Biosynthesis of kratom opioids

Mitragynine, an analgesic alkaloid from the kratom plant, has a more favorable side effect profile than clinical opioids like morphine. The biosynthetic pathway for mitragynine was previously unknown. Researchers identified several reductases and an enol methyltransferase forming a new clade within the SABATH methyltransferase family from kratom and related Rubiaceae transcriptomes. They also discovered a methyltransferase from Hamelia patens that catalyzes the final step. Using a tryptamine 4-hydroxylase from Psilocybe cubensis, they achieved four-step biosynthesis of mitragynine and its stereoisomer speciogynine in yeast and E. coli supplied with tryptamine and secologanin. This marks the first microbial biosynthesis of kratom opioids. The enzyme promiscuity suggests potential for generating derivatives and analogs.

Study at a glance

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.