Thursday, September 08, 2011

What is a nice chloroplast like you doing in a parasite like that?

Cool new paper from Joe Derisi's lab: PLoS Biology: Chemical Rescue of Malaria Parasites Lacking an Apicoplast Defines Organelle Function in Blood-Stage Plasmodium falciparum. by Ellen Yeh and Joseph L. DeRisi. doi: 10.1371/journal.pbio.1001138

In it they use some experimental techniques to try and track down the elusive function of the apicoplast in Plasmodium falciparum, the causative agent of malaria.  The apicoplast is an organelle that is evolutionarily derived from chloroplasts (and thus derived originally from cyanobacteria).  Due to it's cyanobacterial origins many have thought that it might serve as a good target for drugs to try and kill Plasmodium species because in theory such drugs if specific should not have significant detrimental effects on hosts like humans due to our lack of known important cyanobacterial associates.

Here is their abstract:
Plasmodium spp parasites harbor an unusual plastid organelle called the apicoplast. Due to its prokaryotic origin and essential function, the apicoplast is a key target for development of new anti-malarials. Over 500 proteins are predicted to localize to this organelle and several prokaryotic biochemical pathways have been annotated, yet the essential role of the apicoplast during human infection remains a mystery. Previous work showed that treatment with fosmidomycin, an inhibitor of non-mevalonate isoprenoid precursor biosynthesis in the apicoplast, inhibits the growth of blood-stage P. falciparum. Herein, we demonstrate that fosmidomycin inhibition can be chemically rescued by supplementation with isopentenyl pyrophosphate (IPP), the pathway product. Surprisingly, IPP supplementation also completely reverses death following treatment with antibiotics that cause loss of the apicoplast. We show that antibiotic-treated parasites rescued with IPP over multiple cycles specifically lose their apicoplast genome and fail to process or localize organelle proteins, rendering them functionally apicoplast-minus. Despite the loss of this essential organelle, these apicoplast-minus auxotrophs can be grown indefinitely in asexual blood stage culture but are entirely dependent on exogenous IPP for survival. These findings indicate that isoprenoid precursor biosynthesis is the only essential function of the apicoplast during blood-stage growth. Moreover, apicoplast-minus P. falciparum strains will be a powerful tool for further investigation of apicoplast biology as well as drug and vaccine development.

The author summary is a bit nicer in my opinion:
Malaria caused by Plasmodium spp parasites is a profound human health problem that has shaped our evolutionary past and continues to influence modern day with a disease burden that disproportionately affects the world's poorest and youngest. New anti-malarials are desperately needed in the face of existing or emerging drug resistance to available therapies, while an effective vaccine remains elusive. A plastid organelle, the apicoplast, has been hailed as Plasmodium's “Achilles' heel” because it contains bacteria-derived pathways that have no counterpart in the human host and therefore may be ideal drug targets. However, more than a decade after its discovery, the essential functions of the apicoplast remain a mystery, and without a specific pathway or function to target, development of drugs against the apicoplast has been stymied. In this study, we use a simple chemical method to generate parasites that have lost their apicoplast, normally a deadly event, but which survive—“rescued” by the addition of an essential metabolite to the culture. This chemical rescue demonstrates that the apicoplast serves only a single essential function, namely isoprenoid precursor biosynthesis during blood-stage growth, validating this metabolic function as a viable drug target. Moreover, the apicoplast-minus Plasmodium strains generated in this study will be a powerful tool for identifying apicoplast-targeted drugs and as a potential vaccine strain with significant advantages over current vaccine technologies.
Also see their press release here.

Basically they are trying to use various experimental tricks to figure out which functions of the apicoplast are essential.  Many theories have been proposed over the years as to what the apicoplast is doing.  But few have gained significant evidence.  This paper is an important contribution because it suggests that one pathway in particular is most functionally important: the isopentenyl pyrophosphate (IPP) synthesis pathway.  See their model below:

Figure 5. Model of apicoplast function.
(Top) The essential function of the apicoplast is the production of isoprenoid precursors, IPP and DMAPP, which are exported into the cytoplasm and used to synthesize small molecule isoprenoids and prenylated proteins. Parasites that are unable to synthesize isoprenoid precursors either due to inhibition of the biosynthetic pathway by fosmidomycin or loss of the apicoplast following doxycycline inhibition can be chemically rescued by addition of exogenous IPP (red). The exogenous IPP enters the host cell through unknown membrane transporters and fulfills the missing biosynthetic function. (Bottom) Reaction scheme for MEP pathway biosynthesis of IPP and DMAPP with the enzymatic step inhibited by fosmidomycin indicated.

Anyway - I have always been fascinated by apicoplasts because they are so weird.  They reflect a strange evolutionary history of Apicomplexans in that this is a eukaryotic lineage that at some point brought into itself an entire photosynthetic algal cell as a symbiont.  And for reasons still unknown (if there are reasons ...) the chloroplast of the algal symbiont was retained while most of the rest of the symbiont was ditched.  So that the resulting cells looked something like this:


Evolution is indeed very weird.  And once it was discovered that the apicoplast was in fact derived from chloroplasts (this was discovered using molecular phylogenetics) (e.g., see people have been wondering if it might make a good drug target.  But people have also been wondering - what do Apicomplexans do with a chloroplast like organelle when they do not photosynthesize.  So the Derisi paper is interesting both from a drug treatment point of view but also from an evolution point of view.

Anyway - here are some other links worth looking at:

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