Page 611 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 33 Agents Used in Cytopenias; Hematopoietic Growth Factors 597

Pharmacodynamics
A. Methyl transfer
Two essential enzymatic reactions in humans require vitamin B
12
5
(Figure 33–2). In one, methylcobalamin serves as an intermediate N -Methyltetrahydrofolate Tetrahydrofolate
5
in the transfer of a methyl group from N -methyltetrahydrofolate
to homocysteine, forming methionine (Figure 33–2A; Figure 33–3,
section 1). Without vitamin B , conversion of the major dietary Cobalamin Methylcobalamin
12
5
and storage folate—N -methyltetrahydrofolate—to tetrahydrofo-
late, the precursor of folate cofactors, cannot occur. As a result, vita-
min B deficiency leads to deficiency of folate cofactors necessary Methionine Homocysteine
12
for several biochemical reactions involving the transfer of one-car-
bon groups. In particular, the depletion of tetrahydrofolate prevents B. Isomerization of L-Methylmalonyl-CoA
synthesis of adequate supplies of the deoxythymidylate (dTMP)
and purines required for DNA synthesis in rapidly dividing cells,
as shown in Figure 33–3, section 2. The accumulation of folate as Methylmalonyl-CoA
5
N -methyltetrahydrofolate and the associated depletion of tetra- L-Methylmalonyl-CoA mutase Succinyl-CoA
hydrofolate cofactors in vitamin B deficiency have been referred Deoxyadenosylcobalamin
12
to as the “methylfolate trap.” This is the biochemical step whereby
vitamin B and folic acid metabolism are linked, and it explains
12
why the megaloblastic anemia of vitamin B deficiency can be FIGURE 33–2 Enzymatic reactions that use vitamin B 12 .
12
partially corrected by ingestion of large amounts of folic acid. Folic
acid can be reduced to dihydrofolate by the enzyme dihydrofolate

Purines

10
5
N , N -Methylenetetrahydrofolate
dUMP
2
Thymidylate synthase
dTMP
Glycine

Serine transhydroxymethylase
DNA synthesis
Serine

Tetrahydrofolate Dihydrofolate
Folate reductase Folate reductase
3
Folic acid
Methylcobalamin Homocysteine
1
Cobalamin Methionine
5
N -Methyltetrahydrofolate

Dietary folates
FIGURE 33–3 Enzymatic reactions that use folates. Section 1 shows the vitamin B 12 –dependent reaction that allows most dietary folates
to enter the tetrahydrofolate cofactor pool and becomes the “folate trap” in vitamin B 12 deficiency. Section 2 shows the deoxythymidine
monophosphate (dTMP) cycle. Section 3 shows the pathway by which folic acid enters the tetrahydrofolate cofactor pool. Double arrows
indicate pathways with more than one intermediate step. dUMP, deoxyuridine monophosphate.