Kevin Walker, a chemistry and biochemistry and molecular biology assistant professor, in the March 24 issue of Chemistry & Biology, reports a step toward manufacturing more-potent Taxol molecules that could potentially reduce treatment dosages. The methods described minimize dangerous chemical usage, and put E.coli to work in the production process.
"We're trying to develop a biosynthetic process for the drugs that circumvents the use of organic solvent-based methods requiring costly waste management," Walker said. "This attempt is a green chemistry approach to produce more potent versions of Taxol."
Taxol – generically known as paclitaxel – is a top-selling cancer-fighting drug. It's most commonly used against ovarian and breast cancers, but currently is used in certain aspects of heart disease treatment, and is showing promise in Alzheimer's therapy.
Taxol is derived in small quantities from the Pacific yew tree. To fulfill large-scale production, pharmaceutical companies isolate, from the tree, an abundant natural product that is synthetically converted to Taxol in the laboratory.
Now, as abundant molecules from the yew are being synthetically modified for new, more potent versions of Taxol, Walker, along with Catherine Loncaric, a visiting research associate, and undergraduate Erin Merriweather, is looking for alternative, biological routes to introduce the modifications. Walker's laboratory makes use of recently identified genes of the yew that produce enzymes that craft the pathway to Taxol. The targets: five enzymes that biosynthetically decorate the core of the Taxol molecule.
The enzymes in natural and, potentially, genetically modified form can be used to produce second-generation versions of the drug. Walker said the added advantage is that water-based chemicals rather than chlorinated solvents can be used with his methods.
For reasons ranging from competitive advantage to corporate culture, or to a desire to be a good corporate citizen, pharmaceutical companies are drawn to finding ways to minimize their environmental footprint as they make life-saving drugs.
"In fighting one pathological system, it makes sense to not create another problem that can have a global effect," Walker said.
Plus, Walker said assessing the Taxol pathway enzymes opens doors to new, more natural ways to make Taxol. He said that learning to genetically modify the qualities of the Pacific yew organism to make tomorrow's versions of Taxol could mean transferring all the genes – the entire pathway – into a bacterium for large-scale production of the new and improved Taxol, without further depleting the yew plant.
"Eventually, it will be cool when we're able potentially to have bacteria make all of the necessary plant enzymes, and we can sit back and watch E. coli make first- and second-generation Taxol molecules," Walker said.
The research was funded by MSU College of Natural Science. Walker's laboratory also is funded by the Michigan Agricultural Experiment Station.
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