DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1088 methyl group to cobalamin is essential for the adequate
supply of tetrahydrofolate (H 4
PteGlu 1
), the substrate for
a number of metabolic steps. Tetrahydrofolate is a precursor
for the formation of intracellular folylpolyglutamates;
it also acts as the acceptor of a one-carbon unit
in the conversion of serine to glycine, with the resultant
formation of 5,10-methylenetetrahydrofolate (5,10-
CH 2
H 4
PteGlu). The latter derivative donates the
methylene group to deoxyuridylate (dUMP) for the
synthesis of thymidylate (dTMP)—an extremely
important reaction in DNA synthesis. In the process,
the 5,10-CH 2
H 4
PteGlu is converted to dihydrofolate
(H 2
PteGlu). The cycle then is completed by the reduction
of the H 2
PteGlu to H 4
PteGlu by dihydrofolate
reductase, the step that is blocked by folate antagonists
such as methotrexate (Chapter 61). As shown in Figure
37–6, other pathways also lead to the synthesis of 5,10-
methylenetetrahydrofolate. These pathways are important
in the metabolism of formiminoglutamic acid
(FIGLU) and purines and pyrimidines.
In the presence of a deficiency of either vitamin
B 12
or folate, the decreased synthesis of methionine
and S-adenosylmethionine interferes with protein
biosynthesis, a number of methylation reactions, and
the synthesis of polyamines. In addition, the cell
responds to the deficiency by redirecting folate metabolic
pathways to supply increasing amounts of
methyltetrahydrofolate; this tends to preserve essential
methylation reactions at the expense of nucleic acid
synthesis. With vitamin B 12
deficiency, methylenetetrahydrofolate
reductase activity increases, directing
available intracellular folates into the methyltetrahydrofolate
pool (not shown in Figure 37–6). The
methyltetrahydrofolate then is trapped by the lack of
sufficient vitamin B 12
to accept and transfer methyl
groups, and subsequent steps in folate metabolism that
require tetrahydrofolate are deprived of substrate. This
process provides a common basis for the development
of megaloblastic anemia with deficiency of either
vitamin B 12
or folic acid.
The mechanisms responsible for the neurological
lesions of vitamin B 12
deficiency are less well understood
(Solomon, 2007). Damage to the myelin sheath is
the most obvious lesion in this neuropathy. This observation
led to the early suggestion that the deoxyadenosyl
B 12
–dependent methylmalonyl CoA mutase
reaction, a step in propionate metabolism, is related to
the abnormality. However, other evidence suggests that
the deficiency of methionine synthetase and the block
of the conversion of methionine to S-adenosylmethionine
are more likely to be responsible.
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
Nitrous oxide (N 2
O), used for anesthesia
(Chapter 19), can cause megaloblastic changes in the
marrow and a neuropathy that resemble those of vitamin
B 12
deficiency. Studies with N 2
O have demonstrated
a reduction in methionine synthetase and
reduced concentrations of methionine and S-adenosylmethionine.
The latter is necessary for methylation
reactions, including those required for the synthesis of
phospholipids and myelin. Significantly, the neuropathy
induced with N 2
O can be prevented partially by feeding
methionine. A neuropathy similar to that occurring with
vitamin B 12
deficiency has been reported in dentists
who are exposed to N 2
O used as an anesthetic.
Vitamin B 12
Chemistry. The structural formula of vitamin B 12
is shown in
Figure 37–7. These are the three major portions of the molecule:
1. A planar group or corrin nucleus—a porphyrin-like ring structure
with four reduced pyrrole rings (A-D in Figure 37–7)
1
2
CH
H 3
2 NOCCH 2 CH 2
H 3 C CH 2 CONH 2
H 2 NOCCH 2
H
H 3 C A
N
R B
N
CH 2 CH 2 CONH 2
H 3 C
Co
N N
CH 3
H 2 NOCH 2 C C D
CH 3
OCCH 2 CH 2 CH H
3
H3 C CH 2 CH 2 CONH 2
H 3 C
NH
CH 2
CH
O
O
P
O –
O
O
CH 2 OH
HO
N
N
CH 3
CH 3
Vitamin B 12 Congeners
Permissive Name
R Group
Cyanocobalamin
(Vitamin B 12 )
Hydroxocobalamin
Methylcobalamin
5'-Deoxyadenosylcobalamin
–CN
–OH
–CH 3
–5'-Deoxyadenosyl
Figure 37–7. The structures and nomenclature of vitamin B 12
congeners.