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The wonderful world of polyketides. This one helps you “go”. 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

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the wonderful world of polyketides
The wonderful world of polyketides

This one helps you “go”

Ansamycin antibiotics are produced by cultures

of Amycolatopsismediterranei

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.

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.

slide2

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:

Aldol or Claisen reaction forms the ring

Enolization produces phenol

slide3

a metabolite from the mold

Alternariatenuis

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

slide4

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 (Rhamnuspurshianus)

“Sennosides” have sugars

attached to the ring skeleton

slide6

St. John’s Wort

Hypericumperforatum

Senna (Cassia angustifolia)

slide8

Some common themes in polyketides

Alkylations occur

adjacent to

oxygenated C and

prior to cyclization

by aromatization

Radical coupling often joins phenolicrings. Ex: griseofulvin, an

antifungal

Produced by cultures of Penicilliumgriseofulvumand 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.

slide9

Oxidative cleavage, lactone and acetal formation results in major skeletal modifications

Patulin is a potent carcinogen produced by Penicilliumpatulum, 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
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
slide11

Poison Ivy / Oak (Toxicodendronradicans or Rhusradicans; 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.

slide13

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.

slide14

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

Cannabis sativa

Cannabaceae

alpha-linolenic acid (20%–25%)

slide15

aromatic ring dec. activity

heat, light

Ether linkage

necessary

inactive

psychoactive

inactive

slide16

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

slide18

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

slide19

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 Haemophilusinfluenzae.

slide20

produced by fungi

Gibberella, Fusariumspp.

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 macrocycliclactone 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.

slide21

Macrolide antibiotics

Erythromycins

(Saccharopolysporaerythreus)

target Gram-positive bacteria

such as

MRSA

(methicillin-

resistant

Staph. aureus)

Mode of action: “hijacks”

replication by binding to 50S

subunit of bacterial ribosome,

blocking translocation of

growing peptidyl RNA

from Streptomycesantibioticus

slide22

Several different linkers

are used in building

polyketide chain

Spiramycins:

Produced by Streptomycesambofaciens

Used to treat toxoplasmosis,

a feline disease caused by

protozoan Toxoplasmagondii

slide23

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

slide24

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.

slide26

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.

slide27

Kareniabrevisis 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 9-membered 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
  • dinoflagellateLingulodinium
  • polyedrum
slide28

Tamulamides A and B bind to the same

sites as the toxins but do not cause

toxic effects at nM concentrations.