Available online at www.sciencedirect.com
Why transport matters: an update on carrier proteins in
Apicomplexan parasites
Silvia Haase and Adam Sateriale ]]
]]]]]]
]]
The movement of molecules across the membranous barriers of Understanding the biology of these fascinating parasites and
a cell is fundamental to cellular homeostasis in every living the ways in which they interact with their respective host
organism. This vital process is facilitated through a cell is of paramount importance to discover novel drug tar
mechanistically diverse class of proteins, collectively known as gets and inform existing therapeutic interventions.
membrane transporters. Among these are so-called carrier
proteins that can function in passive and active transport Within the host cell, most Apicomplexa reside and develop
mechanisms. They exhibit high substrate specificity and undergo within a parasitophorous vacuole (PV; detailed reviews
conformational changes to transfer a specific solute across the about the origin and function can be found in Refs. [1–3]).
membrane, thereby facilitating diffusion or actively transporting a This peculiar niche presents challenges to the pathogen,
molecule under energy expenditure or against an established which must acquire nutrients from its host and dispose of
electrochemical gradient. Apicomplexan parasites invest up to toxic waste to secure its survival. While the mechanisms of
5% of their genome to encode for membrane transporters; waste removal are less well understood, Plasmodium spp. and
however, only a few have been fully characterised, and their Toxoplasma parasites established remarkable strategies to
specific mechanisms remain largely unknown. Recent advances obtain nutrients from their different host cellular environ
in structural biology and the application of state-of-the-art ments. This includes (but is not limited to) the essential PV
genomic editing tools have greatly accelerated investigations membrane component EXP2 of the ‘Plasmodium Trans
into the intricate mechanisms of Apicomplexan carrier proteins. locon of EXported proteins’ (PTEX) in malaria parasites
Understanding the molecular ‘ins and outs’ of membrane that appears to have a second function as a nutrient-
transporters is fundamental to inform the rational design of permeable channel [4]. The orthologous solute-conducting
inhibitors, as well as to overcome antimicrobial resistance. pore in Toxoplasma that is formed by dense granule proteins
GRA17, GRA23 and accessory proteins is equally crucial to
Address parasite growth and virulence [5–7]. While host cell–derived
Cryptosporidiosis Laboratory, The Francis Crick Institute, London, organelles and vesicles are recruited to the PVM (para
United Kingdom
sitophorous vacuole membrane) of Toxoplasma-infected cells
Corresponding author: Sateriale, Adam (). to mediate the uptake of host nutrients (reviewed in
Ref. [8]), no PVM-resident transporters have been identified
so far. Malaria parasites also hijack host aquaporin 3 (AQP3)
Current Opinion in Microbiology 2025, 88:102663 that localises to the PVM and tubulovesicular network
This review comes from a themed issue on Host-Microbe (TVN, membrane extensions of the PV that increase the
Interactions: Parasites surface area and are hypothesised to aid in nutrient uptake)
Edited by Keith Matthews and Matthias Marti of liver stage schizonts and hypnozoites in P. vivax and is
proposed to mediate solute transport critical to parasite de
velopment [9–11].
Available online xxxx Apicomplexan parasites also contain many other specialised,
https://doi.org/10.1016/j.mib.2025.102663 membrane-bound organelles (Figure 1). The apicoplast (a
1369–5274/© 2025 The Authors. Published by Elsevier Ltd. This is an relict, nonphotosynthetic plastid of prokaryotic origin) har
open access article under the CC BY license (http:// bours important metabolic pathways and housekeeping
creativecommons.org/licenses/by/4.0/). processes that differ from the host (reviewed in Ref. [12]).
The digestive vacuole (DV) of malaria parasites is the
dedicated hub for haemoglobin digestion and haem detox
Introduction ification, and a highly dynamic plant-like vacuolar com
Apicomplexan parasites are the causative agents of a variety partment (PLVAC) is central to the cellular homeostasis and
of diseases in humans and livestock, and many of these metabolism of Toxoplasma gondii that has adapted to dif
obligate intracellular pathogens, including Plasmodium spp., ferent host and cellular environments (reviewed in
Toxoplasma gondii and Cryptosporidium spp., impose major Refs. [13,14]). The intestinal pathogen Cryptosporidium spp.,
public health and socio-economic burdens on affected po however, has lost the apicoplast and a functional mi
pulations worldwide. Several antiparasitic treatments are tochondrium, and developed the feeder organelle, an ela
hitting bottlenecks due to low efficacy, the emergence of borate membranous system [15] that is believed to increase
drug resistance and a changing global environment. the surface area and mediate the uptake of nutrients.
www.sciencedirect.com Current Opinion in Microbiology 2025, 88:102663
, 2 Host–Microbe Interactions: Parasites
Figure 1
Current Opinion in Microbiology
Graphical summary of the carrier proteins highlighted in this review. Apicomplexan parasites infect different host cells and develop within a
parasitophorous vacuole, shown in dark grey. From left to right: Plasmodium spp. predominantly infect red blood cells during their asexual stages,
while Toxoplasma can infect a wide range of nucleated host cells, and Cryptosporidium spp. spend their entire lifecycle within gastrointestinal
epithelial cells. Please note that the transporter PbgABCG2 localises to the plasma membrane (PM) of female gametocytes in the rodent malaria
parasite P. berghei. Carrier proteins have been colour-coded based on substrate class: Sugar (red), lipids (orange), amino acids (grey), nucleotides
(blue), lactate (green), and unknown (black).
Taken together, this implies that a diverse range of [22]. Qureshi et al. demonstrate PfHT1-mediated up
nutrients with different properties need to traverse dis take of various sugars and present a comprehensive
tinct membranous compartments to reach their destina ‘rocker-switch’ model in which the N- and C-terminal
tion. Membrane transporters provide the logistical TM domains undergo conformational changes around a
means by which solutes can cross the biological mem central, positionally conserved sugar-binding pocket,
branes in a cell. Many of these highly specialised pro though mutations of the sugar-binding residues do not
teins are pivotal to parasite survival, making them both alter sugar preference. The rearrangements of the TM
attractive targets for drug development while also domains, however, are coupled with a gating mechanism
playing a crucial role in mediating drug resistance. that enables the promiscuous uptake of different sub
Comprehensive lists of all known transport proteins in strates [20]. The authors also identify a separate vesti
Plasmodium spp. can be found in excellent reviews by bule that appears to contribute towards the binding of
Wunderlich [16] and Martin [17]. In this review, we aim the antimalarial compound MMV009085 to PfHT1.
to summarise the major findings of the last five years and These observations are corroborated by Jiang et al., who
specifically focus on the roles of carrier proteins and their characterise the inhibitory mechanism of the small glu
mechanisms of primary metabolite transport in the cau cose derivative C3361 in great depth. The compound
sative agents of malaria, toxoplasmosis, and cryptospor induces dramatic structural rearrangements and the for
idiosis. mation of a unique allosteric pocket that enabled further
optimisation of C3361, displaying increased potency and
Sugar selectivity [21]. The binding properties towards glucose
Most apicomplexan parasites rely on the continuous and C3361 in the orthologous transporter of P. vivax
uptake of glucose to meet their metabolic needs. Malaria (PvHT1) appear to be similar to those of PfHT1, sup
parasites depend on the uptake of sugar from the host porting its exploration as an antimalarial drug target in
erythrocyte, which is mediated by glucose transporters the most widespread cause of malaria [23].
that belong to the major facilitator superfamily (MFS,
reviewed in Refs. [18,19]). Two groups have recently Cryptosporidium spp. parasites lack the tricarboxylic acid
solved the structure of the essential and plasma mem cycle or alternative pathways for gluconeogenesis. Two
brane (PM)-resident Hexose Transporter in the human putative glucose transporters, CpGT1 and CpGT2, are
pathogen P. falciparum (PfHT1) [20,21]. PfHT1 has shown to salvage glucose-6-phosphate by com
a unique feature that has been exploited to simulta plementation of a mutant E. coli strain that lacks its own
neously target the ortho- and allosteric sites of the sugar transporter. Both transporters localise to the feeder
transporter with a novel series of competitive inhibitors organelle of C. parvum but are dispensable for parasite
Current Opinion in Microbiology 2025, 88:102663 www.sciencedirect.com
Why transport matters: an update on carrier proteins in
Apicomplexan parasites
Silvia Haase and Adam Sateriale ]]
]]]]]]
]]
The movement of molecules across the membranous barriers of Understanding the biology of these fascinating parasites and
a cell is fundamental to cellular homeostasis in every living the ways in which they interact with their respective host
organism. This vital process is facilitated through a cell is of paramount importance to discover novel drug tar
mechanistically diverse class of proteins, collectively known as gets and inform existing therapeutic interventions.
membrane transporters. Among these are so-called carrier
proteins that can function in passive and active transport Within the host cell, most Apicomplexa reside and develop
mechanisms. They exhibit high substrate specificity and undergo within a parasitophorous vacuole (PV; detailed reviews
conformational changes to transfer a specific solute across the about the origin and function can be found in Refs. [1–3]).
membrane, thereby facilitating diffusion or actively transporting a This peculiar niche presents challenges to the pathogen,
molecule under energy expenditure or against an established which must acquire nutrients from its host and dispose of
electrochemical gradient. Apicomplexan parasites invest up to toxic waste to secure its survival. While the mechanisms of
5% of their genome to encode for membrane transporters; waste removal are less well understood, Plasmodium spp. and
however, only a few have been fully characterised, and their Toxoplasma parasites established remarkable strategies to
specific mechanisms remain largely unknown. Recent advances obtain nutrients from their different host cellular environ
in structural biology and the application of state-of-the-art ments. This includes (but is not limited to) the essential PV
genomic editing tools have greatly accelerated investigations membrane component EXP2 of the ‘Plasmodium Trans
into the intricate mechanisms of Apicomplexan carrier proteins. locon of EXported proteins’ (PTEX) in malaria parasites
Understanding the molecular ‘ins and outs’ of membrane that appears to have a second function as a nutrient-
transporters is fundamental to inform the rational design of permeable channel [4]. The orthologous solute-conducting
inhibitors, as well as to overcome antimicrobial resistance. pore in Toxoplasma that is formed by dense granule proteins
GRA17, GRA23 and accessory proteins is equally crucial to
Address parasite growth and virulence [5–7]. While host cell–derived
Cryptosporidiosis Laboratory, The Francis Crick Institute, London, organelles and vesicles are recruited to the PVM (para
United Kingdom
sitophorous vacuole membrane) of Toxoplasma-infected cells
Corresponding author: Sateriale, Adam (). to mediate the uptake of host nutrients (reviewed in
Ref. [8]), no PVM-resident transporters have been identified
so far. Malaria parasites also hijack host aquaporin 3 (AQP3)
Current Opinion in Microbiology 2025, 88:102663 that localises to the PVM and tubulovesicular network
This review comes from a themed issue on Host-Microbe (TVN, membrane extensions of the PV that increase the
Interactions: Parasites surface area and are hypothesised to aid in nutrient uptake)
Edited by Keith Matthews and Matthias Marti of liver stage schizonts and hypnozoites in P. vivax and is
proposed to mediate solute transport critical to parasite de
velopment [9–11].
Available online xxxx Apicomplexan parasites also contain many other specialised,
https://doi.org/10.1016/j.mib.2025.102663 membrane-bound organelles (Figure 1). The apicoplast (a
1369–5274/© 2025 The Authors. Published by Elsevier Ltd. This is an relict, nonphotosynthetic plastid of prokaryotic origin) har
open access article under the CC BY license (http:// bours important metabolic pathways and housekeeping
creativecommons.org/licenses/by/4.0/). processes that differ from the host (reviewed in Ref. [12]).
The digestive vacuole (DV) of malaria parasites is the
dedicated hub for haemoglobin digestion and haem detox
Introduction ification, and a highly dynamic plant-like vacuolar com
Apicomplexan parasites are the causative agents of a variety partment (PLVAC) is central to the cellular homeostasis and
of diseases in humans and livestock, and many of these metabolism of Toxoplasma gondii that has adapted to dif
obligate intracellular pathogens, including Plasmodium spp., ferent host and cellular environments (reviewed in
Toxoplasma gondii and Cryptosporidium spp., impose major Refs. [13,14]). The intestinal pathogen Cryptosporidium spp.,
public health and socio-economic burdens on affected po however, has lost the apicoplast and a functional mi
pulations worldwide. Several antiparasitic treatments are tochondrium, and developed the feeder organelle, an ela
hitting bottlenecks due to low efficacy, the emergence of borate membranous system [15] that is believed to increase
drug resistance and a changing global environment. the surface area and mediate the uptake of nutrients.
www.sciencedirect.com Current Opinion in Microbiology 2025, 88:102663
, 2 Host–Microbe Interactions: Parasites
Figure 1
Current Opinion in Microbiology
Graphical summary of the carrier proteins highlighted in this review. Apicomplexan parasites infect different host cells and develop within a
parasitophorous vacuole, shown in dark grey. From left to right: Plasmodium spp. predominantly infect red blood cells during their asexual stages,
while Toxoplasma can infect a wide range of nucleated host cells, and Cryptosporidium spp. spend their entire lifecycle within gastrointestinal
epithelial cells. Please note that the transporter PbgABCG2 localises to the plasma membrane (PM) of female gametocytes in the rodent malaria
parasite P. berghei. Carrier proteins have been colour-coded based on substrate class: Sugar (red), lipids (orange), amino acids (grey), nucleotides
(blue), lactate (green), and unknown (black).
Taken together, this implies that a diverse range of [22]. Qureshi et al. demonstrate PfHT1-mediated up
nutrients with different properties need to traverse dis take of various sugars and present a comprehensive
tinct membranous compartments to reach their destina ‘rocker-switch’ model in which the N- and C-terminal
tion. Membrane transporters provide the logistical TM domains undergo conformational changes around a
means by which solutes can cross the biological mem central, positionally conserved sugar-binding pocket,
branes in a cell. Many of these highly specialised pro though mutations of the sugar-binding residues do not
teins are pivotal to parasite survival, making them both alter sugar preference. The rearrangements of the TM
attractive targets for drug development while also domains, however, are coupled with a gating mechanism
playing a crucial role in mediating drug resistance. that enables the promiscuous uptake of different sub
Comprehensive lists of all known transport proteins in strates [20]. The authors also identify a separate vesti
Plasmodium spp. can be found in excellent reviews by bule that appears to contribute towards the binding of
Wunderlich [16] and Martin [17]. In this review, we aim the antimalarial compound MMV009085 to PfHT1.
to summarise the major findings of the last five years and These observations are corroborated by Jiang et al., who
specifically focus on the roles of carrier proteins and their characterise the inhibitory mechanism of the small glu
mechanisms of primary metabolite transport in the cau cose derivative C3361 in great depth. The compound
sative agents of malaria, toxoplasmosis, and cryptospor induces dramatic structural rearrangements and the for
idiosis. mation of a unique allosteric pocket that enabled further
optimisation of C3361, displaying increased potency and
Sugar selectivity [21]. The binding properties towards glucose
Most apicomplexan parasites rely on the continuous and C3361 in the orthologous transporter of P. vivax
uptake of glucose to meet their metabolic needs. Malaria (PvHT1) appear to be similar to those of PfHT1, sup
parasites depend on the uptake of sugar from the host porting its exploration as an antimalarial drug target in
erythrocyte, which is mediated by glucose transporters the most widespread cause of malaria [23].
that belong to the major facilitator superfamily (MFS,
reviewed in Refs. [18,19]). Two groups have recently Cryptosporidium spp. parasites lack the tricarboxylic acid
solved the structure of the essential and plasma mem cycle or alternative pathways for gluconeogenesis. Two
brane (PM)-resident Hexose Transporter in the human putative glucose transporters, CpGT1 and CpGT2, are
pathogen P. falciparum (PfHT1) [20,21]. PfHT1 has shown to salvage glucose-6-phosphate by com
a unique feature that has been exploited to simulta plementation of a mutant E. coli strain that lacks its own
neously target the ortho- and allosteric sites of the sugar transporter. Both transporters localise to the feeder
transporter with a novel series of competitive inhibitors organelle of C. parvum but are dispensable for parasite
Current Opinion in Microbiology 2025, 88:102663 www.sciencedirect.com
