Page 76 - Essential Haematology

62 / Chapter 5 Macrocytic anaemias

N N
H 2N 1 8
2 7
O H COOH (α)
3 6 H
N
4 5 CH N C N CH
N N 9 2 10
CH 2
CH 2
COOH (γ)

Figure 5.4 The structure of folic (pteroylglutamic) acid. Dietary folates may contain: (a) additional hydrogen

atoms at positions 7 and 8 (dihydrofolate) or 5, 6, 7 and 8 (tetrahydrofolate); (b) a formyl group at N 5 or N 10 , a
methyl group at N 5 or other 1 - carbon groups; and (c) additional glutamate moiety attached to the γ - carboxyl

group of the glutamate moiety.
some laboratories as tests for B 12 defi ciency (see ciency is thought to cause megaloblastic anaemia
p. 69 ). by inhibiting thymidylate synthesis, a rate - limiting
step in DNA synthesis in which thymidine
monophosphate (dTMP) is synthesized. Th is reac-
Folate
tion needs 5,10 - methylene THF polyglutamate as
Folic (pteroylglutamic) acid is the parent compound coenzyme.
of a large group of compounds, the folates, that are All body cells, including those of the bone
derived from it (Fig. 5.4 ). Humans are unable to marrow, receive folate from plasma as methyl THF.
synthesize the folate structure and thus require pre- B 12 is needed in the conversion of this methyl THF
formed folate as a vitamin. to THF, a reaction in which homocysteine is meth-
ylated to methionine. THF (but not methyl THF)
is a substrate for folate polyglutamate synthesis
Absorption, t ransport and f unction

inside cells. The folate polyglutamates act as intrac-
Dietary folates are converted to methyl THF ellular folate coenzymes, including 5,10 - methylene
(which, like folic acid, contains only one glutamate THF polyglutamate, the coenzyme form of folate
moiety) during absorption through the upper small involved in the synthesis of dTMP and of dTTP
intestine. Once inside the cell they are converted to (Fig. 5.5 ). Lack of B 12 prevents the demethylation
folate polyglutamates (Fig. 5.5 ). Folate binding pro- of methyl THF, thus depriving cells of THF of
teins are present on cell surfaces including the ente- 5,10 - methylene THF polyglutamate and so of
rocyte and facilitate entry of reduced folates into dTMP and dTTP (Fig. 5.5 ).

cells. There is no specific plasma protein that Other congenital or acquired causes of megalo-
enhances cellular folate uptake. blastic anaemia (e.g. antimetabolite drug therapy)
Folates are needed in a variety of biochemical inhibit purine or pyrimidine synthesis at one or

reactions in the body involving single carbon unit other step. The result is a reduced supply of one or
transfer, in amino acid interconversions (e.g. homo- other of the four precursors needed for DNA
cysteine conversion to methionine) (Figs 5.3 , 5.5 ) synthesis.
and serine to glycine or in synthesis of purine pre-
cursors of DNA.
Folate r eduction
During the synthesis of dTMP, the folate polygluta-
Biochemical b asis for m egaloblastic
a naemia (Fig. 5.5 ) mate coenzyme becomes oxidized from the THF
state to dihydrofolate (DHF) (Fig. 5.5 ). Regeneration
DNA is formed by polymerization of the four of active THF requires the enzyme DHF reductase.
deoxyribonucleoside triphosphates. Folate defi - Inhibitors of this enzyme (e.g. methotrexate) there-