Chemistry Reference
In-Depth Information
Glucose-1-phosphate is the most common precursor for biosynthesis of
dNDP-deoxysugars, but mannose-6-phosphate, which is an intermediate in the
cell wall peptidoglycan biosynthesis, may also be used (24). After activation of
a monosaccharide through attachment of dNDP, they are modified by enzymes
such as dehydratases, reductases, epimerase, and aminotransferases to yield
dNDP-deoxysugars (25). dNDP-deoxysugars are substrates for glycosyltrans-
ferases, which are enzymes that link several sugar moieties either with each
other to produce scaffolds for aminoglycoside and oligosaccharide antibiotics,
or with other antibiotic scaffolds to provide glycosylated products (26).
Biosynthesis of terpene antibiotics (e.g., terpentecin and napyradiomycin) usu-
ally follows a mevalonate pathway, where the latter precursor is activated by
the action of both kinase and decarboxylase to yield isopentenyl diphosphate
(IPP). Several IPP molecules are then condensed into polyprenyl diphosphates
by polyprenyl diphosphate synthases (8). It has also been shown that IPP can
be synthesized via the 2-
C
-methyl-
D
-erythritol 4-phosphate pathway in certain
bacteria. In this case, IPP is synthesized from pyruvate and glyceraldehyde-3-
phosphate through a series of complex biochemical reactions (27).
11.2.2 Modification of Antibiotic Scaffolds
Despite the common themes in the scaffold biosynthesis mentioned above,
biosynthetic pathways for different antibiotics, which even belong to the
same chemical class, may differ significantly in the final steps dealing with
scaffold modification. The late steps in antibiotic biosynthesis are performed by
dedicated enzymes that modify assembled scaffolds by means of glycosylation,
methylation, acylation, hydroxylation, and so on. Different types of antibiotic
scaffold modifications and enzymes responsible are shown on Fig. 11.3a.
P450 monooxygenases are heme-contaning enzymes that catalyze a wide
variety of chemical reactions and are involved in biosynthesis of many
antibiotics. These enzymes commonly perform such modifications of antibiotic
scaffolds as hydroxylation (e.g., erythromycin), epoxidation (e.g., pimaricin),
and oxidation (e.g., nystatin). These enzymes have also been shown to be
involved in oxidative cyclization of phenolic side chains during biosynthesis of
certain antibiotics (e.g., vancomycin) (28). FMN-dependent monooxygenases
and dioxygenases are also known to be involved in antibiotic biosynthesis,
which modify antibiotic scaffolds via hydroxylation, as in the biosynthesis of
actinorhodin and tetracenomycin (29, 30).
Several halogen-containing antibiotics have been described, for example,
medically important antibacterial agents such as chlortetracycline and van-
comycin, and chloro-indolocarnazoles with antitumor activity. Attachment of
halogen atoms to antibiotic scaffolds is performed by several types of haloge-
nases, which include haloperoxidases, and flavin- and a-ketoglutarate-dependent
halogenases (31).
Methyltransferases involved in antibiotic biosynthesis commonly use
S-adenosylmethionine as a methyl group donor, and they are mostly responsible
