Biomedical Engineering Reference
In-Depth Information
This early work on the precursor-directed biosynthesis of avermectin is
monumental for several reasons. It appears to be the first successful example of the
unnatural priming of amacrolide PKS that is blocked in its ability to produce thewild-
type substrate. At 800 attempted substrates, it also remains one of the most extensive
efforts to characterize the nature of precursors accepted by a biosynthetic system.
The authors were rewarded for their efforts with the general observations that the
priming mechanism accepted only substrates with eight or fewer carbons, with
preference given to those close in size to butyric acid. It was also observed that
heteroatoms such as sulfur and oxygen were accepted as ethers or included in
aromatic rings, but free hydroxyls and thiols proved too polar for incorporation.
Illustrated in Scheme 14.3 are several of the products resulting from successful
incorporation of unnatural precursors (compounds
).
Perhaps the most iconic feature of this work on avermectin was the inclusion
of cyclohexanecarboxylic acid (CHC) in the panel of 800 tested precursors.
Incorporation of this particular carboxylic acid led to the production of doramectin
11
10
-
14
, a veterinary antiparasitic drug marketed as Dectomax by Pfizer that holds the
distinction of being the first and only commercial product generated through
precursor-directed biosynthesis.
A decade after the initial publication of the structure of
, a subsequent study
identified and cloned a series of genes from
S. collinus
responsible for the conversion
of shikimic acid, a ubiquitous primary metabolite, into the coenzyme A thioester of
CHC. These genes were exogenously expressed in
S. avermitilis
, leading to the
biosynthesis of doramectin in the absence of any exogenous CHC [20].
Doramectin is clearly a success story that provides proof that precursor-directed
biosynthesis is more than just an intellectual curiosity and can produce novel
molecules of practical relevance.
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14.4.1.4. Jadomycin Jadomycins are a series of type II polyketides produced by
S. venezuelae
ISP5230. This bacterial strain is well known as a producer of the
antibiotic chloramphenicol, but it was recently discovered that in response to various
stresses, including those from heat, ethanol, or phage, the secondary metabolite
profile changes and the production of jadomycin is induced. Jadomycins, like many
polyketides, have shown promise in a variety of clinical applications by exhibiting
antiviral, antitumor, and antibiotic activities [21], along with an ability to inhibit the
aurora B kinase.
Jadomycin belongs to a class of angular tetracyclines known as the
angucyclines—a class of compounds that have some rather unique aspects to their
biosynthesis. The type II PKS is primed with acetate or propionate and is then
condensed with nine molecules of malonyl-CoA. Subsequent cyclization produces
the polycyclic polyketide portion of the molecule. This intermediate then undergoes a
Baeyer-Villiger-type oxidation of the third ring. The expanded lactone is then
hydrolyzed and the resulting primary alcohol oxidized to an aldehyde, yielding
intermediate
15
illustrated in Scheme 14.4. This aldehyde then condenses with an
amino acid, L-leucine, to form a Schiff base, which subsequently undergoes a
decarboxylative cyclization to yield a unique oxazolone ring. The final step involves
glycosylation with L-digitoxose, resulting in compound
16
.
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