The wonderful world of polyketides
This one helps you “go”
From Senna leaf and fruit, Cassia
angustifolia (Leguminosae/Fabaceae).
Senna is a stimulant laxative that acts on
the wall of the large intestine, increasing
peristaltic movement.
Ansamycin antibiotics are produced by cultures
of Amycolatopsis mediterranei
Rifamycin SV (below ) is an anti-tuberculosis drug
that works against Gram-positive bacteria by
inhibiting bacterial RNA synthesis - it binds to
DNA-dependent bacterial RNA polymerase.
Starter unit acetyl CoA +
Organisms that produce
polyketides make highly
reactive poly-β-keto chains,
which must be stabilized by
association with groups on
the enzyme surface until
chain assembly is complete
and then cyclizations occur.
Polyketide formation: folding
is the key to ring formation:
1. Aldol or Claisen reaction
forms the ring
2. Enolization produces
phenol
a metabolite from the mold
Alternaria tenuis
Multiple aromatic
rings can result from
longer poly-b-keto
chains
formation of a depside
occurs through
esterification of two
phenolic acid units
A depside from
cranberries
Turner, et al, 2007
Formation of anthrones and anthraquinones:
1. chain folds in half
2. aldol condensation, dehydration, enolization
sequence forms the rings
3. oxidation of hydroxyl groups occurs after
“Emetics” or laxatives found
in Senna (Cassia
angustifolia), Cascara
(Rhamnus purshianus)
“Sennosides” have sugars
attached to the ring skeleton
Assembly of hypericin (St. John’s Wort – Hypericum perforatum)
St. John’s Wort
Hypericum perforatum
Senna (Cassia angustifolia)
Some common themes in polyketides
Alkylations occur
adjacent to
oxygenated C and
prior to
cyclization
by aromatization
Radical coupling often joins
phenolic rings. Ex: griseofulvin, an
antifungal
Produced by cultures of Penicillium
griseofulvum and is effective for
difficult skin infections.
It’s absorbed from the gut and
concentrated in keratin, so it is used
orally to control dermatophytes.
Works by disruption of the mitotic
spindle, inhibiting fungal mitosis.
Oxidative cleavage, lactone
and acetal formation results in
major skeletal modifications
Patulin is a potent carcinogen produced by Penicillium patulum, a
common contaminant on apples.
Products made from contaminated fruit may contain dangerous levels
of patulin, so juices, etc. are routinely screened for patulin content
(max of 50 μg kg−1).
Common reactions in polyketide
biosynthesis
•
•
•
•
Aldol/Claisen condensations  cyclization
Enolization  aromatic ring
Radical coupling  join two pieces together
Aromatic cleavage  open ring & allow for
twisting & reconfiguration of C skeleton
• Lactone or acetal formation  produces a
new ring
Poison Ivy / Oak (Toxicodendron radicans or Rhus radicans; T. toxicaria)
contains urushiols – part fatty acid, part polyketide
Family:
Anacardiaceae
Phenol gets
oxidized to a
quinone,
which is the
active form,
produces
allergic rxn.
The origins of aflatoxins (Aspergillus flavus & Aspergillus parasiticus)
Aflatoxin – producing fungi grow mainly on peanuts, corn, rice, pistachio nuts
Targets the liver, which becomes enlarged due to fat deposition, cell necrosis, etc.
Recent dog food contamination resulted in several pet deaths
Aflatoxin B1 is carcinogenic - after epoxidization by CYP450 it can intercalate DNA,
causing mutations.
Cannabis sativa
Cannabaceae
THC (tetrahydrocannibinol)
works by mimicking the
natural molecules that bind
to endogenous cannabinoid
receptors (analgesia):
CB1 in the brain (mood, memory
motor control, pain, appetite)
CB2 in immune/reproductive
system cells
alpha-linolenic acid (20%–25%)
Ether linkage
necessary
heat, light
inactive
psychoactive
aromatic ring
dec. activity
inactive
Structure-activity studies of natural products:
Many plants produce a range of compounds having similar structures with a few
modifications in substituents, side chains, sugars attached.
Comparison of the relative bioactivities of these molecules allows determination
of which structural features are necessary for activity
Important for turning drug leads into synthetic derivatives with increased activity
Two origins of methyl groups on polyketide skeletons
Methylation using SAM is more common in fungi
Actinomycetes (e.g. Streptomyces)
are filamentous bacteria that
gain methyls by incorporation of
propionate via methylmalonyl-CoA as
a building block.
There are a wide variety of
macrolides produced by Streptomyces
spp., most of which have some
antibiotic activity.
Many are readily identified by names
ending in “mycin”.
Note: Streptococcus are a separate genus
Tetracyclines: produced from polyketide chain through series of aldol condensations,
enolizations, and oxidations, similar to biosynthesis of anthrones. They have broad-spectrum
activity against a variety of Gram-positive and Gram-negative bacteria.
produced by
Streptomyces
Bacterial resistance to tetracyclines has developed in pathogens such as Pneumococcus,
Staphylococcus, Streptococcus, and E.coli. Mechanism of resistance: decreased cell
permeability, and membrane-embedded transport proteins that export the tetracycline out of
the cell before it can exert its effect. Still effective for infections caused by Chlamydia,
Mycoplasma, Brucella, Rickettsia, and chronic bronchitis due to Haemophilus influenzae.
produced by fungi
Gibberella, Fusarium spp.
that cause fruit & root rot
Macrolide ring formation and modification:
The macrolide antibiotics are a large family of compounds, many with antibiotic activity,
- characterized by a macrocyclic lactone ring (12, 14, or 16 membered)
- the poly-b-keto chain undergoes reductions, dehydrations, during chain extension, so the
molecule will not undergo cyclizations to fully aromatic structure.
Macrolide antibiotics
Erythromycins
(Saccharopolyspora erythreus)
target Gram-positive bacteria
such as
MRSA
(methicillinresistant
Staph. aureus)
from Streptomyces antibioticus
Mode of action: “hijacks”
replication by binding to 50S
subunit of bacterial ribosome,
blocking translocation of
growing peptidyl RNA
Several different linkers
are used in building
polyketide chain
Spiramycins:
Produced by Streptomyces ambofaciens
Used to treat toxoplasmosis,
a feline disease caused by
protozoan Toxoplasma gondii
Larger polyene
antifungals
Amphotericin is
commonly used
to treat Candida
infections (with
azoles)
Works by binding
to ergosterol, a
sterol in the fungal
membrane
Disrupts membrane
causing pores to
form, cells leak vital
nutrients &
electrolytes
Used to treat yeasts & Cryptococcus, and
also to reduce mold growth on surfaces
Compounds were isolated from a MeOH/CH2Cl2 extract
of the sponge (3 kg) and found to kill HCT-116 colon
cancer cells at sub uM concentrations.
IC50 = 8 ng/mL for (2)
Hurgholide A inhibited Candida at 31 ug/mL
How do they work?
These macrolides kill cells by disrupting the actin
cytoskeleton.
One dimeric molecule binds simultaneously to two
molecules of G-actin, forming a tertiary complex
and inhibiting polymerization.
The Swinholides also cause the filamentous actin
strands to break.
All caused loss of cellular microfilaments at nM
concentrations.
Cells treated with swinholide I collapsed and
formed neuron-like structures.
Compounds 2 & 3 were isolated
after several rounds of column
chromatography in mg quantities.
Many marine toxins are complex polyethers with origins in the acetate pathway
The brevetoxins are potent
neurotoxins that bind to
sodium channels , keeping
them open.
Brevenal (below) is a functional
antagonist to brevetoxin, inhibiting
its activity in all assays.
Brevenal reduces brevetoxin
binding to rat brain synaptosomes,
blocks brevetoxin-induced
bronchoconstriction in sheep, and
reduces brevetoxin toxicity in fish.
Biosynthetic studies have shown that fragments
from the citric acid cycle and a 4C starter unit from
mevalonate are involved in generating C skeleton.
Some of the methyls originate from methionine.
Karenia brevis is a marine dinoflagellate known
for production of several different families of
bioactive ladder-frame polyether compounds.
They contain similar trans-fused, ladder-shaped,
cyclic ether ring systems; with ring sizes (5 to 9membered rings), number of rings (4, 5, 6, 10,
and 11), and side chains vary among the different
families. Algal blooms by this organism cause
red tide in Florida.
 Red tide off the coast of
San Diego, caused by the
dinoflagellate Lingulodinium
polyedrum
Tamulamides A and B bind to the same
sites as the toxins but do not cause
toxic effects at nM concentrations.