B12 Functions

In the cells of mammals (1), B12 performs two different functions according to its form: (2)

Methylcobalamin - used by the enzyme methionine synthase to turn homocysteine (HCY)

into methionine.
5'-deoxyadenosylcobalamin - used by 1) the enzyme methylmalonyl-CoA mutase in
converting methylmalonyl-CoA to succinyl-CoA, and 2) by the enzyme leucine
aminomutase which converts B-leucine into L-leucine and vice-versa.

Homocysteine Clearance
Methionine is an essential amino acid provided by the diet. Some methionine is turned into
homocysteine. Homocysteine appears to be a nerve and vessel toxin, promoting cardiovascular
disease (CVD) at elevated levels. HCY is thought to cause CVD by way of oxidative and vessel
wall damage (3). The body normally turns HCY into other molecules, one of which is back into
methionine. If this pathway is blocked, HCY levels increase. Methylcobalamin (B12) is needed
by methionine synthase to convert HCY into methionine. Thus, if someone is B12 deficient,
HCY levels will increase.
Anemia, DNA, and Folate
Traditionally, B12 deficiency, normally resulting from the inablity to absorb B12, was diagnosed
by finding abnormally large red blood cells. This sort of anemia has two names:

Macrocytic anemia - when the average volume of the red blood cells, known as the
Mean Corpuscular Volume (MCV), is larger than normal
Megaloblastic anemia - when abnormally large red blood cells are observed under a
microscope

The vitamin folate (aka folic acid) affects the anemia symptoms of B12 deficiency. Folate is
needed to turn uracil into thymidine, an essential building block of DNA (4). DNA is needed for
new red blood cell production and division. B12 is involved in this process because in creating
methylcobalamin (used in the HCY to methionine reaction), B12 produces a form of folate
needed to make DNA. If there is no B12 available, this form of folate can become depleted
(known as the methyl-folate trap) and DNA production slows (5). See MethionineHomocysteine-Folate-B12 Cycle for an illustration of this pathway.
Only RNA is needed to produce the hemoglobin found in the red blood cells. Unlike DNA, RNA
does not require thymidine. Therefore, if there is not adequate folate, the new red blood cells
(which start out as large cells called reticulocytes) divide slowly, as they are dependent on DNA
for division. At the same time, their hemoglobin is only dependent on RNA and it is produced at
a normal rate. This causes large red blood cells known as macrocytes (4, 6). If enough of these
macrocytes accumulate, the result is macrocytic anemia.

If there are large amounts of incoming folate from the diet, the body does not need to rely on
regeneration of folate from the B12 cycle. Instead, it can use the extra dietary folate to produce
DNA, thus preventing macrocytic anemia (see Methionine-Homocysteine-Folate-B12 Cycle,
bottom right-hand portion). This is why high intakes of folate are said to "mask" a B12
deficiency.
To add insult to injury, an iron deficiency (which results in small red blood cells from inadequate
hemoglobin synthesis) can counteract the macrocytic cells, making it appear as though the blood
cells are normal in the face of multiple nutritional deficiencies (7).
Intestinal cells are also rapidly dying and being replaced using DNA. A B12 deficiency can make
itself worse because it can prevent the production of the intestinal cells needed to absorb B12.
Lack of Anemia Does Not Mean B12 Status Is Healthy

Number
of
Patients
2
16
22

Serum
B12

Table 1. B12
Levels in
Neurological
Patients Without
Macrocytic
Anemia (pg/ml)

> 200
100-200
< 100

Traditionally, the existence of macrocytic anemia was relied on to indicate a B12 deficiency.
However, neurological disorders due to B12 deficiency commonly occur in the absence of a
macrocytic anemia.
Lindenbaum et al. (8) (1988, USA) examined 141 cases of neurological problems due to B12
deficiency. 40 (28%) had no macrocytic anemia (iron deficiency may have contributed to a lack
in 6 patients, and folate therapy could account for 2 others). These 40 had very high serum MMA
levels (range: .76-187 mol/l, 78% > 2 mol/l) and homocysteine levels (23-289 mol/l, 45% >
100 mol/l). Characteristic features of patients with B12 deficiency but without macrocytic
anemia included: sensory loss, inability to move muscles smoothly (ataxia), dementia, and
psychiatric disorders. They also had borderline (and sometimes normal) B12 levels (see Table 1).
One patient died during the first week of treatment, but the other 39 benefited from B12 therapy.
Some patients had residual abnormalities after years of treatment.
Methylmalonic Acid (MMA)

The second coenzyme form of B12, adenosylcobalamin, takes part in the conversion of
methylmalonyl-CoA to succinyl-CoA. When B12 is not available, methylmalonyl-CoA levels
increase. Methylmalonyl-CoA is then converted to methylmalonic acid (MMA) which then
accumulates in the blood and urine. Since B12 is the only coenzyme required in this pathway,
MMA levels are the best indicators of a B12 deficiency.
High MMA levels can also (but rarely) be caused by genetic defects, kidney failure, low blood
volume, gut bacteria changes, pregnancy, and thyroid disease (9, 10).
A normal serum MMA level is .07 to .27 mol/l. Above, under Lack of Anemia Does Not Mean
B12 Status is Healthy, we saw that patients with serum MMA levels in the range of .76 to 187
mol/l had neurological problems. What about the range between .27 and .76 mol/l?
In a study of non-vegetarian, older adults with slightly elevated methylmalonic acid (MMA)
levels (.29-3.6 mol/l), higher sMMA levels did not predict neurological problems (10).
However, these individuals were not compared to people with normal sMMA levels. Because
there was no control group, we cannot say that people with slightly elevated sMMA are not at
risk for neurological problems. We can only suggest that increasing sMMA from .29 to 3.6 may
not do any further, measurable neurological harm.
In another study (11), older adults with slightly elevated MMA levels (.27 - 2.00 mol/l) were
treated with cyanocobalamin injections: MMA levels decreased 66% and homocysteine levels
decreased 23%. Patients with MMA in the range of .60-2.00 mol/l had neurological
improvements after B12 therapy.
These studies indicate:

Slightly increasing sMMA levels from .29 to .60 mol/l may not increase one's risk for
neurological problems.
People with MMA levels above .27 mol/l may have elevated homocysteine which can
benefit from B12 therapy.
People with sMMA levels above .60 mol/l may have neurological problems that can
benefit from B12 therapy.

References
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2000;59:337-66.
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SP, Allen RH. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of
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