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. 2022 Jun 24;12:926541. doi: 10.3389/fcimb.2022.926541

Updated List of Transport Proteins in Plasmodium falciparum

Juliane Wunderlich 1,2,3,*
PMCID: PMC9263188  PMID: 35811673

Abstract

Malaria remains a leading cause of death and disease in many tropical and subtropical regions of the world. Due to the alarming spread of resistance to almost all available antimalarial drugs, novel therapeutic strategies are urgently needed. As the intracellular human malaria parasite Plasmodium falciparum depends entirely on the host to meet its nutrient requirements and the majority of its transmembrane transporters are essential and lack human orthologs, these have often been suggested as potential targets of novel antimalarial drugs. However, membrane proteins are less amenable to proteomic tools compared to soluble parasite proteins, and have thus not been characterised as well. While it had been proposed that P. falciparum had a lower number of transporters (2.5% of its predicted proteome) in comparison to most reference genomes, manual curation of information from various sources led to the identification of 197 known and putative transporter genes, representing almost 4% of all parasite genes, a proportion that is comparable to well-studied metazoan species. This transporter list presented here was compiled by collating data from several databases along with extensive literature searches, and includes parasite-encoded membrane-resident/associated channels, carriers, and pumps that are located within the parasite or exported to the host cell. It provides updated information on the substrates, subcellular localisation, class, predicted essentiality, and the presence or absence of human orthologs of P. falciparum transporters to quickly identify essential proteins without human orthologs for further functional characterisation and potential exploitation as novel drug targets.

Keywords: Plasmodium falciparum, malaria, drug target, transport pathway, transporters and channels, systems biology, calcium homeostasis, nutrient uptake

Introduction

To sustain rapid growth within human red blood cells, Plasmodium falciparum requires sufficient nutrients and electrolytes for its active metabolism. Therefore, the parasite expresses a wide range of transport proteins to acquire substrates and efflux metabolites. As the majority of these carriers, channels, and pumps are predicted to be essential during intraerythrocytic stages (Martin, 2020) and have no identified human orthologs, these could be exploited as targets of novel drugs (Ludin et al., 2012). Due to the emergence of parasite resistance to most available antimalarials, new therapeutic strategies are urgently needed (Plowe, 2022). There are many reports on transporters associated with drug resistance (Cowell and Winzeler, 2019; Martin, 2020; Murithi et al., 2021; Shafik et al., 2022), and advances in the development of drugs that target solute transporters were recently reviewed (Belete, 2020; Monteiro Júnior et al., 2022). Here, an extended list of P. falciparum transport proteins is presented with many new additions and updated information on transporter localisation and essentiality based on experimental evidence and orthology inference.

The last two transporter lists were published in 2020 and 2016 and contained 117 (Martin, 2020) and 139 (Weiner and Kooij, 2016) proteins, corresponding to 2.2% and 2.6% of the predicted P. falciparum proteome, respectively. The localisation within the parasite-infected host cell was not indicated for all of these, as microscopic examination after endogenous tagging with fluorescent proteins or staining using specific antibodies was not conducted for all transporters. However, precise knowledge of the location of a transport protein and its orientation in the membrane is paramount for understanding its function and the dynamics of solute transport processes between cellular compartments. Therefore, the list presented here contains new information on subcellular localisation and function based on results from recent microscopy experiments (Edaye and Georges, 2015; Haase et al., 2021; Murithi et al., 2021; Wichers et al., 2021; Ahiya et al., 2022; Wichers et al., 2022), solubility assays, immunoprecipitation, proximity-dependent biotinylation or subcellular fractionation followed by immunoblot or proteomic analyses (Boucher et al., 2018; Balestra et al., 2021; Bullen et al., 2022), functional and structural studies (Shafik et al., 2020; Beck and Ho, 2021), the presence of targeting signals (Sayers et al., 2018; van Esveld et al., 2021), and Gene Ontology (GO) annotations (Blake et al., 2015). In addition, data on essentiality of P. falciparum genes are usually based on a large piggyBac screen (Zhang et al., 2018) that is known to contain some false-positive and false-negative results (Martin, 2020), highlighting the need for verification by other studies. Thus, results from the latest publications (Jiang et al., 2020; Swift et al., 2020; Oberstaller et al., 2021; Wichers et al., 2022) were included in the list along with information on the presence or absence of human orthologs, as this is important for therapeutic development and was not systematically specified previously. Of note, this mini review focuses mainly on asexual blood-stage parasites and also contains recent data on other stages, as transporters are likely important throughout the life cycle.

Plasmodium gene annotations are still incomplete with a large proportion of genes completely lacking characterisation of their function and localisation or only having sparse functional annotation deduced by orthology (Böhme et al., 2019). The lower number of genes representing the malaria transportome reported in earlier studies may be due to the lack of conventional transmembrane domains in some P. falciparum transporters (Desai, 2012) and difficult analysis by mass spectrometry. The reduced number of detected peptides (Lu et al., 2021) stems both from the typically low protein amounts extracted from parasite culture that are subjected to subcellular fractionation or immunoprecipitation and from the fact that membrane proteins such as transporters are less amenable to proteomics compared to soluble proteins. This has resulted in the conclusion that P. falciparum may have a reduced set of transporters compared to metazoan reference genomes (Weiner and Kooij, 2016; Martin, 2020).

Here, additional putative transporters were detected by compiling data from several databases (Aurrecoechea et al., 2009; Blake et al., 2015; Saier et al., 2016; Elbourne et al., 2017) and the literature. This mini review also covers newly identified putative calcium transporters (Balestra et al., 2021; Gupta et al., 2022), as calcium homeostasis is thought to be critical for all parasite stages (Brochet and Billker, 2016) and likely a promising drug target (Gupta et al., 2022). However, the molecular identity of most of the transporters involved in calcium transport has remained unclear (Lourido and Moreno, 2015), with contrasting results and conclusions regarding their substrates and subcellular localisation as well as the cellular compartment used for calcium storage (Brochet and Billker, 2016). The manually curated list of 197 transporter genes presented here represents almost 4% of 5720 P. falciparum 3D7 genes, of which 5318 are protein-coding (Aurrecoechea et al., 2009), a proportion that is comparable to the 3 – 5% reported for well-studied metazoan species (Elbourne et al., 2017). It includes the most recent published data and provides an updated overview on the substrates, localisation, function, classification, essentiality, and human orthologs of P. falciparum transporters and may serve as a basis for improved annotations of transporter genes and further functional characterisation of potential drug targets.

Approaches for Transport Protein Identification and Compilation of a Comprehensive List

Whole-genome sequencing, genome-wide searches and comparative genomics enabled the detection and fast annotation of many P. falciparum transporter genes by assigning functions that are computationally inferred from orthology across hundreds of species, facilitating functional characterisation at a large scale. However, molecular pathways and mechanisms that occur in parasites can differ tremendously from model organisms (Woo et al., 2015), and some known Plasmodium transporters are genus-specific and/or lack conventional transmembrane domains (Desai, 2012). Thus, function predictions based on the presence of protein features and on orthology inference harbour the possibility of incomplete or incorrect annotations. For example, PF3D7_1368200 was annotated as “ABC transporter E family member 1, putative (ABCE1)” due to its ATP-binding cassette that similar to that of ABC transporters (Koenderink et al., 2010). However, it is unlikely to be a transporter because of its function in RNA processing (Mather et al., 2007; Sinha et al., 2021), demonstrating the need for manual curation of GO terms and gene annotations.

The existing transporter list published in 2020 (Martin, 2020) was extended by collating data from various sources. Therefore, a table of 123 transport proteins from the P. falciparum strain 3D7 (genome version 3.0) with information on substrates, transporter classes and families was downloaded from http://www.membranetransport.org/transportDB2/index.html (Elbourne et al., 2017). Additional transporters associated with the GO term “transmembrane transporter activity” (GO:0022857) (Blake et al., 2015), mentioned on Malaria Parasite Metabolic Pathways (https://mpmp.huji.ac.il/maps/transporters.html) (Ginsburg and Tilley, 2011) or in research articles were included. For example, PfTMCO1 (transmembrane and coiled-coil domain-containing protein, PF3D7_1362300), identified based on orthology to proteins in other protozoan parasites (Gupta et al., 2022), was added. In contrast, glideosome-associated protein 40 (PfGAP40, PF3D7_0515700) and rhoptry protein PfROP14 (PF3D7_0613300) were removed, as new data on their function and localisation suggest that these are not transporters (Anantharaman et al., 2007; Zuccala et al., 2012; Ferreira et al., 2020).

As different names were sometimes used for the same protein (Weiner and Kooij, 2016; Staines et al., 2017; Martin, 2020), all alternative names found in the literature are mentioned in the table for clarification ( Table 1 ). Transporter localisation, substrates and functions are indicated as in Martin, (2020) and predicted gene essentiality according to Zhang et al. (2018), unless stated otherwise. Transporter classes were assigned according to the Transport Classification Database (TCDB) (Saier et al., 2016) and if the transporter family was unknown, it was assigned according to the top TCDB blast hit (http://www.tcdb.org/progs/blast.php) based on sequence similarity to known transport proteins (Altschul et al., 1997). Data on the presence of human orthologs was retrieved from https://mpmp.huji.ac.il/maps/orth_hsap.html (Ginsburg and Tilley, 2011), a list compiled using recent publications. The existence of human orthologs was further verified using the TCDB protein blast.

Table 1.

Characteristics of known and putative P. falciparum transport proteins.

Gene ID Product Substrate and function Family Localisation Essential Human ortholog
PF3D7_1227200 K1, Kch1 voltage-gated potassium channel 1.A.1 e - EPM (Waller et al., 2008) b - yes yes
PF3D7_1465500 K2, Kch2 voltage-gated potassium channel 1.A.1 e - PPM (Waller et al., 2008) b - no yes
PF3D7_1436100 NIC putative K+ channel (Ginsburg and Tilley, 2011) 1.A.1 c - PPM b - yes no
PF3D7_1132800 AQP channel for water, glycerol and polyols 1.A.8 e - PPM (Swearingen et al., 2016) b - yes yes
PF3D7_1438100 SEC62 protein import in complex with Sec61 (Marapana et al., 2018) 1.A.15 e - ER (Marapana et al., 2018) b - yes yes
PF3D7_1250200 CSC, CSC1 calcium-activated stress-gated channel for Ca2+, K+ and Na+ 1.A.17 c - PPM (Blake et al., 2015) b - yes yes
PF3D7_1107900 MSCS putative mechanosensitive anion channel 1.A.23 c - PPM? (Blake et al., 2015) b - no no
PF3D7_1120300 MIT1 magnesium/nickel/cobalt ion channel (Ginsburg and Tilley, 2011) 1.A.35 c - mitochondrion (van Esveld et al., 2021) b - no yes
PF3D7_1304200 MIT2 magnesium/nickel/cobalt ion channel (Ginsburg and Tilley, 2011) 1.A.35 c - mitochondrion (Blake et al., 2015) b - yes no
PF3D7_1427600 MIT3 magnesium/nickel/cobalt ion channel (Ginsburg and Tilley, 2011) 1.A.35 c - mitochondrion (Blake et al., 2015) b - no yes
PF3D7_1333800 ICln anion channel 1.A.47 c - PPM b - no no
PF3D7_1439000 CTR1 copper channel 1.A.56 e - EPM, PPM b - yes no
PF3D7_1421900 CTR2 copper channel 1.A.56 c - apicoplast b - yes no
PF3D7_0306700 MMgT, EMC5 magnesium channel 1.A.67 c - ER b - yes no
PF3D7_0302500 CLAG3.1, RhopH1 PSAC/RhopH complex components for nutrient uptake (anions/organic cations) 1.A.91.1.1 e - EPM b - no no
PF3D7_0302200 CLAG3.2, RhopH1 e - EPM b - no no
PF3D7_0220800 CLAG2 c - EPM b - no no
PF3D7_0831600 CLAG8 c - EPM b - no no
PF3D7_0935800 CLAG9 c - EPM b - no (Nacer et al., 2011) no
PF3D7_0929400 RhopH2 e - EPM b - yes no
PF3D7_0905400 RhopH3 e - EPM b - yes no
PF3D7_1362300 TMCO1 Ca2+ channel, prevents ER overfilling? (Wang et al., 2016) 1.A.106 c - ER? (Blake et al., 2015) unknown yes
PF3D7_1432100 OMPP, VDAC solute channel 1.B.8.5.2 c - mitochondrion (Blake et al., 2015) unknown no
PF3D7_0823700 TOM7 components of TOM complex for protein import across outer membrane (Sheiner and Soldati-Favre, 2008; Schmidt et al., 2010) 1.B.8 c - mitochondrion (Schmidt et al., 2010) b - yes no
PF3D7_0524700 TOM22 e - mitochondrion (van Dooren et al., 2006) b - yes no
PF3D7_0617000 TOM40 e - mitochondrion (Das et al., 2017) b - yes no
PF3D7_0408700 PLP1, PPLP1 erythrocyte permeabilisation and rupture (Garg et al., 2013) 1.C.39 e - EPM (Garg et al., 2013) b - no, s - yes (Yang et al., 2017) no
PF3D7_1216700 PLP2, PPLP2 erythrocyte permeabilisation and rupture (Wirth et al., 2014) 1.C.39 e - EPM (Wirth et al., 2014) b - no, g - yes (Wirth et al., 2014) no
PF3D7_0923300 PLP3, PPLP3 host cell permeabilisation and rupture (Sassmannshausen et al., 2020) 1.C.39 c - host cell membrane (Sassmannshausen et al., 2020) unknown no
PF3D7_0819400 PLP4, PPLP4 rupture of mosquito midgut epithelial cells (Wirth et al., 2015) 1.C.39 e - host cell membrane (Sassmannshausen et al., 2020) b - no, o - yes (Wirth et al., 2015) no
PF3D7_0819200 PLP5, PPLP5 host cell permeabilisation and rupture (Sassmannshausen et al., 2020) 1.C.39 c - host cell membrane (Sassmannshausen et al., 2020) b - yes no
PF3D7_1331500 putative calcium channel (Gupta et al., 2022) 1.C.105 c - PPM? (Blake et al., 2015) unknown yes
PF3D7_1234600 TOC75 protein import across 2nd inner membrane (Agrawal and Striepen, 2010) 1.C.105 c - apicoplast (Boucher et al., 2018) b - yes no
PF3D7_0104100 E140, MPMP unknown 1.C.105 c - PPM? (Blake et al., 2015) b - yes no
PF3D7_1455400 HlyIII forms pore (~3.2 nm) for solutes and ions 1.C.113 e - EPM b - yes no
PF3D7_0204700 HT1 imports glucose and fructose 2.A.1.1 e - PPM b - yes yes
PF3D7_0516500 MFS1, MDT putative metabolite/drug transporter 2.A.1.2 unknown b - no yes
PF3D7_0916000 MFS2 putative sugar transporter 2.A.1.1 unknown b - no yes
PF3D7_0919500 MFS3 putative sugar transporter 2.A.1.1 e - PPM? (Swearingen et al., 2016),
c - mitochondrion (Blake et al., 2015)		 b - no yes
PF3D7_1203400 MFS4 putative transporter 2.A.1 unknown b - no no
PF3D7_1428200 MFS5 putative metabolite transporter 2.A.1 unknown b - no no
PF3D7_1440800 MFS6 H+ import, metabolite/drug export 2.A.1 e - apicoplast b - no no
PF3D7_1117000 P115 unknown 2.A.1 c - PPM (Blake et al., 2015) b - no no
PF3D7_0614300 MFR1 putative organic anion transporter 2.A.1.2 unknown b - no no
PF3D7_0104700 MFR2, ApiAT9 putative amino acid transporter 2.A.1 e - PPM (Wichers et al., 2021) b - no no
PF3D7_0312500 MFR3, ApiAT10 putative amino acid transporter 2.A.1 e - PPM (Wichers et al., 2021) b - no no
PF3D7_0914700 MFR4, ApiAT2 putative amino acid transporter 2.A.1 e - PPM (Wichers et al., 2021) b - no no
PF3D7_1129900 MFR5, ApiAT4 putative amino acid transporter 2.A.1 e - PPM (Wichers et al., 2021) b - no no
PF3D7_0104800 NPT1, ApiAT8 putative amino acid transporter 2.A.1 e - PPM (Wichers et al., 2021) b - no no
PF3D7_0210300 MCT1, MCP1 exports monocarboxylate 2.A.1 c - PPM b - yes yes
PF3D7_0926400 MCT2, MCP2 exports organic solutes, imports H+ 2.A.1 e - apicoplast (Boucher et al., 2018) b - no no
PF3D7_1036800 ACT, AT, AT1 imports acetyl-CoA, exports CoA 2.A.1.25 e - ER b - no yes
PF3D7_1104800 UMF pantothenate:H+ import 2.A.1.63 c - PPM b - yes no
PF3D7_0206200 TFP1, PAT pantothenate:H+ import (Ginsburg and Tilley, 2011) 2.A.1.66 e - PPM b - no yes
PF3D7_0529200 GPH putative sugar:cation symporter 2.A.2 unknown b - no no
PF3D7_0715900 CDF, ZIP3 Zn2+ import? (Huang et al., 2014) 2.A.4 e - cytoplasmic vesicle (Wichers et al., 2022) b - no yes
PF3D7_0609100 ZIP1 Zn2+ import? (Ginsburg and Tilley, 2011) 2.A.5 e - PPM (Wichers et al., 2022) b - no yes
PF3D7_1022300 ZIPCO, ZIP2 Zn2+/Fe2+ import into cytosol 2.A.5 c - PPM? (Blake et al., 2015) b - no yes
PF3D7_0107500 NCR1, NPC1R cholesterol/sterol/lipid export, H+ import 2.A.6.6 e - PPM b - yes yes
PF3D7_0715800 DMT1 organic solute transport 2.A.7.3 c - apicoplast b - no yes
PF3D7_0716900 DMT2 IPP export 2.A.7 e - apicoplast b - yes no
PF3D7_0709000 CRT drug/peptide:H+ export 2.A.7.3 e - DV b - yes no
PF3D7_0508300 TPT, oTPT, opPT PEP/3GP import, Pi export 2.A.7.9 e - apicoplast b - yes yes
PF3D7_0530200 PPT, iTPT, ipPT PEP/3GP import, Pi export 2.A.7.9 e - apicoplast b - yes (Swift et al., 2020) yes
PF3D7_1218400 TPT3 putative organic phosphate ester:Pi antiporter 2.A.7.9 unknown b - no yes
PF3D7_0505300 NGT UDP-N-acetylglucosamine import, UMP export 2.A.7.10 c - Golgi b - no yes
PF3D7_1113300 UGT UDP-galactose/UDP-glucose import, UMP export 2.A.7.11 e - ER b - yes yes
PF3D7_0212000 GFT GDP-fucose import, GMP export 2.A.7.16 c - Golgi b - yes yes
PF3D7_0522600 NIPA Mg2+ import 2.A.7.25 e - PPM b - yes yes
PF3D7_0629500 AAT1 transports Ile, Leu, Met 2.A.18 c - PPM, DV b - yes yes
PF3D7_1208400 AAT2 transports amino acids, GABA 2.A.18 c - PPM b - no yes
PF3D7_1231400 AAAP3, ICM1 transports Ile, Leu, Met or Ca2+ (Balestra et al., 2021) 2.A.18 unknown b - yes no
PF3D7_0603500 CAX, CHA imports H+, exports Ca2+/Mg2+/Mn2+ 2.A.19 e - mitochondrion (Rotmann et al., 2010) b - no no
PF3D7_1340900 PiT imports phosphate and Na2+ into cytosol 2.A.20 e - PPM b - yes yes
PF3D7_0209600 NSS1 putative amino acid transporter 2.A.22 c - PPM (Blake et al., 2015) b - yes yes
PF3D7_0515500 GEP1, NSS2 neurotransmitter:Na2+ symport (Ginsburg and Tilley, 2011) 2.A.22 c - cytoplasmic vesicle (Jiang et al., 2020) b - no no
PF3D7_1132500 NSS3 amino acid/GABA transport 2.A.22 c - PPM b - no yes
PF3D7_0714100 MAATS1 export of H+ and amino acids (Ginsburg and Tilley, 2011) 2.A.22 unknown b - no yes
PF3D7_1368700 TPC, DNC thiamine pyrophosphate import, nucleotide export 2.A.29 c - mitochondrion b - yes yes
PF3D7_0905200 MRS3, MC5 putative Fe2+ importer (Blake et al., 2015) 2.A.29 c - mitochondrion b - yes yes
PF3D7_0407500 MTM1, MC3 unknown 2.A.29 c - mitochondrion b - yes yes
PF3D7_1241600 SAMC, PET8 imports S-adenosylmethionine, exports S-adenosylhomocysteine 2.A.29 e - mitochondrion b - yes yes
PF3D7_0108400 MME1, MC1 unknown 2.A.29 c - mitochondrion b - no yes
PF3D7_0108800 AMC1, MC2 unknown 2.A.29 c - mitochondrion b - yes no
PF3D7_0811100 AMC2, MC4 unknown 2.A.29 c - mitochondrion b - no yes
PF3D7_0908800 AMC3, MC6 unknown 2.A.29 c - mitochondrion b - yes yes
PF3D7_1037300 AAC1, ADT ADP/ATP antiporter (Blake et al., 2015) 2.A.29 e - mitochondrion (Hatin et al., 1992) b - yes yes
PF3D7_1004800 AAC2, PAAC ADP/ATP antiporter (Blake et al., 2015) 2.A.29 c - mitochondrion (van Esveld et al., 2021) b - yes yes
PF3D7_1223800 COC, YHM2 imports oxoglutarate, exports citrate 2.A.29 c - mitochondrion b - no yes
PF3D7_0823900 DTC, OMT imports dicarboxylate, exports tricarboxylate 2.A.29 e - mitochondrion b - yes yes
PF3D7_1202200 MPC, PIC, PIC2 Pi:H+ import 2.A.29 c - mitochondrion b - no yes
PF3D7_1303500 NHE H+ import into cytosol in exchange for Na+ 2.A.36 c - PPM (Blake et al., 2015) b - no yes
PF3D7_0924500 putative Na+:H+ exchanger (Saier et al., 2016) 2.A.36 unknown b - yes yes
PF3D7_0827700 MgT1 Mg2+:H+ antiporter (Blake et al., 2015) 2.A.36 unknown b - no yes
PF3D7_1135000 unknown 2.A.43 c - apicoplast (Boucher et al., 2018) unknown no
PF3D7_0316600 FNT lactate/formate and H+ release from cytosol 2.A.44 e - PPM, DV b - no no
PF3D7_1471200 SuIP inorganic anion antiporter 2.A.53 e - PPM b - yes yes
PF3D7_0523800 NRAMP2, NRAMP, FVRT1 Fe2+/ Mn2+:H+ export 2.A.55 e - DV (Wichers et al., 2022) b - yes yes
PF3D7_1347200 NT1, ENT1 purine base import 2.A.57 e - PPM b - yes no
PF3D7_0824400 NT2, ENT2 nucleoside/nucleobase import 2.A.57 e - ER b - no no
PF3D7_1469400 NT3, ENT3 putative nucleoside transporter 2.A.57 unknown b - no no
PF3D7_0103200 NT4, ENT4 adenine/adenosine import 2.A.57 c - PPM b - yes no
PF3D7_0212800 MATE putative organic solute:Na+/H+ antiporter 2.A.66.1 unknown b - no yes
PF3D7_0828600 FT1 imports pABA and folates 2.A.71 e - PPM b - no no
PF3D7_1116500 FT2 imports pABA, folates, 5-methyltetrahydrofolate 2.A.71 e - PPM b - no no
PF3D7_1223700 VIT imports Fe2+ for detoxification, exports H+ 2.A.89 unknown b - no no
PF3D7_0417300 LETM1 imports H+, exports Ca2+/K+ 2.A.97 c - mitochondrion (van Esveld et al., 2021) b - yes yes
PF3D7_1340800 MPC1 pyruvate:H+ importer 2.A.105 c - mitochondrion b - yes yes
PF3D7_1470400 MPC2 pyruvate:H+ importer 2.A.105 c - mitochondrion unknown yes
PF3D7_1033000 HPR1, AMC4 unknown 2.A.123 c - mitochondrion? (van Esveld et al., 2021) b - yes no
PF3D7_0216600 SWEET putative glucose/galactose transporter 2.A.123 c - ER/Golgi b - yes yes
PF3D7_0305300 unknown 2.A.123 unknown b - no no
PF3D7_0523000 MDR1, ABCB1, Pgh1 active drug and solute import (Friedrich et al., 2014) 3.A.1.201 e - DV (Papalexis et al., 2001) b - yes yes
PF3D7_1447900 MDR2, ABCB2 active Cd2+ extrusion from cytosol 3.A.1.210 e - PPM, DV b - no (van der Velden et al., 2015) yes
PF3D7_1145500 MDR3, ABCB3 active peptide efflux 3.A.1.209 e - apicoplast (Boucher et al., 2018) b - no yes
PF3D7_0302600 MDR4, ABCB4 active peptide/heavy metal cation transport 3.A.1.209 e - apicoplast b - no yes
PF3D7_1339900 MDR5, ABCB5 active solute export 3.A.1.201 e - PPM b - no yes
PF3D7_1352100 MDR6, ABCB6, Atm1 active glutathione trisulfide efflux 3.A.1.210 c - mitochondrion, apicoplast b - yes yes
PF3D7_1209900 MDR7, ABCB7 active peptide efflux 3.A.1.209 c - mitochondrion b - no yes
PF3D7_0112200 MRP1, ABCC1 active export of drugs and glutathione conjugates 3.A.1.208 e - PPM b - no yes
PF3D7_1229100 MRP2, ABCC2 active export of glutathione conjugates 3.A.1.208 e - PPM b - no yes
PF3D7_0813700 ABCF1 heme import? (Blake et al., 2015) 3.A.1 e - apicoplast (Boucher et al., 2018) b - yes yes
PF3D7_1426500 ABCG, ABCG1, ABCG2 putative cell metabolite exporter (Edaye and Georges, 2015) 3.A.1.204 e - PPM (Edaye and Georges, 2015) b - no yes
PF3D7_0319700 ABCI3 active solute transport (Murithi et al., 2021) 3.A.1 e - cytoplasmic vesicle (Murithi et al., 2021) unknown yes
PF3D7_0810200 ABCK1 active peptide efflux (Ginsburg and Tilley, 2011) 3.A.1 c - mitochondrion (van Esveld et al., 2021) b - yes yes
PF3D7_1004600 drug transport? (Park et al., 2012) 3.A.1 unknown b - no no
PF3D7_0812900 drug transport? (Park et al., 2012) 3.A.1 unknown b - no no
PF3D7_1434000 CAF16 putative ABC transporter (Blake et al., 2015) 3.A.1 unknown b - yes yes
PF3D7_0614900 unknown 3.A.1 c - PPM (Blake et al., 2015) b - no yes
PF3D7_1144700 TIC20 protein import across innermost membrane (Agrawal and Striepen, 2010) 3.A.1 c - apicoplast (Boucher et al., 2018) b - yes no
PF3D7_1121600 EXP1 pore for solutes < 1.4 kDa with EXP2 (Mesén-Ramírez et al., 2019) 3.A.1 e - PVM (Mesén-Ramírez et al., 2019) b - yes (Maier et al., 2008) no
PF3D7_0217100 ATPα, F1 α H+-importing ATP synthase subunits 3.A.2 e - mitochondrion b - yes yes
PF3D7_1235700 ATPβ, F1 β b - no yes
PF3D7_1311300 ATPγ, F1 γ b - yes yes
PF3D7_1147700 ATPδ, F1 δ b - no no
PF3D7_0715500 ATPϵ, F1 ϵ b - no no
PF3D7_1310000 OSCP b - yes yes
PF3D7_0719100 Fo a b - yes no
PF3D7_1125100 Fo b b - yes no
PF3D7_0705900 Fo c b - yes yes
PF3D7_0311800 Fo d b - yes no
PF3D7_1311900 vapA, V1 subunit A V-ATPase subunits: active H+ export from cytosol 3.A.2 e - PPM, DV, cytoplasmic vesicle (Hayashi et al., 2000) b - yes yes
PF3D7_0406100 vapB, V1 subunit B b - yes yes
PF3D7_0106100 vapC, V1 subunit C b - yes yes
PF3D7_1341900 vapD, V1 subunit D b - yes yes
PF3D7_0934500 vapE, V1 subunit E b - yes yes
PF3D7_1140100 vapF, V1 subunit F b - no yes
PF3D7_1323200 vapG, V1 subunit G b - yes no
PF3D7_1306600 vapH, V1 subunit H b - yes yes
PF3D7_0806800 Vo subunit a b - yes yes
PF3D7_0519200 Vo subunit c, 16-kDa proteolipid b - no yes
PF3D7_1354400 Vo subunit c", 21-kDa proteolipid b - yes yes
PF3D7_1464700 Vo subunit d, C/AC39 b - yes yes
PF3D7_0721900 Vo subunit e b - yes no
PF3D7_0516100 ATP1 extrusion of inorganic cations from cytosol 3.A.3 e - PPM, DV b - no yes
PF3D7_1219600 ATP2 putative phospholipid flippase 3.A.3 c - PPM b - yes yes
PF3D7_0504000 ATP3 active Mg2+ transport 3.A.3 c - apicoplast b - yes yes
PF3D7_1211900 ATP4 H+ import, Na+ export 3.A.3 e - PPM b - yes yes
PF3D7_0106300 ATP6 active Ca2+ import for storage 3.A.3 c - ER b - yes yes
PF3D7_0319000 ATP7 putative phospholipid flippase 3.A.3 c - PPM (Blake et al., 2015) b - no yes
PF3D7_1223400 ATP8 putative phospholipid flippase 3.A.3 c - PPM b - yes yes
PF3D7_1348800 ATP9 active Ca2+ import? 3.A.3 c - DV? b - no yes
PF3D7_0727800 ATP10 active Mn2+ transport 3.A.3 c - apicoplast b - yes yes
PF3D7_1468600 ATP11 putative phospholipid flippase 3.A.3 c - PPM (Blake et al., 2015) b - no yes
PF3D7_0904900 CuTP active Cu2+ export 3.A.3 e - EPM, PPM b - no yes
PF3D7_1138400 GCα phospholipid flippase 3.A.3 c - cytoplasmic vesicle (Jiang et al., 2020) b - yes (Taylor et al., 2008) yes
PF3D7_1360500 GCβ phospholipid flippase 3.A.3 c - PPM b - no yes
PF3D7_1346100 SEC61α components of ER translocon for import of proteins destined for export, interact with SEC62 (Marapana et al., 2018) 3.A.5 e - ER (Marapana et al., 2018) b - no yes
PF3D7_0821800 SEC61β b - no yes
PF3D7_0210000 SEC61γ b - yes yes
PF3D7_1318800 SEC63 b - yes yes
PF3D7_0724400 TIM14, PAM18 components of TIM23/PAM complex for protein import across inner membrane (Sheiner and Soldati-Favre, 2008; Schmidt et al., 2010) 3.A.8 c - mitochondrion (van Esveld et al., 2021) b - yes yes
PF3D7_0513500 TIM16, PAM16 unknown no
PF3D7_1434700 TIM17 b - yes yes
PF3D7_1356200 TIM23 b - yes no
PF3D7_1125400 TIM44 b - yes yes
PF3D7_0726900 TIM50 b - yes yes
PF3D7_0627400 TIM22 protein import across inner membrane (Sheiner and Soldati-Favre, 2008; Schmidt et al., 2010) 3.A.8 c - mitochondrion (van Esveld et al., 2021) b - yes yes
PF3D7_1456800 VP1 active H+ export 3.A.10 e - PPM (Ahiya et al., 2022) b - yes no
PF3D7_1235200 VP2 putative Ca2+-dependent H+ export from cytosol 3.A.10 e - PPM, cytoplasmic vesicles (Marchesini et al., 2000) b - no no
PF3D7_0810400 AQP2 water channel (Blake et al., 2015) 3.A.16 c - PPM (Blake et al., 2015) b - no no
PF3D7_0314300 Der1-1 protein import across periplastid membrane (Spork et al., 2009) 3.A.25.2.1 e - apicoplast (Spork et al., 2009) b - yes no
PF3D7_1452300 Der1-2 protein import across periplastid membrane (Spork et al., 2009) 3.A.25.2.1 e - apicoplast (Spork et al., 2009) unknown yes
PF3D7_0216800 unknown 3.A.25 unknown b - yes yes
PF3D7_0315700 unknown 3.A.25 unknown b - no no
PF3D7_1471100 EXP2 PTEX core components for protein export (Beck and Ho, 2021), EXP2 also functions as a pore for solutes < 1.4 kDa together with EXP1 (Garten et al., 2018; Mesén-Ramírez et al., 2019) 3.A.26.1.1 e - PVM (de Koning-Ward et al., 2009) b - yes no
PF3D7_1436300 PTEX150 b - yes (de Koning-Ward et al., 2009) no
PF3D7_1116800 HSP101 b - yes yes
PF3D7_1404600 ACα putative K+ channel 8.A.85 unknown b - no no
PF3D7_1022700 PLSCR phospholipid scramblase (Haase et al., 2021) 9.A.36 e - parasite periphery (Haase et al., 2021) b - no no
PF3D7_1332100 putative transporter 9.B.14 unknown b - no no
PF3D7_0530500 putative transporter 9.B.14 unknown b - no no
PF3D7_0628400 unknown 9.B.14 unknown b - no no
PF3D7_1135300 PMRT1 unknown 9.B.14 e - PPM (Wichers et al., 2022) b, g - yes (Wichers et al., 2022) no
PF3D7_1022200 FBT putative metabolite/vitamin transporter (Ginsburg and Tilley, 2011) 9.B.14 unknown b - yes no
Pf3D7_0321900 CARL unknown 9.B.314 e - cis-Golgi (LaMonte et al., 2016) b - no yes
PF3D7_0824700 LMF1 putative transporter 9.B.365.5.1 c - ER (Blake et al., 2015) b - no yes
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Substrates, functions, and localisations are indicated as in Martin (2020), unless stated otherwise. Known or putative localisation refers to the site of active function of the transport protein regardless of its trafficking route, as evidenced either by experimental data (e) or computational analysis (c). DV: digestive vacuole, EPM, erythrocyte plasma membrane; PPM, parasite plasma membrane; PVM, parasitophorous vacuole membrane. Transporter families were assigned according to the Transport Classification Database (Saier et al., 2016). 1: channels and pores, 1.A: α-type channels, 1.B: β-barrel porins, 1.C: pore-forming toxins. 2: electrochemical potential-driven transporters, 2.A: porters (uniporters, symporters, antiporters), 3: primary active transporters, 3.A: P-P-bond-hydrolysis-driven transporters, 8: accessory factors involved in transport, 8.A: auxiliary transport proteins, 9: incompletely characterised transport systems, 9.A: recognised transporters of unknown biochemical mechanism, 9.B: putative transport proteins. Predicted gene essentiality refers to Zhang et al. (2018), unless another reference is given. The tested life cycle stages are indicated as b, asexual blood stage; g, gametocytes; o, ookinetes; s, sporozoites. Information on the presence of human orthologs is listed according to https://mpmp.huji.ac.il/maps/orth_hsap.html (Ginsburg and Tilley, 2011).

In total, 197 transport proteins were identified ( Table 1 ), with some of these forming a complex, e.g. the Plasmodium Translocon of EXported proteins (PTEX), consisting of three core components (de Koning-Ward et al., 2009; Beck and Ho, 2021). Protein complex components residing in or associated with the respective membrane that are required for substrate translocation were included, whereas accessory and auxiliary subunits were excluded. For clarity, only the likely site of active transport is indicated for each protein, although it might be detectable in other subcellular compartments during trafficking.

Calcium Transport Proteins as Potential Drug Targets

Calcium homeostasis was chosen as an example for illustrating transport pathways in the P. falciparum-infected erythrocyte ( Figure 1 ), as Ca2+ signalling is known to be critical throughout the parasite life cycle (Brochet and Billker, 2016) and a link between Ca2+ uptake and virulence has been proposed in the related parasite Toxoplasma gondii (Pace et al., 2014). In fact, Ca2+ transporters such as PfATP6 (PF3D7_0106300) are currently under investigation as novel antimalarial drug targets (Gupta et al., 2022; Monteiro Júnior et al., 2022). While the concentration of free Ca2+ is ~1.8 mM in the blood plasma, mature erythrocytes only contain 30 – 60 nM Ca2+ (Brochet and Billker, 2016) due to active ion extrusion by the P-type plasma membrane Ca2+ ATPases (PMCA) 1 and 4 and slow Ca2+ uptake via several channels such as Piezo1, the erythroid N-methyl D-aspartate (NMDA) receptor, and the voltage-dependent anion channel (VDAC) (Kaestner et al., 2020).

Figure 1.

Figure 1

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Calcium homeostasis in a trophozoite-stage P. falciparum-infected erythrocyte. Under resting conditions, the concentration of free Ca2+ is ~1.8 mM in the blood plasma, 30 – 60 nM in cytosol of an uninfected erythrocyte (Brochet and Billker, 2016), ~90 nM in the cytosol of the infected erythrocyte (Rohrbach et al., 2005), and ~100 nM in the cytosol of P. falciparum (Garcia et al., 1996). Transport proteins affecting intracellular calcium concentrations in the parasite-infected erythrocyte include the human P-type plasma membrane Ca2+-ATPases (PMCA) 1 and 4, human Piezo1, the erythroid N-methyl D-aspartate (NMDA) receptor, the voltage-dependent anion channel (VDAC) (Kaestner et al., 2020), and likely the parasite-encoded hemolysin III (PfHlyIII) (Moonah et al., 2014). A nutrient pore formed by PfEXP1 and PfEXP2 mediates passage through the parasitophorous vacuole membrane (Garten et al., 2018; Mesén-Ramírez et al., 2019) and the calcium-permeable stress-gated cation channel PfCSC may be responsible for Ca2+ entry into the parasite cytosol (Martin, 2020). The SERCA-type Ca2+-ATPase PfATP6 actively imports Ca2+ into the endoplasmic reticulum as an intracellular reservoir (Lourido and Moreno, 2015; Martin, 2020), while the putative calcium load-activated calcium channel PfTMCO1 (Gupta et al., 2022) may release ions back into the cytosol to avoid overload (Lourido and Moreno, 2015; Wang et al., 2016). Ca2+ efflux from the mitochondrion is likely mediated by the cation/H+ antiporters PfCAX (Rotmann et al., 2010) and PfLETM1 (Martin, 2020) via secondary active transport. Human-encoded transporters and channels are shown in blue and parasite-encoded proteins in orange.

A malaria parasite that resides within an erythrocyte maintains a cytosolic calcium level of approximately 100 nM by permeabilising its host cell and using a regulatory Ca2+ pool (Garcia et al., 1996). Extracellular Ca2+ is thought to first pass through a parasite-encoded channel in the erythrocyte plasma membrane (EPM) that is independent of PSAC (plasmodial surface anion channel), thereby increasing the intracellular Ca2+ concentration of the infected red blood cell (Zipprer et al., 2014). One candidate for this channel is hemolysin III (PfHlyIII, PF3D7_1455400), which forms an ion-permeable pore of approximately 3.2 nm in EPMs after its release from the parasite digestive vacuole (DV) upon merozoite egress (Moonah et al., 2014). Another potential route of Ca2+ entry into the infected erythrocyte is via enhanced activity of a host channel induced by the parasite, as suggested for VDAC (Bouyer et al., 2011).

Passage through the parasitophorous vacuole membrane (PVM) likely occurs via a nutrient pore for solutes < 1.4 kDa formed by PfEXP1 (PF3D7_1121600) and PfEXP2 (PF3D7_1471100) (Garten et al., 2018; Mesén-Ramírez et al., 2019). The ion may then enter the parasite cytosol via a parasite-encoded channel, one candidate being the calcium-permeable stress-gated cation channel PfCSC (PF3D7_1250200) that is activated by high external calcium levels (Martin, 2020). The localisation of this transporter at the PPM was inferred from an ancestral gene (Gaudet et al., 2011) and although this remains to be confirmed experimentally, it seems plausible due to the identification of this protein as an immunoreactive antigen with high serodominance in exposed individuals (Doolan et al., 2008). As PfCSC is highly expressed in sporozoites (Le Roch et al., 2003), its exposure to the immune system may occur at this parasite stage.

Calcium can then be stored in the endoplasmic reticulum upon active import by the SERCA-type Ca2+-ATPase PfATP6 (Lourido and Moreno, 2015; Martin, 2020). In case of Ca2+ overload of the ER, the putative calcium load-activated calcium channel PfTMCO1 (Gupta et al., 2022) may become active and release ions into the cytosol (Lourido and Moreno, 2015; Wang et al., 2016). Ca2+ efflux from the mitochondrion is likely mediated by the cation/H+ antiporters PfLETM1 (PF3D7_0417300) (Martin, 2020) and PfCAX/PfCHA (PF3D7_0603500) in exchange for protons that travel along the H+ gradient across the inner mitochondrial membrane (Rotmann et al., 2010).

Another putative intracellular Ca2+ pool may consist of acidocalcisomes – small electron-dense vesicles that are conserved from bacteria to humans and contain high concentrations of Ca2+, pyrophosphate, polyphosphate, iron, and zinc (Huang et al., 2014). Accordingly, acidocalcisome membranes contain a variety of specific transporters for these substrates across the tree of life (Huang et al., 2014). While many transporters were shown to reside in the acidocalcisome membrane in Trypanosoma brucei through proteomic studies and microscopy (Huang et al., 2014), no protein has been definitely localised to these organelles in P. falciparum (Magowan et al., 1997; Ruiz et al., 2004). Their low internal pH is likely required for the secondary active import of various ions and thought to be established and maintained by the plant-like H+-pump V-ATPase (Wunderlich et al., 2012; de Oliveira et al., 2021). This has yet to be verified experimentally, and there may be differences between parasite species. For example, PfVP1 (PF3D7_1456800), an ortholog of the acidocalcisome marker in T. brucei (Huang et al., 2014) and T. gondii (Rohloff et al., 2011), was previously suggested to localise to the parasite plasma membrane (PPM), DV and acidocalcisomes in P. falciparum, but could only be detected at the PPM by microscopy (Ahiya et al., 2022).

Other proteins that may translocate calcium and whose subcellular localisation has not yet been confirmed are PfATP9 (PF3D7_1348800), the putative calcium channel PF3D7_1331500, and PfICM1 (PF3D7_1231400). Elucidating their location and function is an important knowledge gap to be addressed (Kustatscher et al., 2022). Of the aforementioned putative Ca2+ transport proteins, PfICM1 and PfHlyIII may be worth exploring as drug targets due to their predicted essentiality and the absence of human counterparts.

Conclusions and Future Perspectives

This mini review consolidates data from various databases and provides an up-to-date overview of the subcellular localisation, function, predicted essentiality, and human orthologs of P. falciparum transporters for the fast identification of essential parasite transporters without human orthologs that may be promising novel targets for therapeutic development. Many of these candidates localise to the apicoplast, the mitochondrion, or the digestive vacuole, which are known to be “druggable” (Wunderlich et al., 2012; Oberstaller et al., 2021).

Moreover, the new transporter list will improve gene annotations and serve as a basis for further functional characterisation of the proteins. It will also be useful for systems biology approaches as it allows more reliable screening of e.g. genomic, transcriptomic, and proteomic data for P. falciparum transporters. The low coverage of the P. falciparum membrane proteome that complicates target profiling (Lu et al., 2021) may be overcome by large-scale culturing (Dalton et al., 2012) and more sensitive mass spectrometry techniques (McClure and Williams, 2018). Chemogenomic and transcriptional profiling of mutant-parasite libraries with altered drug sensitivities will further guide the determination of the mechanisms of drug action (Adjalley et al., 2015; Pradhan et al., 2015).

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Funding

JW was supported by the Boehringer Ingelheim Foundation and the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement 759534).

Author Disclaimer

The funders had no role in study design, data collection, decision to publish, or preparation of the manuscript.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

The author thanks Jan Strauss for providing many helpful tips and gratefully acknowledges Silvia Portugal and Eileen Devaney for critical reading of the manuscript.

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