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588 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 589

4 8 NUTRITION
6
5 7 Sources
3 A B 9 Cobalamin is synthesized only by certain microorganisms; animals ulti-
2 N N 10 mately depend on microbial synthesis for their cobalamin supply. Foods
20 21 that contain cobalamin are of animal origin: meat, liver, seafood, and
11 dairy products. Cobalamin has not been found in plants.
23 22
1 NH N 12
19 D C 13 Daily Requirements
The average daily diet in Western countries contains 5 to 30 mcg of
17 15 cobalamin, of which 1 to 5 mcg is absorbed. Less than 250 ng appears
67
16
18 14 in the urine; the unabsorbed remainder appears in the feces. Total body
content is 2 to 5 mg in an adult, with approximately 1 mg in the liver.
68
Figure 41–7. Corrin ring showing ring designations and standard The kidneys also are rich in cobalamin. Relative to the daily require-
69
numbering of the atoms. ment, body reserves of cobalamin are much larger than those of folate.
Cobalamin has a daily rate of obligatory loss of approximately 0.1
percent of the total-body pool, irrespective of the pool size. For this
reason, a deficiency state does not develop for several years after cessa-
Four cobalamins are important in animal cell metabolism. Two are tion of cobalamin intake. The officially recommended dietary allowance
cyanocobalamin (CnCbl; vitamin B ) and hydroxocobalamin (OHCbl) (RDA) for adults is 2.4 mcg ; growth, hypermetabolic states, and preg-
2
12
or aquocobalamin (HOH Cbl). The other two cobalamins are alkyl nancy increase daily requirements. The RDA for children ages 1 to 13
derivatives that are synthesized from OHCbl and serve as coenzymes. years is 0.9 to 1.8 mcg. Because of insufficient data, no RDA has been
In one, adenosylcobalamin (AdoCbl), a 5′-deoxyadenosyl replaces OH established for infants. Instead, adequate intakes of 0.4 mcg for age 0 to
65
as the cobalt ligand above the ring (Fig. 41–8). In the second, meth- 6 months and 0.5 mcg for age 7 to 12 months have been estimated.
ylcobalamin (MeCbl), the upper ligand is a methyl group. MeCbl is the
major form of cobalamin in human blood plasma. 66
ROLE IN METABOLISM
The only two recognized cobalamin-dependent enzymes in human cells
N are AdoCbl-dependent methylmalonyl CoA (coenzyme A) mutase and
OH NH 2
OH MeCbl-dependent methyltetrahydrofolate-homocysteine methyltransferase.
N
N
Methylmalonyl Coenzyme A Mutase
O N Methylmalonyl CoA mutase is a mitochondrial enzyme that partic-
CH 2 ipates in the disposal of the propionate formed during breakdown of
R valine, isoleucine, and odd-carbon fatty acids. The enzyme is a homod-
CH 3 imer of a 78-kDa subunit that is encoded by a gene on chromosome 6.
70
CH 3 R′
N In the reaction catalyzed by methylmalonyl CoA mutase, methylmalo-
R′ nyl CoA, which is produced during catabolism of propionate, is con-
71
R N Co N CH 3 verted to succinyl CoA, a Krebs cycle intermediate. In the course of this
H C CH 3 reaction, a hydrogen on the methyl carbon of the substrate exchanges
3
H 3 C N places with the —COSCoA group (Fig. 41–9).
R′
R H C The coenzyme serves as an intermediate hydrogen carrier, accept-
3
H CH 3 ing the hydrogen from the substrate in the initial phase of the reaction
N and returning it to the product after migration of —COSCoA.
C
5
H 3 CH 2 N -Methyltetrahydrofolate-Homocysteine Methyltransferase
N MeCbl participates in cobalamin-dependent synthesis of methionine
CH 2 OH from homocysteine by the enzyme N -methyltetrahydrofolate–homo-
5
C O cysteine methyltransferase. S-adenosylmethionine (SAMe) and a
H 3
CO O second enzyme, methionine synthase reductase are required for meth-
72
yltransferase activity. The reductase converts the oxidized cobalt to
NH O
CH OH
2
P
CH 2 COSCoA COSCoA
O O
CH 2 CH COOH CH 2 CH COOH
CH AdoCbl
H H
C
H 3
Methylmalonyl CoA Succinyl CoA
Figure 41–8. Adenosylcobalamin (AdoCbl). R = CH CONH ; R′ = Figure 41–9. Methylmalonyl coenzyme A (CoA) mutase reaction.
2
2
CH CH CONH . AdoCbl, adenosylcobalamin.
2 2 2
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