TY - JOUR
T1 - Ancient gene clusters govern the initiation of monoterpenoid indole alkaloid biosynthesis and C3 stereochemistry inversion
AU - Hwang, Jaewook
AU - Kirshner, Jonathan
AU - Deschênes, Daniel André Ramey
AU - Richardson, Matthew Bailey
AU - Fleck, Steven J.
AU - Mann, Scott Galeung Alexander
AU - Guo, Jun
AU - Perley, Jacob Owen
AU - Shahsavarani, Mohammadamin
AU - Garza-Garcia, Jorge Jonathan Oswaldo
AU - Seveck, Alyssa Dawn
AU - Doiron, Savannah Sadie
AU - Mai, Zhan
AU - Silliphant, Stephen Nelson
AU - Englehart, Sarah Anne
AU - Blight, Barry A.
AU - Calhoun, Larry
AU - Gao, Di
AU - Lian, Jiazhang
AU - Deslongchamps, Ghislain
AU - Albert, Victor A.
AU - Qu, Yang
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - The inversion of C3 stereochemistry in monoterpenoid indole alkaloids (MIAs), derived from the central precursor strictosidine (3S), is essential for producing pharmacologically important 3 R MIAs and spirooxindoles such as reserpine. While early MIA biosynthesis preserves the 3S configuration, the mechanism underlying C3 inversion has remained unresolved. Here, we identify and biochemically characterize a conserved oxidase-reductase pair in Gentianales: heteroyohimbine/yohimbine/corynanthe C3-oxidase (HYC3O) and C3-reductase (HYC3R), which together invert the 3S stereochemistry to 3 R across diverse substrates. HYC3O and HYC3R are encoded within biosynthetic gene clusters in Rauvolfia tetraphylla and Catharanthus roseus, homologous to a geissoschizine synthase (GS) cluster also uncovered. Comparative genomics indicate that the GS cluster originated at the base of Gentianales (~135 Mya), coinciding with the evolution of the strictosidine synthase cluster, whereas the reserpine cluster arose later. These findings uncover the genomic and biochemical basis of key events driving MIA diversification beyond canonical vinblastine and ajmaline pathways.
AB - The inversion of C3 stereochemistry in monoterpenoid indole alkaloids (MIAs), derived from the central precursor strictosidine (3S), is essential for producing pharmacologically important 3 R MIAs and spirooxindoles such as reserpine. While early MIA biosynthesis preserves the 3S configuration, the mechanism underlying C3 inversion has remained unresolved. Here, we identify and biochemically characterize a conserved oxidase-reductase pair in Gentianales: heteroyohimbine/yohimbine/corynanthe C3-oxidase (HYC3O) and C3-reductase (HYC3R), which together invert the 3S stereochemistry to 3 R across diverse substrates. HYC3O and HYC3R are encoded within biosynthetic gene clusters in Rauvolfia tetraphylla and Catharanthus roseus, homologous to a geissoschizine synthase (GS) cluster also uncovered. Comparative genomics indicate that the GS cluster originated at the base of Gentianales (~135 Mya), coinciding with the evolution of the strictosidine synthase cluster, whereas the reserpine cluster arose later. These findings uncover the genomic and biochemical basis of key events driving MIA diversification beyond canonical vinblastine and ajmaline pathways.
UR - https://www.scopus.com/pages/publications/105022886110
U2 - 10.1038/s41467-025-65543-z
DO - 10.1038/s41467-025-65543-z
M3 - Article
C2 - 41290611
AN - SCOPUS:105022886110
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 10495
ER -