How does it catalyze iridoid cyclization? Well, we don’t know its catalytic mechanism in detail yet, that will be the subject of future research. We do know it retains general esterase activity but based on mutagenesis studies this esterase activity is not essential for cyclization (unsurprising).

ICYC turned out to be a member of the methylesterase enzyme family which is interesting and was surprising to us. And it actually was already noticed once as associated with monoterpenoid indole alkaloid biosynthesis 20 years ago but a function could not be assigned:

So, why and how did we finally find it now? Quite simply we had the right combination of datasets (including snRNA-seq) in hand for co-expression analyses and were lucky in that the pathway is very neatly co-expressed. The result was an extremely short candidate list.

Iridoid cyclase had been a highly sought-after enzyme and @oconnorlab.bsky.social members (and perhaps other labs?) had searched for this enzyme on and off for nearly a decade. Turns out it was hiding in plain sight to another iridoid pathway enzyme in a highly conserved mini gene cluster.

Iridoids are widespread cyclic monoterpenes associated with plant defense and essential precursors for the lab’s favorite monoterpenoid indole and ipecac alkaloids. They are ancestral to asterids but have been lost and re-invented at least once (check out @lichmanlab.bsky.social past work on catnip)

#terpnet2025 is starting today

My first time at terpnet and first time in Australia!
So glad to have been invited to this.

Also, ICYC has all the hallmarks of an esterase (i.e. the catalytic triad) and residual esterase activity. In the future we aim to unravel how this enzyme functions at the mechanistic level.

ICYC is stereo-selective and generates the two most abundant stereoisomers found in nature.

ICYC orthologs are found throughout iridoid-producing asterid species and interestingly cluster with one other iridoid pathway enzyme (G8H) on the genome but none of the other iridoid pathway genes clusters.

Many different enzyme families could have evolved to perform iridoid cyclisation so functional annotations are not so helpful in this case. By combining single cell and bulk tissue RNA-seq co-expression data from Ipecac we achieved an extremely short candidate list of four uncharacterized genes.

Our most relaxed co-worker at his new favourite hangout spot

Carapichea ipecacuanha and Alangium salviifolium both independently invented ipecac alkaloid biosynthesis. Some might remember Ipecac syrup that used to be a medicine in case of intoxication.

Carapichea ipecacuanha and Alangium salviifolium both independently invented ipecac alkaloid biosynthesis. Some might remember Ipecac syrup that used to be a medicine in case of intoxications.

Tiger, the “institute cat”, demanding the doors to open. Can’t wait to get in and offer emotional support to stressed scientists! Open now!