Biosynthesis of kratom opioids
Kyunghee Kim, Mohammadamin Shahsavarani, Jorge Jonathan Oswaldo Garza-García, Jack Edward Carlisle, Jun Guo, Vincenzo de Luca, Yang Qu
New Phytologist July 30, 2023 DOI: 10.1111/nph.19162 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Keywords | Mitragyna speciosa Enol methyltransferase Mitragynine microbial biosynthesis Monoterpenoid indole alkaloid Opioid Synthetic biology Synthetic-biology Pain-medication Kratom-compounds Pharmaceutical-research |
| Citations | 43 |
| Key findings | The first microbial biosynthesis of mitragynine and speciogynine was achieved in yeast and E. coli using identified enzymes from kratom, firebush, and a psychedelic mushroom. |
Abstract
Summary Mitragynine, an analgesic alkaloid from the plant Mitragyna speciosa (kratom), offers a safer alternative to clinical opioids such as morphine, owing to its more favorable side effect profile. Although kratom has been traditionally used for stimulation and pain management in Southeast Asia, the mitragynine biosynthesis pathway has remained elusive. We embarked on a search for mitragynine biosynthetic genes from the transcriptomes of kratom and other members of the Rubiaceae family. We studied their functions in vitro and in vivo . Our investigations led to the identification of several reductases and an enol methyltransferase that forms a new clade within the SABATH methyltransferase family. Furthermore, we discovered a methyltransferase from Hamelia patens (firebush), which catalyzes the final step. With the tryptamine 4‐hydroxylase from the psychedelic mushroom Psilocybe cubensis , we accomplished the four‐step biosynthesis for mitragynine and its stereoisomer, speciogynine in both yeast and Escherichia coli when supplied with tryptamine and secologanin. Although we have yet to pinpoint the authentic hydroxylase and methyltransferase in kratom, our discovery completes the mitragynine biosynthesis. Through these breakthroughs, we achieved the microbial biosynthesis of kratom opioids for the first time. The remarkable enzyme promiscuity suggests the possibility of generating derivatives and analogs of kratom opioids in heterologous systems.