section 38.2
Water-Soluble Vitamins
919
F IG U R E 3 8 -1 7
Metabolism of cobalamins in mammalian cells. Note the compartmentalization of the synthesis of the two coenzymes:
adenosylcobalamin (AdoCbl) synthesis occurs in mitochondria, whereas that of methylcobalamin (MeCbl) occurs in
cytoplasm. TCII, Transcobalamin II; OH-Cbl, hydroxocobalamin; T, transport protein for TCII-OHCbl complex; FH
4
,
MeFH
4
, tetrahydrofolate and methyltetrahydrofolate, respectively; Cbl, a cobalamin in which the ligand occupying the
sixth coordination position of the cobalt is not known. The numerical superscripts adjacent to some of the cobalamins
indicate the oxidation state of the cobalt ion. Cobalamins in the +1, +2, and +3 oxidation states are also known as B;
2
S,
B]
2
r, and B]
2
a, respectively.
IF. Transfer to IF is aided by the bicarbonate of pancre-
atic juice. At duodenal pH, IF has a greater affinity than
cobalophilin for B
12
. Patients with pancreatic insufficiency
may have vitamin B
12
deficiency.
The IF-cobalamin complex binds to specific receptors
on the luminal surface of ileal mucosal cells. Binding re-
quires Ca2+ and occurs optimally at pH >
6
.
6
. IF may enter
the mucosal cell with cobalamin, or it may bind to the re-
ceptor and release the vitamin into the cell interior. The IF-
receptor complex may then remain on the cell membrane
and transport other molecules of cobalamin into the cell.
Transfer of cobalamin to plasma is specifically to
transcobalamin II (TCII). The TCII-B
12
complex enters
virtually all cells of the body via a specific cell surface
receptor. The ligand-receptor complex is internalized and
appears in lysosomes, where TCII is degraded, thus free-
ing the cobalamin. Passage of cobalamin from lysosomes
into the cytoplasm may be mediated by a specific transport
mechanism. Fibroblasts from a child with developmental
delay and mild, B12-responsive methylmalonic aciduria
took up TCII-B
12
normally and released B
12
from the com-
plex, but the free B
12
accumulated within the lysosomes
rather than being released into the cytoplasm. This finding
suggests that the putative lysosomal B
12
transport system
was defective in this patient.
Thus, four major types of binding protein are needed
for absorption of cobalamin and for its uptake by tissues.
1.
Cobalophilins (R-proteins; R-binders).
These
proteins occur in plasma, gastric juice, saliva,
granulocytes, and other tissues and body fluids. Most
of the cobalophilin found in the stomach probably
comes from saliva. Cobalophilins are glycoproteins
(M.W. 56,000-66,000) that contain variable amounts
