Intelligent cells improve production of pharmaceutical raw materials.

Recent progress in synthetic biology offers the potential to optimize the production of virtually any compound, as well as the development of previously unknown ones.  Engineered synthetic biological systems are now being designed for the production of biofuels, polymers, bulk chemicals, and pharmaceuticals.  However, these systems will also need their artificial cells to be smart or intelligent, it is in this way they can create autonomous metabolic pathways on cue to produce the desired material efficiently.  The current study from researchers led by Kobe University develops intelligent cells to improve the production of pharmaceutical raw materials.  The team states their smart systems create metabolic pathways and engineer enzymes within microorganisms to produce analgesics.  The opensource study is published in the journal Nature Communications.

Previous studies show the goal of these smart cell systems is to achieve mass production of target materials by introducing genes encoding improved pathways into host microbes. This process relies on re-designing metabolic systems and pathways to increase production.  Recently, the production of alkaloid derived pain medicine has been achieved using microbes. The key alkaloid intermediate tetrahydropapaveroline (THP) was produced, however, the specificity of monoamine oxidase (MAO) has been a barrier to efficient production. The current study develops an integrated synthetic biology system to construct new metabolic pathways and enzymes within microbes to produce THP-based opioid analgesics.

The current study optimizes the production of pharmaceutical raw materials via a metabolic design program called M-path.  M-path identified novel enzymes to bypass MAO for improved pathways to the key alkaloid intermediate THP. Results show the M-path analysis led to the identification of a natural enzyme found in silkworms called 3,4-dihydoxyphenylacetaldehyde synthase (DHPAAS) as an alternative to MAO.  Data findings show structure-based enzyme engineering methods enabled the development of artificial DHPAAS enzymes capable of tuning the ratio of decarboxylase and amine oxidase activities, leading to improved production of THP.

Results show the introduction of the newly designed metabolic pathway, including engineered enzymes, into the bacterium Escherichia coli, allowing the precise control of the ratio of key intermediates dopamine (decarboxylation production) and DHPAA (oxidation product). Data findings show balancing dopamine and DHPAA levels led to improved alkaloid production within the re-designed smart cells. The team state to optimize the microbial production system further, over 100 metabolites were analyzed, enabling the identification of bottleneck reactions and by-product forming side reactions.

The team surmises they have combining synthetic biology and computer science to develop smart cell factories which can produce many different materials in the most efficient manner. For the future, the researchers state their synthetic biology workflow is expected to make significant contributions to the next-generation smart cell industry for the production of complex pharmaceuticals and chemicals, as well as newly discovered materials.

Source: Kobe University


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