Chemistry Reference
In-Depth Information
p
-hydroxyphenylglycine, and
β
-hydroxyasparagine. Monosaccharides activated
by attachment of deoxynucleotidetriphosphates are used as building blocks in
biosynthesis of aminoglycoside and oligosaccharide antibiotics, and also for
modification of many chemically diverse antibiotic scaffolds (6, 7). In the biosyn-
thesis of terpene antibiotics, which are relatively rare in bacteria, mevalonic
acid is used as a precursor. Mevalonate is synthesized from two acetyl-CoA
molecules via sequential action of acetyl-CoA acetyltransferase, 3-hydroxy-3-
methyl-glutaryl(HMG)-CoA synthase, and HMG-CoA reductase (8).
Primary metabolites, such as S-adenosyl methionine, formate, carbamoyl phos-
phate, nucleotides, as well as inorganic substrates, are also used as precursors for
modification of certain antibiotic scaffolds.
The use of primary metabolites as precursors for antibiotic biosynthesis implies
that their supply may be a limiting factor for the latter process in some cases, espe-
cially when the organism is actively growing. Early studies have indeed confirmed
that antibiotic biosynthesis starts when the growth of the organism is slowing
down, and it reaches its maximum with the cessation of growth (9). Understand-
ing of the antibiotic biosynthetic pathways, especially the origins of precursors,
is therefore important from the practical point of view in terms of increasing
the yields during industrial production of antibiotics. Engineering of primary
metabolic pathways that result in redirection of precursor flow toward antibi-
otic biosynthesis have been described for several antibiotic-producing organisms
(10 - 12).
11.1.2 Regulation of Antibiotic Biosynthesis and Mechanisms
of Self-Protection
It has been now firmly established that biosynthesis of antibiotics is subject to
control by multiple regulatory systems. Several biological reasons may explain
this complex regulation. Active synthesis of antibiotics represents a metabolic
burden for the producing organisms, which draws heavily on the precursor, ATP,
and electron carrier pools from primary metabolism (13). The latter suggests
that, in natural environment, antibiotics are synthesized only when they provide
a survival benefit. Antibiotic biosynthesis in most organisms is indeed activated
in response to certain environmental stimuli. Such factors as nutrient limitation,
change of temperature and pH in the environment, phage infection, presence of
other organisms, or organic solvents are known to trigger antibiotic biosynthesis
(14). Many antibiotic-producing organisms have a genetic capacity to synthesize
several antibiotics with diverse chemical structures and biological activities. Con-
sequently, in some cases, a competition for precursor supply may occur between
the antibiotic biosynthesis pathways present in one organism, and a decision must
be made on which pathway shall be activated in current circumstances. Although
the global regulatory network involved in regulation of antibiotic biosynthe-
sis remains poorly understood, considerable progress has been made toward
unraveling parts of it. The latter can be exemplified by the regulatory cascades
that involve
γ
-butyrolactones as signaling molecules discovered in
Streptomyces
