918
chapter 38
Vitamin Metabolism
neuropathy with ataxia occurred in seven patients who re-
ceived daily doses of 2-6 g of pyridoxine for 2-34 months.
The central nervous system was spared, and all showed re-
covery following cessation of pyridoxine ingestion. Four
of the patients had taken the vitamin to treat premenstrual
edema, for which there is no clinical support. Others be-
lieved that “more is better.” The toxicity may be caused
by displacement of pyridoxine cofactors from pyridoxine-
requiring enzymes by abnormal metabolites of vitamin
B
6
. These metabolites have little or no activity as enzyme
cofactors, resulting in loss of the reactions catalyzed by
the affected enzyme. The metabolites occur because of
“activation” by high substrate (pyridoxine) concentration
of minor pathways for B
6
metabolism.
Cobalamin (Vitamin B
12
)
Vitamin B
12
is unusual among the vitamins because its two
coenzyme forms contain an organometallic bond between
cobalt and carbon—the only such bonds known in biolog-
ical systems. The vitamin was first crystallized in 1948 as
the cyano derivative (cyanocobalamin), the principal form
of commercially available cobalamin. Anions such as hy-
droxyl, chloride, nitrite, and sulfate can replace the CN-
without affecting the activity. Hydroxocobalamin is the
form usually found in the body. Animals and higher plants
cannot synthesize cobalamin, although several animal tis-
sues can concentrate it, making lean meat, liver, seafood,
and milk important dietary sources.
De novo
synthesis of
cobalamin is accomplished only by microorganisms, in-
cluding some in the human colon. However, absorption
of B
I2
occurs only in the ileum, making cobalamin in
the colon of no nutritional value. Some species of bacteria
that colonize the lower ileum synthesize B i
2
and may con-
tribute to the cobalamin requirement of their host. Many
species of bacteria cannot make vitamin BI2, and microbi-
ological assays are based on stmulation of growth of some
of these species by exogenous cobalamin.
Vitamin Bi
2
is stable to temperatures up to 250°C
(482°F) in acidic or neutral solutions. Dietary B
!2
defi-
ciency is rare among meat eaters but not in strict vege-
tarians. The average total body content of vitamin B
]2
is about 2.5 mg, most of which is in the liver (1 /xg of
B i
2
per gram of hepatic tissue). There is extensive reuti-
lization of cobalamin and an active enterohepatic circu-
lation. The principal disease caused by vitamin B
i2
defi-
ciency is
megaloblastic anemia.
Deficiency also causes
neurological abnormalities that become irreversible if
allowed to persist.
The structure of the cobalamin family of compounds
is shown in Figure 38-16. The corrin ring system of four
pyrrole rings linked by three methene bridges is sim-
FIGURE 38-16
Structure of the cobalamin family of compounds. A through D are the four
rings in the corrinoid ring system. The B ring is important for cobalamin
binding to intrinsic factor. If R = -CN, the molecule is cyanocobalamin
(vitamin B
12
); if R = 5'-deoxyadenosine, the molecule is
adenosylcobalamin; if R = -CH
3
, the molecule is methylcobalamin.
Arrows pointing toward the cobalt ion represent coordinate-covalent bonds.
ilar to the porphyrin ring system. The 5,6-dimethyl-
benzimidazole ring is sometimes replaced by 5-hydroxy-
benzimidazole, adenine, or similar groups. Although the
cobalt is shown in the +1 oxidation state (B12s), it
is readily oxidized to +2 (B|2r) or +3 (B]2a). Dietary
cobalamins generally contain Co3+ while the coenzyme
forms have CoI+. Reduction of B]2s to Bi2r, and Bi2r to
BI2a, is catalyzed by specific NADH-dependent reductases
(Figure 38-17). In the coenzyme form, the group at-
tached to the sixth position of cobalt is 5'-deoxy-
adenosine
(adenosylcobalamin)
or
a
methyl
group
(methylcobalamin). In the liver and several other tissues,
about 70% of the cobalamin is present as adenosylcobal-
amin in mitochondria, 1-3% as methylcobalamin in the
cytoplasm, and the rest probably as hydroxocobalamin
(Figure 38-17). Absorption, transport, and cellular up-
take of vitamin B
l2
are summarized in Figure 38-18.
Dietary cobalamins are released by gastric acid and bind to
cobalophilins (R-proteins), derived primarily from saliva,
and to intrinsic factor (IF), a glycoprotein secreted by
gastric parietal cells. At pH 2, the relative affinities
of cobalophilin and IF for cobalamin are about 50:1.
In the duodenum, pancreatic proteases partially degrade
cobalophilins, allowing more of the cobalamin to bind to
