Chemistry Reference
In-Depth Information
antibiotic cephalosporin C in
Acremonium chrysogenum
is performed by
a specific acyltransferase that attaches an acetyl moiety to the precursor
deacetylcephalosporin C (39). Acylation as a late step of antibiotic biosynthesis
has also been demonstrated for chromomycin, where an acyl group is attached
to the sugar moiety of glycosylated antibiotic scaffold (40).
Besides being responsible for assembly of aminoglycoside and oligosaccharide
antibiotics, glycosyltransferases perform modification of many antibiotic scaf-
folds by attaching specific sugar moieties. Glycosylation is considered one of the
most important modifications of antibiotic scaffolds, because chemical groups of
sugar moieties are often directly involved in interaction of antibiotic with its cellu-
lar target. In addition, glycosylation helps to solubilize certain antibiotic scaffolds,
which are otherwise highly hydrophobic (41). Some glycosyltransferases display
relaxed specificity toward both dNDP-deoxysugar donor and antibiotic scaffold
acceptor, which enables them to glycosylate structurally distinct antibiotic scaf-
folds (26). Usually, glycosyltransferase attaches sugar moiety through a hydroxyl
group on antibiotic aglycone, such as in the biosynthesis of erythromycin, van-
comycin, nystatin, and so on. However, several examples of glycosyltransferases
attach a sugar moiety to a carbon or nitrogen atom, such as in the biosynthesis
of antitumor antibiotics urdamycin and rebeccamycin, respectively (26).
Oxidoreductases catalyze several types of reactions in modification of antibi-
otic scaffolds, which perform dehydration, keto reduction (42), oxygenation (43),
and oxidative cyclization (44). The enzymes responsible for these reactions are
usually flavin- or a-ketoglutarate-dependent oxidoreductases.
11.2.3 Genetics of Antibiotic Biosynthesis
Biosynthesis of antibiotics requires concerted action of enzymes involved in both
assembly of the scaffold and its modification. The latter is achieved through coor-
dinated expression of genes that encode these enzymes ensured by the following:
1) colocalization (clustering) of biosynthetic genes in the genomes of producing
organisms and 2) regulation of gene expression by pathway-specific regulatory
genes. A schematic presentation of a typical gene cluster that governs biosynthe-
sis of antibiotic is shown on Fig. 11.3b. The “core” of the antibiotic biosynthesis
gene cluster is represented by the genes encoding enzymes responsible for
scaffold biosynthesis (such as PKS, NRPS, glycosyltransferase, etc.). Genes
for scaffold modification enzymes (hydroxylases, methyltransferases, acyltrans-
ferases, halogenases, glycosyltransferases, etc.) are usually found in the vicinity
of the “core”. One or more pathway-specific regulatory genes are typically
present in the cluster, which regulate expression of biosynthetic genes. Resistance
to its own antibiotic is ensured by the presence of genes encoding enzymes that
inactivate endogenously accumulated antibiotic or modify antibiotic target in the
producing organism. Often, genes encoding efflux pumps that export antibiotic
molecules outside the cells are also found with the cluster. The latter enzymes not
only protect the producing organisms from harmful action of their own antibiotics
but also ensure delivery of the antibiotics to the surrounding environment.
