Inflammatory Bowel Disease (Crohn’s disease and ulcerative colitis) - one-half to two-thirds of
those with Crohn’s Disease become deficient in B12.
o
Surgery – gastric or intestinal re-sectioning.
 Nitric Oxide - a free radical which can oxidize B12.
 Drug interactions – B12 deficiency can be caused by drugs such as: Metformin, Colchicine,
Cholestyramine, Para-aminosalicylic acid, Phenytoin, antibiotics, and anticonvulsants.
 Acid lowering agents – whether prescribed proton-pump inhibitors or over-the-counter antacids –
they create conditions of low stomach juices needed for the breakdown, binding and absorption of
B12. This also creates an environment for SIBO.
 Supplements - Vitamin C, used to promote wound healing, may cause the conversion of some
vitamin B12 into a metabolically inactive analogue.
 Alcohol
Misdiagnosis of B12 Deficiency
Many health care professionals mistakenly misdiagnose and attribute signs and symptoms of B12
deficiency to:
Dementia & Alzheimer’s
Parkinson’s disease
Multiple sclerosis
Diabetic neuropathy
Mini strokes
Depression
Psychosis
Bipolar
Vertigo
Anemia
Congestive heart failure
Autism
Restless Leg Syndrome
Chronic pain
Chronic Fatigue Syndrome
Fibromyalgia
Renal failure
Erectile dysfunction
Infertility
Testing for B12 Deficiency
As with so many medical test… the blood test for vitamin B12 are not conclusive. For example;
In a 1997 study of 12 patients with Fibromyalgia and Chronic Fatigue Syndrome, most had little or no
detectable B-12 in their cerebrospinal fluid - despite the fact that all had normal B-12 blood levels.
Conversely, they had high levels of homocysteine in their cerebrospinal fluid.
“One study found improved energy levels even in people who were not deficient in
vitamin B-12 but were administered the vitamin anyway. B-12 (2,500–5,000 mcg)
administered every two to three days was associated with improvement in 50% to
80% of a group of people with ME/CFS. Most improvement was seen after several
weeks of vitamin B-12 administration.” (Myatt 2008)
“Blood laboratory levels were generally normal. The most obvious finding was that,
in all the patients, the homocysteine (HCY) levels were increased in the
cerebrospinal fluid (CSF). There was a significant positive correlation between CSFHCY levels and fatigability, and the levels of CSF-B12 correlated significantly with
the item of fatigability and with the Comprehensive Psychopathological Rating Scale
(CPRS-15). The correlations between vitamin B12 and clinical variables of the CPRSscale in this study indicate that low CSF-B12 values are of clinical importance.
Vitamin B12 deficiency causes a deficient re-methylation of HCY and is therefore
probably contributing to the increased homocysteine levels found in our patient
group.” (Regland 1997)
Tufts University reported that at least 40% of the population is B12 deficient. They also mentioned
that many more people are deficient because many subjects who test normal for B12 actually have a
positive therapeutic effect when supplemented with B12.
“Those patients who respond to B12 are not obviously deficient in B12; indeed,
blood tests usually show normal levels. The "normal" levels of B12 have been set at
those levels necessary to prevent pernicious anemia - this may not be the same as
those levels for optimal biochemical function.” (Myhill 2012)
Also, as mentioned above the accumulation of methylmalonyl-CoA also causes a build-up of
methylmalonic acid in body fluids. High levels of methylmalonic acid in the blood or urine can be an
indication of a possible B12 deficiency.
Delivery Systems for Supplemental B12
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Intramuscular Injection
Oral Dosing
Sublingual Form
Intranasal Forms
Both sublingual and intranasal forms bypass the digestive system. In doing so the production of the
intrinsic factor - which decreases with age, poor diet and medications - is no longer a factor. Sublingual
and intranasal pathways provide an alternate absorption route for absorbing B12 directly into the blood
stream.
Forms of Cobalamin (B12)
“As a food additive and a supplement pill, vitamin B12 is usually found in the form
cyanocobalamin. The effectiveness of this “cyanide complex” for treating neurologic
problems has been questioned; therefore, other forms, such as methylcobalamin
and hydroxycobalamin may be better choices for the prevention and treatment of
B12-related conditions.
Choosing a bioactive form of B12 is important. There are many B12-like substances
called analogues found in food supplements, such as spirulina and other algae—
these are ineffective and should not be relied upon.” (McDougall 2007)
1. Cyano-cobalamin (inactive form): a cyanide (CN) group is attached to the cobalt atom.
o
The most common form of B-12 found in nutritional supplements, is a synthetic form of B-12
not found in nature.
o
It has the lowest biological activity and must be converted in the liver to a more biologically
active form of cobalamin: either methyl- or adenosyl-cobalamins. This conversion removes the
cyanide which now must be disposed of by the body.
o
Although the amount of cyanide is miniscule enough that it is not thought to be harmful to most
people, it could be dangerous for those who have cyanide metabolism defects or kidney failure.
o
NOTE: cyanide is found naturally occurring in foods at low doses. According to the U.S. Agency
for Toxic Substances and Disease Registry the following foods naturally contain cyanide:
-
o
almonds
soy
cassava
- millet sprouts
- lima beans
- spinach
- bamboo shoots
- fruits with a pit or core (cherries, apricots, apples, etc.)
NOTE: cyanide is also used as a food additive. Due to the high stability of their complexation
with iron, ferrocyanides (Sodium ferrocyanide, Potassium ferrocyanide, and Calcium
ferrocyanide) are used in the food industry (e.g., an anticaking agent in table salt).
2. Hydroxo-cobalamin (inactive form): a hydroxo (OH) group is attached to the cobalt atom.
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Form found in foods (along with adenosylcobalamin)
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May undergo methylation in the cytosol to generate methylcobalamin or may undergo
reduction and subsequent reaction with ATP in the mitochondria to yield adenosylcobalamin.
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Studies have found that hydroxocobalamin raises B12 levels higher and lasts longer and is the
parent to the short acting forms of methyl- & adenosyl-cobalamin.
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Is the most powerful scavenger of nitric oxide(NO). It is the only form of B12 that effectively
neutralizes the NO-molecule and breaks the NO/ONOO vicious cycle of cellular damage.
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Has a high affinity for cyanide. It pulls the cyanide out of the mitochondria of the cell and
combines with it to form cyanocobalamin, which is then excreted in the urine. In 2006
hydroxocobalamin was approved by the FDA as an antidote for cyanide poisoning.
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Hydroxo- & methyl cobalamins play an important role in addressing neurological disorders.
3. Methyl-cobalamin (active form): a methyl (CH3) group is attached to the cobalt atom.
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Is the primary form found in the blood, accounting for as much as 60% to 80%
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It is the required form in the methylation cycle as a coenzyme for methionine synthase.
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Is the only form of B12 found in the brain where it increases mental focus and clarity. Also
promotes protein synthesis for maintaining nerve cells and myelin.
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Protects cortical neurons against NMDA receptor-mediated glutamate cytotoxicity and
promotes nerve cell regeneration.
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Is the only form of vitamin B-12 that participates in regulating circadian rhythms (sleep/wake
cycles). It has been shown to support improved sleep quality and refreshment from sleep, as
well as increased feeling of well-being, concentration and alertness.
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Is considered by many researchers to be the most active form of vitamin B-12.
4. Adenosyl-cobalamin (active form): a 5’-deoxydenosyl group is attached to the cobalt atom.
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Form found in foods (along with hydroxocobalamin)
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Makes up 20% of the form found in the blood.
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The major form used as storage in the liver and other organs.
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Is the required form as a coenzyme for methylmalonyl CoA mutase,
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Is required for normal myelin sheath formation and nucleoprotein synthesis
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Deficiencies are associated with nerve and spinal cord degeneration.
Doctor’s B12 Protocols for Myalgic Encephalomyelities (ME/CFS)
There is no set upper dose limit for hydroxocobalamin because there are no known toxic effects, even at
extremely high dosages. Many of the studies used 1,000 or 2,000 mcg/day.
Dr. Paul Cheney MD, utilizes large doses of hydroxocobalamin as part of his treatment protocol. He
believes it is a potent brain detoxifier and says data suggests that mega doses in the range of 10,000
mcg or more per day, given before bedtime, may be effective.
Dr. Susan Solomon MD, recommends at least 5,000 mcg/day of sublingual hydroxocobalamin for
chronically ill patients.
Dr. Sarah Myhill MD, usually starts with 5,000 mcg/day of hydroxocobalamin for ME/CFS and then
adjusts the frequency according to the response.
Dr. Richard Van Konynenburg PhD,
“I prefer hydroxocobalamin for several reasons. One is that it allows the cells to
control the amounts of the coenzyme forms of B12 (methylcobalamin and
adenosylcobalamin) that they make, so that they can be matched to the need. Taking
methylcobalamin in large dosages by injection or sublingually can overdrive the
methylation cycle…
… My other concern is that methylcobalamin is known to be chemically able to
methylate inorganic mercury. Many PWCs have significant body burdens of
inorganic mercury as a result of having amalgam fillings in their teeth during an
extended period while glutathione has been low, so that they have not been able to
detox mercury at normal rates. Methylmercury can cross the blood-brain barrier
readily. Mercury is a potent neurotoxin if it gets into the brain…
However…
… In cases in which glutathione or SAMe are extremely low, it will be difficult to get
the methylation cycle going using hydroxocobalamin as the form of B12. This is the
form included in the simplified protocol I have suggested, and it was found to be
helpful for more than two-thirds of the people in our clinical study, but this may
explain why some of the people did not receive benefit from this protocol…
… Recently I have been suggesting that if the simplified protocol does not produce
benefits within three months, either testing should be performed to determine why,
or a change should be made in the protocol used. One possibility would be to add
methylcobalamin, starting at low dosage and working up, as tolerated.”
Dr. Richard Deth, Glutathione itself is needed for converting other forms of B12 to the active forms.
Indeed, there is a type of cobalamin called glutathionylcobalamin that is an intermediate for making
the active forms. Evidence from a rat experiment showed that – major glutathione depletion blocks the
conversion of hyroxocobalamin to methylcobalamin.
Folate (Vitamin B-9) and Folic Acid
The folate cycle (described above) is dependent on the supply of B12. Naturally, the folate cycle is also
dependent on the supply of folate to perform its metabolic functions. However, when supplementing
the diet, there is confusion over the differences between folate and folic acid. Even medical
professionals, nutrition experts, and health practitioners frequently mix up the two, simply because the
terms are often used interchangeably. Unfortunately, this is incorrect.
“Folic Acid is not the same as folate!” (Wright 2010)
Folate – also known as vitamin B-9 is a general term for a group of tetrahydrofolate (THF) derivatives
which are naturally occurring and found in leafy green vegetables, corn, beets, tomatoes, sunflower
seeds, and some fruits. None of these sources contain folic acid. Unfortunately, naturally occurring
folates break down quite rapidly with heat, cold, light, even when they’re still in the food. Because of
this naturally rapid breakdown, even the most avid vegetable and fruit eaters often need folate
supplementation.
At present, two types of folates are available as over-the-counter supplements:
1. Folinic Acid (calcium folinate)
2. 5-methyltetrahydorfolate (5-MTHF)
Folic acid – is not found naturally in food, rather it is a fully oxidized synthetic compound used in dietary
supplements and food fortification. Folic acid is cheaper, more stable and has a long shelf life. The body
is unable to use folic acid but is able to convert it - via the enzyme dihydrofolate reductase - into the
bioactive folate forms. And this is the reason why folic acid can have some use in the body.
However, as a person ages this conversion becomes more inefficient and could be one of the reasons
why scientists are finding an association between folic acid intake and cognitive decline. Also, the low
activity of dihydrofolate reductase in the human liver, combined with a high intake of folic acid, can
result in unnatural levels of unmetabolized folic acid entering the systemic circulation.
“Some of these studies have shown significantly elevated levels of un-metabolized
(and therefore not useful) folic acid building up in the bloodstreams of
supplemented older individuals.”(Wright 2010)
In addition to worsening folic acid metabolism with age, there are also a significant number (as high as 5
percent or more) of survivable human genetic defects of folate metabolism which make it more difficult
or, in some circumstances, impossible for sufferers to make metabolic use of folic acid.
A little bit of folic acid (100 to 200 micrograms, the amount found in many multiple vitamins at present)
is not likely to be a problem, but more taken daily for years just might raise your long-term risk of
colorectal cancer or cognitive decline.
“In the United States, Canada, and Chile, the institution of a folic acid
supplementation program was associated with an increased prevalence of colon
cancer. A random control trial found that daily supplementation with 1 mg of folic
acid was associated with an increased risk of prostate cancer…
… Excess folic acid may stimulate the growth of established neoplasms, which can
eventually lead to cancer. The presence of unmetabolized folic acid in the blood is
associated with decreased natural killer cytotoxicity. Since natural killer cells play a
role in tumor cell destruction, this would suggest another way in which excess folic
acid might promote existing premalignant and malignant lesions.” (Kresser 2012)
A high intake of folic acid might mask detection of vitamin B12 deficiency and lead to a deterioration of
central nervous system function in the elderly.
“In one study, consumption of folic acid in excess of 400 micrograms per day among
older adults resulted in significantly faster rate of cognitive decline than supplement
nonusers. Another study found a higher prevalence of both anemia and cognitive
impairment in association with high folic acid intake in older adults with a low
vitamin B12 status. As vitamin B12 deficiency is a common problem for many older
adults, these studies suggest that high folic acid intake could cause serious cognitive
consequences in the elderly.” (Kresser 2012)
Other Nutrients Needs for the Folate – Methylation Cycles
By now the flow chart below should look familiar. The circle on the left is the folate cycle and the circle
on the right is the methylation cycle. As described above they work together with the vitamin B12
enzyme – methionine synthase (MS) - being the connecting point between the two cycles.
The chart below also shows that there are several other important enzymatic reactions involved in these
two cycles. The chart nicely indicates each enzyme and its associated co-enzyme. Below the chart, I took
the liberty to compile these enzymes and co-enzymes into an easy to read list.
Enzyme
1. Thymidline Synthase (TS)
2. Serine-Hydroxy-Methyl Transferase (SHMT)
3. Methylene-Tetra-Hydro-Folate Reductase (MTHFR)
4. Methionine Synthase (MS)
5. Methionine-Adenosyl Transferase (MAT)
6. Methyl Transferase (MT)
7. Glycine N-Methyl Transfease (GNMT)
8. S-Adenosyl-Homosysteine Hydolase (SAHH)
9. Cystathionine-Beta Synthase (CBS)
10. Betaine-Homocysteine-Methyl Transferase (BHMT)
Co-Enzyme
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B6, Zinc
B2, B3, Ascorbate, Selenium
Methyl-B12, Copper, Zinc
Magnesium
Glycine
B3, Copper
B6, Zinc
Betaine, Zinc
Bottom Line
A B12 deficiency is associated with the accumulation of 5’-methyltetrahydrofolate (5-MTHF),
homocystiene, and methylmalonyl-CoA, as well as a deficiency of tetrahydrofolate, methionine and
succinyl-CoA which together manifest as a long list of medical disorders and symptoms.
References
Books
Note: all books were obtained either at UW Library, King County Library, Snohomish County Library or Bastyr
University Library. A couple of books were available on line (e-books, PDFs, googlebooks). Links are provided to
give a visual of book cover and other information.
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Advanced Human Nutrition by Robert Medeiros, Jones & Bartlett Publishers (2011) Link
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Advanced Nutrition and Human Metabolism, by Sareen Gropper, Cengage Learning (2005) Link
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Essentials of Biochemistry, by Pankaja Naik, JP Medical Ltd. (2012) Link
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Introduction to Clinical Nutrition, by Vishwanath Sardesai, CRC Press (2003) Link
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Todar’s OnlineTextbook of Bacteriology, by Kenneth Todar, (2012) Link
Publications
Gotoh N., et al, Metabolism of Odd-Numbered Fatty Acids and Even-Numbered Fatty Acids in Mouse, Journal of
Oleo Science, 57(5):293-299 (2008) Link
Henrik B., The Kidney in Vitamin B12 and Folate Homeostasis, Renal Physiology, 291(1):F22-F36 (2006) Link
Regland B., et al, Increased Concentrations of Homocysteine in the Cerebrospinal Fluid in Patients with
Fibromyalgia and Chronic Fatigue Syndrome, Scandinavian Journal of Rheumatology, 26:301-307 Link
Main P., et al, Folate and Methionine metabolism in Autism: A Systematic Review, The American Journal of
Clinical Nutrition, 91(6):1598-1620 (2010) Link
Weir D.G., et al, Brain Function in the Elderly: Role of Vitamin B12 and Folate, British Medical Bulletin, 55(3):669682 (1999) Link
Videos and Audio Productions
Video and Audio Productions are sited within the report
WWW
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B12 Awareness Link
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B-12 Deficiency in ME/CFS and FM May Provide Clues & Relief, by Dana Myatt, ProHealth (2008) Link
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Dr. John Douillard’s Life Spa Link
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Dr. Jonathan Wright’s Tahoma Clinic Blog Link
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Dr. Mercola Link
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Dr. McDougall Newsletter, 6(11) 2007 Link
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Dr. Sarah Myhill, Rationale for using Vitamin B12 in CFS Link
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Chris Kresser L.Ac Medicine for the 21 Century Link
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HealthAliciousNess.com Link
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Methylation Overview for Professionals, by Dr. Kendall Stewart Link
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The Brain Boosting B-12: Hydroxocobalamin, by Karen Lee Richards, ProHealth (2010) Link
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Vitamin B12 Deficiency, by T.S. Dharmarajan, Geriatrics, 58(3):30-38 (2003) Link
st