QUEEN'S BIOLOGY MCIB SEMINAR SERIES
  • Home
  • Schedule
  • Contact

Seminar series of the Molecular, Cellular & Integrative Biology
research groups at Queen's University

Tuesday Sept. 17 //  Driving metabolic flux and avoiding carbon loss; lessons from opiate alkaloid biosynthesis

9/10/2019

 
Picture
 Mehran Dastmalchi
Department of Biological Sciences,
Brock University, St. Catharines, ON
Opium poppy has been in use as a medicinal plant since before the dawn of civilization. Today, it remains the only source for natural opiate analgesics, codeine and morphine, and precursors used to synthesize derivatives such as the overdose antidote, naloxone. Total chemical synthesis of opiates is not commercially feasible due to complex stereochemistry. Engineering microbes with alkaloid biosynthetic machinery from opium poppy has the potential of providing a sustainable global supply of opiate pharmaceuticals. However, microbial bioproduction often suffers from carbon loss to alternative pathways. In the latter stages of opiate biosynthesis, thebaine is converted, via codeine, to morphine. When this pathway is simulated in vitro or in microbial systems, two undesirable isomers accumulate: neopine and neomorphine. We addressed this aberrant pathway in two studies: 1) In the penultimate step of morphine biosynthesis COR reduces codeinone to codeine. However, codeinone exists in an apparent equilibrium with its isomeric form, neopinone. We showed that COR irreversibly reduces neopinone to neopine. Using natural and synthetic protein variation we also identified four residues that can confer COR with higher protein stability and performance, improving metabolic flux. 2) We sought an explanation for why the plant does not accumulate the isomeric byproducts. Using a proteomics approach, we found a novel enzyme, neopinone isomerase (NISO) that catalyzes the assumed spontaneous conversion of neopinone to codeinone. NISO provides the substrate for COR to produce codeine and precludes the formation of neopine. Inclusion of NISO in yeast strains engineered to convert thebaine to natural or semisynthetic opiates dramatically enhances formation of the desired products and avoids carbon loss.

Comments are closed.

    Archives

    February 2021
    January 2021
    December 2020
    November 2020
    October 2020
    September 2020
    August 2020
    June 2020
    April 2020
    March 2020
    February 2020
    January 2020
    November 2019
    October 2019
    September 2019
    August 2019
    July 2019
    May 2019
    April 2019
    March 2019
    February 2019
    January 2019
    November 2018
    October 2018
    September 2018
    June 2018
    May 2018
    April 2018
    March 2018
    February 2018
    January 2018
    November 2017
    October 2017
    September 2017
    June 2017
    May 2017
    April 2017
    March 2017
    February 2017
    January 2017
    December 2016
    November 2016
    October 2016
    September 2016
    August 2016

Powered by Create your own unique website with customizable templates.
  • Home
  • Schedule
  • Contact