Green Chemistry Mimics the Cellular Process of Drug Synthesis

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Two studies were published in the September 2007 issue of Nature Chemical Biology demonstrating for the first time that it’s possible to take a complex chain of enzymatic reactions and reconstruct them in vitro (meaning in a test tube) to synthesize a natural product that has therapeutic potential.

Many natural products have prospective use as drugs. However, the chemistry required to create the molecules is complex. Penicillin was one of the earliest discovered antibiotic compounds produced and isolated from a living organism. In 1928, Sir Alexander Fleming observed that the mold Penicillium notatum could kill colonies of the bacteria Staphylococcus aureus [1]. Over a decade later, Howard Florey and Ernst Chain isolated the active ingredient and successfully treated mice that had been given lethal doses of bacteria [2]. The combined efforts of these three men and others literally changed the practice of medicine by the mid-1940s.

With advances in organic chemistry, many antibiotics today are created by chemical synthesis. However, mimicking nature by identifying, producing and characterizing the appropriate enzymes, not to mention ensuring each enzyme enters the reaction at the proper time in the biosynthetic pathway, is exceedingly complicated. Two U.S. research groups have demonstrated the ability to do just this, thus imitating a biosynthetic process outside the cell.

The first study, carried out at the University of California, demonstrated the multienzyme biosynthesis of the Streptomyces maritimus bacteriostatic agents (meaning an antibiotic that inhibits the growth and reproduction of bacteria without killing them) enterocin and wailupemycin [3]. The production of enterocin from benzoic acid required 12 enzymes. Both antibiotics are naturally created by a Hawaiian sea sediment bacterium.

The second study done at Harvard Medical School in Boston, Massachusetts, demonstrated the biosynthesis of the antitumor fungal metabolite terrequinone A [4]. The researchers first identified the biosynthetic pathway in the fungi Aspergillus nidulans and then reconstituted it in a test tube. The reaction required 5 enzymes and the study constitutes the first identification of a biosynthetic pathway for that class of fungal toxins.

Until now, only the complex biosynthetic pathways inside a cell could manipulate the chemical structure of a substance and produce a natural molecule. One of the lead authors of the University of California study said [5] that it:

… may signal the start of a new era in how drugs are synthesized. Assembling all the enzymes together in a single reaction vessel is a different way to make a complex molecule.

More work is required to scale up the process for mass production. However, the studies prove that biosynthesis of natural products is possible without the use of man-made chemicals – a concept known as green chemistry – and can be done relatively cheaply.

Green chemistry attempts to reduce or eliminate the generation and use of hazardous substances in the design and development of chemical products and processes. Green chemistry began in the United States following the passage of the Pollution Prevention Act of 1990, which established a national policy to prevent or reduce pollution at its source whenever feasible. Following the act’s passage, the EPA Office of Pollution Prevention and Toxics (OPPT) launched a program that included grant support of research to prevent pollution in the synthesis of chemicals. Today, the mission of the EPA Green Chemistry Program is to promote innovative chemical technologies that reduce or eliminate the use or generation of hazardous substances in the design, manufacture, and use of chemical products.

References

1. The Most Important People of the Century – Scientists & Thinkers – Alexander Fleming. The Time 100. 2003.
2. Chain et al. Penicillin as a Chemotherapeutic Agent. Lancet, vol. 2. 1940, pp. 226-228.
3. Cheng et al. Enzymatic total synthesis of enterocin polyketides. Nat Chem Biol. 2007 Sep;3(9):557-8. Epub 2007 Aug 12.
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4. Balibar et al. Terrequinone A biosynthesis through L-tryptophan oxidation, dimerization and bisprenylation. Nat Chem Biol. 2007 Sep;3(9):584-92. Epub 2007 Aug 12.
   View abstract
5. Simple Method To Create Natural Drug Products Developed. ScienceDaily. 2007 Sept. 5.