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Effective biosynthetic alternative to Taxol production discovered

By Gregory Roumeliotis , 03-May-2006

Researchers at Michigan State University have found that second-generation taxols, which currently rely on assembly by semisynthetic organic chemistry approaches, can be produced in a cheap and environmentally friendly fashion using enzymes in Pacific yew trees.

Taxol (paclitaxel), an anticancer drug, is derived from the bark of the Pacific yew, which is one of the slowest growing trees in the world, so reliance on it can create a supply problem.

Moreover, synthetic methods are costly for the chemical industry to synthesise from scratch, as these methods require several considerations regarding minimising the overall synthetic steps to maximise product yield and awareness of waste containment and disposal.

 

Nearly as expensive is extracting the natural product from plant material, entailing copious organic solvent and separation techniques.

 

Now scientists who are looking at alternative biological routes have discovered that enzymes from the yew tree can be used to modify Taxol pathway intermediates that can be isolated in abundance from the yew tree to produce second-generation, more potent versions of the drug.

 

Ultimately they hope to use genetically engineered bacteria to make Taxol in a biosynthetic approach which would circumvent the laborious protecting group manipulation, stereocontrol and regiochemistry obligatory to synthetic methods today.

 

"Our immediate goal is to systematically assess the range of substrate specificity of the five acyltransferase enzymes on the Taxol pathway," Kevin Walker, a chemistry, biochemistry and molecular biology assistant professor Michigan State University, told In-PharmaTechnologist.com.

 

"Ideally, we wish to apply a modular approach to the bioassembly of taxol - that is, we want to obtain abundant pathway intermediates from renewable portions of the plant, and then feed the acquired metabolites to engineered bacteria so that these bugs can produce precursors of second-generation taxols."

 

In an article in Chemistry & Biology, Walker reported the discovery of one of the acyltransferases which is able to transfer unnatural acyl groups to the hydroxyl group on a natural precursor of Taxol.

 

Crucially, the derived unnatural precursors have been demonstrated as effective modifications that increase drug potency.

 

Walker's team also found that bacteria engineered to produce the desired acyltransferase are capable of converting an advanced pathway intermediate to baccatin III, the penultimate natural product intermediate in the Taxol pathway.

 

Placing the acyltransferase gene into bacteria gives them the ability to make baccatin III and modified baccatin III quickly, efficiently and cheaply, in a green chemistry manner.

 

"Initially, it will be difficult to attempt to patch together the entire Taxol pathway gene system from yew trees in a host organism considered easy to bioengineer, such as bacteria, since Taxol biosynthesis requires an estimated 19+ genes to assemble the tricyclic ring and incorporate 8 oxidative modifications, 5 acylations, and 11 stereocenters," Walker admits.

 

"However, bioengineering bacteria for taxol production foreseeably can be accomplished, based on a model system in which 10 genes, including control elements, from various sources, were assembled in bacteria to produce the antimalarial drug arteminisin."

 

Nevertheless, Walker pointed out that biological approaches to molecule assembly can obviously complement rather than replace synthetic strategies.

 

Thus, a portion of a desired bioactive molecule can be synthesised in the laboratory and the few remaining alterations can be acquire biochemically, or vice versa.

 

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