Understanding How Yeast Can Produce Two Types of Plant-Based Alkaloids

Greg Howard
3rd July, 2024

Understanding How Yeast Can Produce Two Types of Plant-Based Alkaloids

Image Source: Natural Science News, 2024

Key Findings

  • Researchers from China Pharmaceutical University studied the biosynthesis of aporphine alkaloids
  • They identified two cytochrome P450 enzymes, CYP80G6 and CYP80Q5, which work on different substrate configurations
  • They also found two more P450 enzymes, CYP719C3 and CYP719C4, that form a critical methylenedioxy bridge in these alkaloids
  • Using yeast, they successfully produced aporphine alkaloids like (R)-glaziovine and magnoflorine, showing a new way to make these compounds
Aporphine alkaloids are a class of compounds known for their diverse pharmacological activities, including anti-inflammatory, anti-cancer, and anti-microbial properties. Despite their potential, the biosynthesis of these alkaloids has remained relatively obscure. Recent research from China Pharmaceutical University has illuminated the biosynthetic pathways of these compounds, specifically focusing on the roles of cytochrome P450 enzymes[1]. Cytochrome P450 enzymes are known for their role in catalyzing oxidative reactions in plant secondary metabolism, contributing to the structural diversity of plant metabolites[2]. In this study, researchers identified two specific cytochrome P450 enzymes, CYP80G6 and CYP80Q5, from the herbaceous perennial vine Stephania tetrandra. These enzymes exhibited distinct activities toward (S)-configured and (R)-configured substrates, respectively, providing insight into the stereochemical features of aporphine alkaloid biosynthesis. The researchers also characterized two additional P450 enzymes, CYP719C3 and CYP719C4, which catalyze the formation of the methylenedioxy bridge on the A- and D-rings of aporphine alkaloids. The methylenedioxy bridge is a critical pharmacophoric group, essential for the biological activity of these compounds. This finding builds on previous studies that have identified similar P450 enzymes involved in the formation of methylenedioxy bridges in other alkaloid biosynthetic pathways[2][3]. To further explore the biosynthetic pathways, the researchers leveraged the functional characterization of these enzymes to reconstruct the biosynthetic pathways for two types of aporphine alkaloids in Saccharomyces cerevisiae (yeast). This approach allowed for the de novo production of compounds such as (R)-glaziovine, (S)-glaziovine, and magnoflorine. This is a significant advancement, as previous studies have highlighted the potential of using yeast as a production platform for benzylisoquinoline alkaloids (BIAs) due to its ability to be genetically engineered for high-yield production[4]. The findings from this study not only provide a deeper understanding of the biosynthesis of aporphine alkaloids but also pave the way for the production of these valuable compounds through synthetic biology. By utilizing yeast as a production platform, the researchers have demonstrated a viable alternative to traditional agriculture-based supply chains, which are often limited by low yields and environmental factors. This synthetic biology approach could potentially lead to more efficient and sustainable production methods for pharmacologically important alkaloids. In summary, the research conducted by China Pharmaceutical University has identified key cytochrome P450 enzymes involved in the biosynthesis of aporphine alkaloids, elucidated their stereochemical features, and demonstrated the feasibility of producing these compounds in yeast. This study not only advances our understanding of plant secondary metabolism but also offers promising avenues for the sustainable production of pharmacologically active compounds.

BiotechGeneticsBiochem

References

Main Study

1) Identification of the cytochrome P450s responsible for the biosynthesis of two types of aporphine alkaloids and their de novo biosynthesis in yeast.

Published 2nd July, 2024

https://doi.org/10.1111/jipb.13724

Related Studies

2) Molecular cloning and characterization of CYP80G2, a cytochrome P450 that catalyzes an intramolecular C-C phenol coupling of (S)-reticuline in magnoflorine biosynthesis, from cultured Coptis japonica cells.

https://doi.org/10.1074/jbc.M705082200

3) Characterization of two methylenedioxy bridge-forming cytochrome P450-dependent enzymes of alkaloid formation in the Mexican prickly poppy Argemone mexicana.

https://doi.org/10.1016/j.abb.2010.11.016

4) Engineering Saccharomyces cerevisiae to produce plant benzylisoquinoline alkaloids.

https://doi.org/10.1007/s42994-021-00055-0


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