618
chapter 27
Nucleotide Metabolism
N '.N '-M ethenyi F H 4
N1 -Form im ino FH .
FIGURE 27-4
The six one-carbon substituents of tetrahydrofolate. The oxidation state is
the same in the one-carbon moiety of N
5
-formyl, NK)-formyI, and
N
5
,N10-methenyl FH4. Nlo-Formyl FH4 is required for
de novo
synthesis
of purine nucleotides, whereas N
5
,Nl0-methylene FH4 is needed for
formation of thymidilic acid.
FH
4
are shown below.
3. Hydrolysis of N
5
,N10-methenyl FH
4
by a
cyclohydrolase yields N5-formyl FH
4
(folinic acid)
and N10-formyl FH4. The oxidation state of the
one-carbon moiety is the same in all three species.
N10-Formyl FH4
N5,N10-Methenyl F 14
Ns-Formyl FH4
4. N10-Formyl FH
4
can be formed directly from formate
in an ATP-requiring reaction.
FH
4
+ HCOO
+ ATP
NI0-formyl FH
4
-----------
>
synthetase
N5-formyl FH
4
+ ADP + P,
5. The formimino group (-CH=NH) of
formiminoglutamate (Figlu), a catabolite of histidine
(Chapter 17), forms formimino FH4.
O
‘ O—C—CH2—CH2—CH—C—O’ + FH4 ■
I
NH
I
HC=NH
Formiminoglutamate (Figlu)
1. Serine is the principal source of one-carbon units.
serine hydroxymethyltransferase
FH
4
+ serine ,
— ^
pyridoxal phosphate
N
5
,NI0-methylene FH
4
+ glycine + H
2
O
2. N
5
,NI0-Methylene FH
4
plays a central role, since it
can be reduced to N5-methyl FH
4
or oxidized to
N
5
,N10-methenyl FH4.
Red.
reductase
N5, N
1
°-Methylene FH
4
+ NADH + H+ ------ ^
N5-methyl FH
4
+ NAD+
Ox
c
. dehydrogenase
N
5
,N10-Methylene FH
4
+ NADP+ , .
-
N
5
,N10-methenyl FH
4
+ NADPH + H+
where “Ox.” is oxidation and “Red.” is reduction.
N5-Formimino FH4
II
H
||
’ O—C—CH2—CH2—C—C—O’
I
nh2
Glutamate
N5-Formiminoglutamate undergoes deamination to N5,
N10-methenyl FH4. If a loading dose of histidine is given
to a patient who is deficient in folic acid, urinary excretion
of Figlu is increased. This
Figlu excretion test
is useful
in the diagnosis of folate deficiency, which clinically is
manifested as a megaloblastic anemia (Chapter 38).
The various catalytic roles of folate-mediated one-
carbon
transfer reactions
in
anabolic
and
catabolic
