Biosynthesis of kratom opioids

Author:

Kim Kyunghee1,Shahsavarani Mohammadamin2ORCID,Garza‐García Jorge Jonathan Oswaldo2,Carlisle Jack Edward2,Guo Jun2,De Luca Vincenzo1ORCID,Qu Yang2ORCID

Affiliation:

1. Department of Biological Sciences Brock University St. Catharines ON L2S 3A1 Canada

2. Department of Chemistry University of New Brunswick Fredericton NB E3B 5A3 Canada

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.

Funder

Natural Sciences and Engineering Research Council of Canada

New Brunswick Innovation Foundation

Publisher

Wiley

Subject

Plant Science,Physiology

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