delighted that our latest paper is accepted and online for your viewing pleasure at:
https://elifesciences.org/articles/56376 

So what's in it?

(1/several)

parasitic worms (Ascaris, hookworm etc) infect >1BILLION people.

To survive in the host they must switch to anaerobic metabolism but do this in a very unusual way. This requires rhodoquinone (RQ) as an electron carrier (2/n)

RQ is very similar to ubiquinone (UQ) but is NOT found in any host, only in the parasites. If we could block RQ synthesis or use, we would thus be able to kill the parasite while leaving host alone.

Key question in this paper is how the worms switch from making UQ to RQ (3/n)

we previously showed that RQ and UQ synthesis both require the polyprenyltransferase COQ-2.

If it uses 3HA as a substrate it makes RQ
If it uses 4HB (or similar) it makes UQ

So how does COQ-2 decide which substrate to use and how does it switch substrate preference? (4/n)

Unexpectedly (to us), we find that all animals that make RQ have a pair of mutually exclusive exons in COQ-2. This gene structure is unique to animals that make RQ – other animals only have one exon.

Switching between these exons changes the catalytic core of COQ-2. (5/n)

thanks to the magic of CRISPR engineering we (along with collabs @NivenShepherd and Gustavo Salinas) showed that the exon that is unique to RQ-synthesising animals is required for RQ synthesis and for survival in conditions where RQ is required. (6/n)

Crucially, we also found (collab with Dick Davies and Jianbing Wang) that when parasites migrate from aerobic conditions outside host to the anaerobic conditions inside host, they switch the splicing of COQ-2 from the standard animal form to the RQ-specific form. (7/n)

So the final model that emerges is that the switch in quinone synthesis from making UQ in aerobic conditions to RQ in anaerobic conditions is driven by a switch between 2 mutually exclusive exons that changes the catalytic core of COQ-2. (8/n)

For drug development, beautiful thing is that the RQ-specific COQ-2 isoform has two 100% conserved residues across all RQ-synthesising animals that differ to host COQ-2. It should therefore be possible to make parasite-specific COQ-2 inhibitors that block RQ synth. (9/n)

Final note:
this was a great collaboration that came about from openness and early data sharing, helped by attending the fabulous Hydra Helminth meeting.
Lesson 1: collab >>> compete
Lesson 2: meetings are critical. This would not have happened over zoom!

thx for reading! (end)