Kennedy, J. Auclair, K. Kendrew, S. G. Park, C. Vederas, J. C. and Hutchinson, C. R. Modulation of
polyketide synthase activity by accessory proteins during lovastatin biosynthesis.
Khosla, 34, has been investigating the microbial genes that
make polyketides, a class of complex molecules that fungi and bacteria use for chemical defense.
His work has contributed to Nobel Prize - winning research, and in his own lab, he uncovered the inner workings
of polyketide synthases, natural enzymes that act as factories to assemble complex chemicals that have antibiotic and anticancer properties.
But to make it
produce polyketides, chemical engineer Chaitan Khosla of Stanford University and his colleagues had to overcome several hurdles.
Rapamycin belongs to a medically and agriculturally important class of compounds
called Polyketides.
Taek Soon Lee earned a B.S. in Chemistry at Seoul National University (Korea) and a Ph.D. in Chemistry at Stanford University in 2006 studying type II
aromatic polyketide synthases with Professor Chaitan Khosla.
Khosla and his colleagues have co-opted bacteria into making novel
polyketides by creating novel building blocks that the bacteria take up and then modify into compounds resembling antibiotics (Science, 18 July 1997, p. 367).
Or it might be made by a symbiotic microorganism living in or on the snow flea, perhaps by
polyketide synthesis, Schulz says.
Initially he wanted to work
on polyketide synthases, huge factories that bacteria use to make novel antibiotics.
Amoroso, Jon William (2014) Reactive Probes for
Manipulating Polyketide Synthases, and Photoreactive Probes for Strained Alkyne Kilauea; Mount Etna; Mount Yasur; Mount Nyiragongo and Nyamuragira; Piton de la Fournaise; Erta Ale
These enzymes join up small molecules containing the keto group into chain -
like polyketides, and then link the chains into rings.
The compounds are known
as polyketides, because their molecules all contain several «keto» groups, in which a carbon atom is linked to an oxygen atom by a double bond.
Professor Wilkinson explains: «We think this process mimics and accelerates the processes that are prevalent during
natural polyketide evolution.»
Walsh (p. 1805) focuses on the modular protein machinery that
constructs polyketide and nonribosomal peptide antibiotics.
Powell, K. J., Richens, J. L., Bramble, J. P., Han L. - C., Sharma, P., O'Shea P. and Moses, J. E., Photochemical activity of membrane -
localised polyketide derived marine natural products, Tetrahedron, 2017, 74, 1191.
In 2014, in collaboration with Life Sciences Institute colleagues Janet Smith and David Sherman, Skiniotis published two Nature papers that describe his use of cryo - EM to reveal the structure of a
modular polyketide synthase (PKS).
Hendrickson, L. Davis, C. R. Roach, C. Nguyen, D. K. Aldrich, T. McAda, P. C. and Reeves, C. D. Lovastatin biosynthesis in Aspergillus terreus: characterization of blocked mutants, enzyme activities and a
multifunctional polyketide synthase gene.
The other focus of his lab involves understanding, and ultimately modifying, the molecular factories within microorganisms that
make polyketides and other chemicals with high medicinal value.
But over the past few years, researchers have discovered that the pKS enzymes that produce
aromatic polyketides are assemblies of several proteins, each of which catalyses a particular step of the synthesis.
As a next step, Skiniotis is working to obtain higher resolution cryo - EM structures
of polyketide synthases.
Amoroso, Jon William (2014) Reactive Probes for
Manipulating Polyketide Synthases, and Photoreactive Probes for Strained Alkyne,, May, 2004.
The bacteria make
polyketides with the assistance of a family of enzymes called polyketide synthases (PKSs).
Pks13 is
a polyketide synthase, which links the two chains of the mycolic acids into a single molecule.
Now researchers led by David Hopwood from the John Innes Centre in Norwich and Chaitan Khosla at Stanford University in California have figured out which combination of proteins is needed in a PKS to produce
a polyketide with a specific structure.
Khosla and Hopwood hope to use their approach to produce an entirely new class of rationally designed aromatic
polyketides.
Thousands of sweet - tasting compounds belonging to more than 150 chemical classes have been discovered, including low - molecular - weight carbohydrates, aminoacyl sugars, amino acids, peptides, proteins, terpenoids, chlorinated hydrocarbons, halogenated sugars, N - sulfonyl amides, sulfamates,
polyketides, anilines, and ureas.
Researchers have coaxed a common lab bacterium, Escherichia coli, to produce large amounts of
polyketides, the raw material for a large class of drugs that have often been difficult to produce.
Polyketides — which include such therapeutic mainstays as the antibiotic erythromycin, the immunosuppressive drug FK506, and the cholesterol - lowering drug lovastatin — have combined sales exceeding $ 10 billion per year.
They're also tricky to alter genetically, hampering efforts to tweak
the polyketide - synthesizing enzymes so that they make new variants.
Related sites Kosan Biosciences Review about
polyketide synthesis in Science Page about polyketides
Finally, the researchers genetically altered two metabolic pathways to provide E. coli with the chemical building blocks needed to make
the polyketide.
In the 2 March issue of Science, the team reports that their bacterial strain can pump out
the polyketide at rates approaching those of industrial S. erythraea strains.
But
polyketide synthases don't work without a co-factor called phosphopantetheine, so the researchers also introduced a gene from the soil bacterium Bacillus subtilis that encodes the enzyme that attaches phosphopantetheine to the polyketide synthase.
And by replacing one component of the S. erythraea
polyketide synthase with a portion of an enzyme that makes a different type of drug, the Stanford team generated a hybrid enzyme that makes a polyketide unlike any found in nature.
They first introduced three genes from a soil bacterium called Saccharopolyspora erythraea, which together produce an enzyme called
a polyketide synthase, which produces one particular polyketide.
By swapping or changing the modules that contain the active sites of
polyketide synthases, researchers could engineer the enzymes to make novel polyketides in E. coli.
Polyketides and non-ribosomal peptides are two large families of complex natural products that are built from simple carboxylic acid or amino acid monomers, respectively, and that have important medicinal or agrochemical properties.
Polyketide (PK) and nonribosomal peptides (NRP), constructed on multimodular enzymatic assembly lines, often attain the conformations that establish biological activity by cyclization constraints introduced by tailoring enzymes.
Defense: «Effects of canopy cover and pH on
polyketide synthase gene transcription in Cladonie stygia and the polyketides produced in natural conditions.»
There are a number of constituents in the natural product including pigments, fatty acids, and
polyketides (monacolins).