Featured Research

from universities, journals, and other organizations

Shifting evolution into reverse promises cheaper, greener way to make new drugs

Date:
March 23, 2014
Source:
Vanderbilt University
Summary:
By shifting evolution into reverse, it may be possible to use “green chemistry” to make a number of costly synthetic drugs as easily and cheaply as brewing beer. Normally, both evolution and synthetic chemistry proceed from the simple to the complex. Small molecules are combined and modified to make larger and more complex molecules that perform specific functions. Bioretrosynthesis works in the opposite direction. It starts with the final, desired product and then uses natural selection to produce a series of specialized enzymes that can make the final product out of a chain of chemical reactions that begin with simple, commonly available compounds.

Illustration of the pathway determined by bioretrosynthesis for making an HIV drug out of a simple sugar.
Credit: Jenny Ohnstad & Brian Bachmann / Vanderbilt University

This alternative approach to creating artificial organic molecules, called bioretrosynthesis, was first proposed four years ago by Brian Bachmann, associate professor of chemistry at Vanderbilt University. Now Bachmann and a team of collaborators report that they have succeeded in using the method to produce the HIV drug didanosine. The proof of concept experiment is described in a paper published online March 23 by the journal Nature Chemical Biology.

"These days synthetic chemists can make almost any molecule imaginable in an academic laboratory setting," said Bachmann. "But they can't always make them cheaply or in large quantities. Using bioretrosynthesis, it is theoretically possible to make almost any organic molecule out of simple sugars."

Putting natural selection to use in this novel fashion has another potential advantage. "We really need a green alternative to the traditional approach to making chemicals. Bioretrosynthesis offers a method to develop environmentally friendly manufacturing processes because it relies on enzymes -- the biological catalysts that make life possible -- instead of the high temperatures and pressures, toxic metals, strong acids and bases frequently required by synthetic chemistry," he said.

Normally, both evolution and synthetic chemistry proceed from the simple to the complex. Small molecules are combined and modified to make larger and more complex molecules that perform specific functions. Bioretrosynthesis works in the opposite direction. It starts with the final, desired product and then uses natural selection to produce a series of specialized enzymes that can make the final product out of a chain of chemical reactions that begin with simple, commonly available compounds.

Bachmann got the idea of applying natural selection in reverse from the retro-evolution hypothesis proposed in 1945 by the late Caltech geneticist Norman Horowitz. Horowitz envisioned an early stage in the development of life where early organisms were swimming in a primordial soup rich in organic material. In this environment, imagine that one of the species finds a use for the complex chemical compound A that gives it a competitive advantage. As a result, its population expands, consuming more and more compound A. Everything goes well until compound A becomes scarce. When that happens, individuals who develop an enzyme that allows them to substitute the still plentiful compound B for the scarce compound A gain a reproductive advantage and continue to grow while those who remain dependent on compound A die out. And so it goes until many generations later the survivors have developed multi-step chemical pathways to produce the molecules that they need to survive from the molecules available in their environment.

To test Bachmann's retro approach, the Vanderbilt chemists first identified the drug that they wanted to produce -- in this case didanosine, an anti-HIV drug sold under the trade names of Videx and Videx EC that is very costly to manufacture. Then they identified a similar "precursor" molecule that can be converted into didanosine when it is subject to a specific chemical transformation along with an enzyme capable of producing the type of transformation required.

Once they identified the enzyme, the researchers made use of the power of natural selection by making thousands of copies of the gene that makes the enzyme using a special copying technique that introduces random mutations. The mutant genes were transferred into the gut bacteria E. coli in order to produce the mutant enzymes and placed into different "wells." After the cells were broken open and the contents mixed with the precursor compound, the amount of didanosine, in each well was measured. The researchers selected the enzyme that produced the greatest amount of the desired drug and then made enough of this optimized enzyme for the next step.

Next the researchers identified a second precursor -- an even simpler molecule that could be chemical converted into the first precursor -- and an associated transformative enzyme. Again they made thousands of mutated versions of the transformative enzyme's gene, inserted them in E. coli, put them in wells, broke open the cells and mixed the content with the optimized enzyme and second precursor. Once again, they tested all the wells for the anti-HIV drug. The well with the highest level of didanosine was the one in which the mutant enzyme was most effective in making the first precursor, which the optimized enzyme then converted into didanosine. This gave them a second optimized enzyme.

The researchers carried out this reverse selection process three times, until they could make didanosine out a simple and inexpensive sugar named dideoxyribose. One of the key technical challenges was rapidly determining the three-dimensional structures of the enzymes that were generated during the evolutionary process. Associate Professor of Pharmacology Tina Iverson provided this capability. Her team analyzed the laboratory-evolved enzymes after each round of mutagenesis and identified how the structural changes caused by the mutations improved the enzyme's ability to produce the desired transformation. This information helped the collaborators figure out why some mutant enzymes did a better job at producing the desired compounds than others, which guided their choices about the areas of the precursor proteins to target.

The proof-of-concept experiment was performed in vitro instead of in living cells to keep things simple. However, the ultimate goal is to use the approach to produce artificial compounds by fermentation.

Graduate students William Birmingham, Chrystal Starbird, Timothy Panosian and David Nannemann contributed to the study.


Story Source:

The above story is based on materials provided by Vanderbilt University. Note: Materials may be edited for content and length.


Journal Reference:

  1. William R Birmingham, Chrystal A Starbird, Timothy D Panosian, David P Nannemann, T M Iverson, Brian O Bachmann. Bioretrosynthetic construction of a didanosine biosynthetic pathway. Nature Chemical Biology, 2014; DOI: 10.1038/nchembio.1494

Cite This Page:

Vanderbilt University. "Shifting evolution into reverse promises cheaper, greener way to make new drugs." ScienceDaily. ScienceDaily, 23 March 2014. <www.sciencedaily.com/releases/2014/03/140323151724.htm>.
Vanderbilt University. (2014, March 23). Shifting evolution into reverse promises cheaper, greener way to make new drugs. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2014/03/140323151724.htm
Vanderbilt University. "Shifting evolution into reverse promises cheaper, greener way to make new drugs." ScienceDaily. www.sciencedaily.com/releases/2014/03/140323151724.htm (accessed July 31, 2014).

Share This




More Matter & Energy News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Britain Testing Driverless Cars on Roadways

Britain Testing Driverless Cars on Roadways

AP (July 30, 2014) British officials said on Wednesday that driverless cars will be tested on roads in as many as three cities in a trial program set to begin in January. Officials said the tests will last up to three years. (July 30) Video provided by AP
Powered by NewsLook.com
Amid Drought, UCLA Sees Only Water

Amid Drought, UCLA Sees Only Water

AP (July 30, 2014) A ruptured 93-year-old water main left the UCLA campus awash in 8 million gallons of water in the middle of California's worst drought in decades. (July 30) Video provided by AP
Powered by NewsLook.com
Smartphone Powered Paper Plane Debuts at Airshow

Smartphone Powered Paper Plane Debuts at Airshow

AP (July 30, 2014) Smartphone powered paper airplane that was popular on crowdfunding website KickStarter makes its debut at Wisconsin airshow (July 30) Video provided by AP
Powered by NewsLook.com
U.K. To Allow Driverless Cars On Public Roads

U.K. To Allow Driverless Cars On Public Roads

Newsy (July 30, 2014) Driverless cars could soon become a staple on U.K. city streets, as they're set to be introduced to a few cities in 2015. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins