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. 2023 Mar 8;145(9):4957-4963.
doi: 10.1021/jacs.2c13644. Epub 2023 Feb 22.

Directed Biosynthesis of Mitragynine Stereoisomers

Carsten Schotte  1 , Yindi Jiang  1 , Dagny Grzech  1 , Thu-Thuy T Dang  1 , Larissa C Laforest  2 , Francisco León  3 , Marco Mottinelli  3 , Satya Swathi Nadakuduti  2   4 , Christopher R McCurdy  3 , Sarah E O'Connor  1
Affiliations

Directed Biosynthesis of Mitragynine Stereoisomers

Carsten Schotte et al. J Am Chem Soc. .

Abstract

Mitragyna speciosa ("kratom") is used as a natural remedy for pain and management of opioid dependence. The pharmacological properties of kratom have been linked to a complex mixture of monoterpene indole alkaloids, most notably mitragynine. Here, we report the central biosynthetic steps responsible for the scaffold formation of mitragynine and related corynanthe-type alkaloids. We illuminate the mechanistic basis by which the key stereogenic center of this scaffold is formed. These discoveries were leveraged for the enzymatic production of mitragynine, the C-20 epimer speciogynine, and fluorinated analogues.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a, b) Representative kratom alkaloids. (c) TIC of kratom leaf and root extracts. * observed in EIC.
Scheme 1
Scheme 1. (a) Reduction of 4 by CpDCS and (b) Proposed Pathway Toward Major Kratom Alkaloids
Scheme 2
Scheme 2. (a) Expression Profiles of Identified Genes in Kratom; (b) Proposed Mechanism for the Formation of the Corynanthe-Type Skeleton; (c) EIC (m/z = 355) of Assays Featuring Combinations of 8, CrSGD, and MsDCS1/MsDCS2/CpDCS; (d) EIC (m/z = 369) of Assays Featuring Combinations of 8, CrSGD, MsEnolMT, and MsDCS1/MsDCS2/CpDCS; and (e) EIC (m/z 369) Corresponding to Transient Expression of CrSTR, CrSGD, MsDCS1/CpDCS, and MsEnolMT in Tobacco
Expression levels are represented as FPKM of the M. speciosa transcriptome.
Figure 2
Figure 2
(a, b) Structural model of MsDCS1 in complex with NADPH and dehydrogeissoschizine (15). (c) Key active site residues directing the stereoselectivity. (d) Sequence alignment between MsDCS1, MsDCS2, and CpDCS. (e, f) Levels of (20S)-5a and (20R)-5b in mutants of MsDCS1/CpDCS; displayed are EICs (m/z 369) corresponding to transient expression of CrSTR, CrSGD, and ADH mutants and MsEnolMT in Nicotiana benthamiana.
Scheme 3
Scheme 3. (a) N. benthamiana Infiltration Strategy; and (b, c) EICs of Methanolic Extracts from the Transient Expression of CrSTR, CrSGD, MsEnolMT, and Indicated ADH Enzymes with Different Tryptamine Analogues
See this image and copyright information in PMC

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