Chemistry Reference
In-Depth Information
N
O
N
L
-Ser
Gly
H
2
N
N
H
2
N
N
HN
HN
HN
H
N
O
N
O
HN
O
N
deoxyribose-
P
N
,N
-methylene-FH
4
5 0
FH
4
dUMP
NADPH
O
N
H
2
N
N
dihydrofolate
reductase
CH
3
HN
HN
N
O
N
O
HN
deoxyribose-
P
FH
2
dTMP
Folic acid derivatives are essential for DNA synthesis, in that they are cofactors for certain reactions in purine
and pyrimidine biosynthesis, including the uracil - thymine methylation just described. They are also cofactors
for several reactions relating to amino acid metabolism. The folic acid system thus offers considerable scope for
drug action.
Mammals must obtain their tetrahydrofolate requirements from their diet, but microorganisms are able to
synthesize this material. This offers scope for selective action and led to the use of
sulfanilamide
and other
antibacterial sulfa drugs, compounds that competitively inhibit the biosynthetic enzyme (dihydropteroate synthase)
that incorporates
p
-aminobenzoic acid into the structure (see Box 7.23).
Rapidly dividing cells need an abundant supply of dTMP for DNA synthesis, and this creates a need for
dihydrofolate reductase activity. Specific
dihydrofolate reductase inhibitors
have become especially useful as
antibacterials, e.g.
trimethoprim
, and antimalarial drugs, e.g.
pyrimethamine
.
OMe
H
2
N
N
H
2
N
N
N
H
2
N
N
OMe
Me
N
N
N
N
N
OMe
N
NH
2
CO
2
H
NH
2
NH
2
Cl
trimethoprim
pyrimethamine
methotrexate
O
CO
2
H
These are pyrimidine derivatives and are effective because of differences in susceptibility between the enzymes
in humans and in the infective organism. Anticancer agents based on folic acid, e.g.
methotrexate
, inhibit
dihydrofolate reductase, but they are less selective than the antimicrobial agents and rely on a stronger binding
to the enzyme than the natural substrate has. They also block pyrimidine biosynthesis. Methotrexate treatment is
potentially lethal to the patient, and is usually followed by 'rescue' with folinic acid (
N
5
-formyl-tetrahydrofolic
acid) to counteract the folate-antagonist action. The rationale is that folinic acid 'rescues' normal cells more
effectively than it does tumour cells.
Box 11.14
Riboflavin
Riboflavin
(vitamin B
2
) is a component of
flavin mononucleotide (FMN)
and
flavin adenine dinucleotide
(FAD)
, coenzymes that play a major role in oxidation - reduction reactions (see Section 15.1.1). Many key enzymes
involved in metabolic pathways are actually covalently bound to riboflavin, and are thus termed flavoproteins.
