Engineered bacteria could transform cannabis medicine production

Structural and biochemical basis for cannabinoid cyclase activity in marine bacterial flavoenzymes.

Nature chemical biology • • Moderately Relevant
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AI Summary

Scientists have discovered how marine bacterial enzymes can produce cannabichromenic acid (CBCA), a lesser-known cannabinoid found in cannabis. Two enzymes called Clz9 and Tcz9 work in a fundamentally different way than the enzymes naturally found in cannabis plants themselves. By analyzing the three-dimensional crystal structures of these enzymes and studying their chemical behavior, researchers revealed that each bacterial enzyme uses its own unique biological mechanism to transform the precursor compound cannabigerolic acid into CBCA—insights that were previously unknown.

The research team also engineered improvements to these enzymes that enhanced their ability to produce specifically the right-handed or left-handed versions of CBCA with greater precision. This level of control is crucial because the different molecular "handedness" of these compounds (called stereoisomers) could potentially have different effects and applications. The findings position Clz9 and Tcz9 as promising tools for biocatalytic cannabinoid production—essentially using engineered microbes to manufacture cannabinoids in laboratories instead of relying on traditional cannabis cultivation.

These discoveries have significant implications for the future of cannabinoid medicine and research. By understanding how different enzymes can produce cannabinoids through alternative biochemical pathways, scientists can potentially synthesize rare or minor cannabinoids like CBCA more efficiently and cost-effectively. This could accelerate the study of cannabinoids that are difficult to obtain from plants, ultimately enabling researchers to explore therapeutic properties of compounds that have been largely overlooked due to their scarcity in nature.

📄 Original Abstract

The marine bacterial flavoenzymes Clz9 and Tcz9 can process cannabigerolic acid to the minor cannabinoid, cannabichromenic acid (CBCA); however, the mechanistic details of this extrinsic transformation are still obscure. Here we report a thorough analysis of CBCA formation by Clz9 and Tcz9 through high-resolution crystallographic characterization, biochemical analysis and spectroscopic interrogation. Our work reveals that Clz9 and Tcz9 use different biochemical mechanisms from Cannabis cyclases and each other in their production of CBCA. Collection of a high-resolution substrate-bound structure provides additional key insights into how active site architecture affects substrate binding and stereoselectivity. Engineering approaches improve the stereoselectivity of CBCA formation by Clz9 and Tcz9, providing access to (R) and (S)-CBCA. Collectively, our work advances understanding of enzymatic cannabinoid formation and cements Clz9 and Tcz9 as two unique members of the BBE-like enzyme family with encouraging potential for biocatalytic cannabinoid production applications.

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