Heterocycles - Essentials of Organic Chemistry - page 454

Box 11.13 (continued)
In any case, you might be able to analyse some of the relationships on a purely chemical basis. For example,
tetrahydrofolic acid reacts readily and reversibly with formaldehyde to produce N 5 , N 10 -methylene-FH 4 .You
could consider N-5 of the reduced pteridine ring reacting with formaldehyde (a one-carbon reagent) to give
an iminium cation, which could then cyclize via nucleophilic attack of N-10. We might also consider reducing
the iminium cation with, say, borohydride to give the N -methyl derivative. These are not necessarily the same
as what is occurring in the enzymic reactions, but they should help to make the structures appear rather more
familiar.

N N N

N

H 2 N N H 2 N N H 2 N N

H 2 N N

− H 2 O

HN HN HN

HN

5

N

H N N

HN 10

O

O O HN O N N

H H

OH

H H

H H

FH 4

H

N ,N -methylene-FH 4

5 0

iminium cation
formation

nucleophilic
attack on carbonyl

nucleophilic attack
on iminium cation

O

H

Now we have seen that the usual reagent for biological methylations is S -adenosylmethionine (SAM) (see
Box 6.4). One occasion where SAM is not employed, for fairly obvious reasons, is the regeneration of methionine
from homocysteine, after a SAM methylation. For this, N 5 -methyl-FH 4 is the methyl donor, with vitamin B 12
(see Box 11.4) also playing a role as coenzyme.

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S CO 2 H S CO 2 H

ROH

H 3 C H 3 C

NH 2

NH 2

S -adenosylmethionine
(SAM)

FH 4

methylation
using SAM

methylation using
N -methyl-FH 4

5

5

N -methyl-FH 4

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R OCH 3

H

S CO 2 H HS CO 2 H

NH 2 NH 2

homocysteine S -adenosylhomocysteine

ROCH 3

Another vitally important methylation reaction involving folic acid derivatives is the production of the nucleic
acid base thymine from uracil . Uracil is found in RNA, and thymine is a component of DNA; thymine is
the methyl derivative of uracil. For continuing DNA synthesis, it is necessary to methylate uracil. In practice,
it is the nucleotide deoxyuridylate (dUMP) that is methylated to deoxythymidylate (dTMP) (see Section 14.1).
The methylating agent employed here is N 5 , N 10 -methylene-FH 4 . As a consequence of this reaction, N 5 , N 10 -
methylene-FH 4 is converted into dihydrofolic acid. To keep the reaction flowing, this is reduced to FH 4 ,and
further N 5 , N 10 -methylene-FH 4 is produced using a one-carbon reagent. In this process, the one-carbon reagent
comes from the amino acid serine, which is transformed into glycine by loss of its hydroxymethyl group. The
chemistry of the transformations is fairly complex and outside our requirements.