“…The broad substrate spectrum of many P450s can complicate biosynthesis studies and metabolic engineering efforts ( Hidalgo et al, 2017 ; De La Peña and Sattely, 2021 ). Nevertheless, such promiscuity sheds light into the evolution of these enzymes, and indicates their crucial role as part of the catalytic reservoirs whose members can be recruited for emerging pathways and further drive the chemical diversity of plants ( Tawfik, 2010 ; Ikezawa et al, 2011 ; Weng et al, 2012 ; Guo et al, 2016 ; Dang et al, 2017 , 2018 ; Forman et al, 2018 ; Christ et al, 2019 ; Nguyen et al, 2019 ; Lichman et al, 2020 ; Nguyen and O’Connor, 2020 ). Even for non-native or new-to-nature substrates including halogenated analogues, P450s display a certain degree of natural tolerance as observed in the multiple-step biotransformation of 7-chlorotryptamine to 12-chloro-19,20-dihydroakuammicine in MIA metabolism of C. roseus cultures ( Glenn et al, 2011 ).…”