Chemistry Reference
In-Depth Information
consumption of large amounts of uncooked liver. If diagnosed timely, the dis-
ease can now be cured easily by the parenteral administration of vitamin B
12
.
Notably, the liver can store large amounts of the vitamin.
10.3.2 Coenzyme Biosynthesis Enzymes as Anti-infective Drug Targets
Enzymes involved in coenzyme biosynthesis represent targets for anti-infective
agents (77). The sulfonamides that were discovered in the 1930s were the first
group of synthetic agents with a broad spectrum of activity against pathogenic
bacteria and protozoa. Their mode of action, via inhibition of dihydropteroate syn-
thetase in the biosynthetic pathway of tetrahydrofolate biosynthesis (Fig. 10.3),
was elucidated only much later. Subsequent studies on compounds with antifolate
activity afforded inhibitors of dihydrofolate reductase, which is the enzyme in
that pathway that catalyzes the formation of tetrahydrofolate from dihydrofolate
in organisms that synthesize the coenzyme
de novo
and from folate in organisms
that rely on dietary sources. Trimethoprim, which is an inhibitor of dihydrofo-
late reductase (that is required for the use of nutritional folate and dihydrofolate
as well as for the metabolic recycling of tetrahydrofolate coenzymes) became a
widely used antimicrobial agent that is typically applied in combination with a
sulfonamide.
Fosmidomycin, initially discovered as a product of
Streptomyces lavendu-
lae
with antibacterial and herbicide activity, was shown to act via the
inhibition of IspC protein that catalyzes the first committed step in the
nonmevalonate pathway of isoprenoid biosynthesis that is absent in humans
(
43
→
90
, Fig. 10.11). Based on these findings, the compound is now under
clinical evaluation as an antimalarial drug (78).
In principle, other coenzyme biosynthetic pathways that occur in pathogenic
bacteria but not in humans should qualify as anti-infective drug targets with a
favorable toxicity profile. Novel anti-infective principles would be highly desir-
able in light of the rapid spread of resistant pathogens.
10.3.3 Coenzyme Biosynthesis as a Target for Cytostatic Agents
The development of the sulfonamides as antibacterial and antiprotozoan agents
had preceded the discovery of its metabolic target in the biosynthesis of tetrahy-
drofolate (that was
per se
unknown in the 1930s) (Fig. 10.3). The discovery of the
vitamin in the 1940s triggered a wave of research directed at additional inhibitors
of its biosynthesis. This work resulted in the discovery of methotrexate that is
widely used as a cytostatic agent predominantly for hematological malignancy,
and also as an immunosuppressive agent used in the therapy of autoimmune
disease such as Crohn's disease (79).
10.3.4 Drug Interaction with Coenzyme Biosynthesis Pathways
Mevastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase
(Fig. 10.11), (
84
→
85
) that was isolated from
Penicillium citrinum
in 1971. A
