Di- or tripeptide:H⁺ symporter of 497 aas and 13 or 14 TMSs. DtpT is specific for di- and tripeptides, with the highest affinities for peptides with at least one hydrophobic residue. The effect of the hydrophobicity, size, or charge of the amino acid was different for the amino- and carboxyl-terminal positions of dipeptides. Free amino acids, omega-amino fatty acidss, and peptides with more than three amino acid residues do not interact with DtpT. For high-affinity interaction, the peptides need to have free amino and carboxyl termini, amino acids in the L configuration, and trans-peptide bonds. Comparison of the specificity of DtpT with those of the eukaryotic homologues PepT(1) and PepT(2) showed that the bacterial transporter is more restrictive in its substrate recognition. (Fang et al. 2000). 

Bacteria

DtpT of Lactococcus lactis (P0C2U2)

The di/tripeptide:H⁺ symport permease, TppB (DtpA or YdgR) (transports di and tripeptides and peptidomimetics such as aminocephalosporins (Weitz et al., 2007).  The transporter has two alternate conformations, one of which is promoted by inhbitor binding (Bippes et al. 2013).

Bacteria

TppB of E. coli (P77304)

DtpD (YbgH) peptide transporter.  A projection structure at 19 Å resolution and a high resolution x-ray structure are available; Casagrande et al., 2009; Zhao et al. 2014). Glu21 is the only conserved proton-titratable amino acyl residue (among POTs) that is located in the central cavity, and it is critical for in vivo transport (Zhao et al. 2014).

Bacteria

DtpD of E. coli (P75742)

Peptide transporter, YjdL (preference for di-peptides) (Ernst et al., 2009; Gabrielsen et al., 2011; Jensen et al., 2011).  The motif, ExxERFxxYY has been shown to be involved in proton translocation, and the nearby K₁₁₇ may play a dual role in protonation and substrate binding (Jensen et al. 2014).

Bacteria

YjdL of E. coli (P39276)

POT famiy di- and tri-peptide porter, DtpT. 3-d structures (PDB:24APS; 5MMT: 5D58' 5D59) are available for an inward open conformation. A hinge-like movement in the C-terminal half facilitates opening of an intracellular gate controlling access to a central peptide binding site. Salt bridges may orchestrate alternating access (Solcan et al., 2012; Quistgaard et al. 2017).

Bacteria

Peptide porter, DtpT of Streptococcus thermophilus (Q5M4H8)

Peptide uptake transporter of 496 aas, POT.  The 3-d structure has been determined to 1.9Å resolution leading to a proposed mechanism (Doki et al. 2013).  Glu310 first may bind the carboxyl group of the peptide substrate. Then deprotonation of Glu310 in the inward open state triggers the release of the bound peptide toward the intracellular space, and salt bridge formation between Glu310 and Arg43 induces the transition state to the occluded conformation.

Firmicutes

POT of Geobacillus kaustophilus

Proton-coupled oligopeptide uptake transporter of 485 aas and 14 TMSs, DtpT or Pot.  Expression of the encoded gene is upregulated upon infection. Transports di- and tripeptides but can not accumulate peptides with a positively charged residue in the C-terminal position.  An aromatic residue patch in the active site of the transporter may be responsible for it's unusual specificity (Sharma et al. 2016).

DtpT of Neisseria meningitidis

Peptide:H⁺ symporter (dipeptides and tripeptides preferred (Cai et al., 2007). Substrate preference is altered by mutations in the fifth TMS of Ptr2p (Hauser et al. 2013).

Yeast

PTR2 of Saccharomyces cerevisiae

Dipeptide uptake porter, Ptr2.  Transports dipeptides such as Ala-Leu, Ala-Tyr and Tyr-Ala (Belmondo et al. 2014).

Fungi

Ptr2 of Rhizophagus irregularis (Arbuscular mycorrhizal fungus) (Glomus intraradices)

Di- and tripeptide uptake transporter, Ptr2 of 577 aas and 12 TMSs. The ptr2 gene showed increased expression upon interaction with the plant-pathogenic fungus Botrytis cinerea, suggesting that it is involved in the mycoparasitic process. Its expression was triggered by nitrogen starvation (Vizcaíno et al. 2006).

Ptr2 of Trichoderma harzianum (Hypocrea lixii)

Oligopeptide transporter of 576 aas and 12 TMSs, PTR22. Transports a variety of peptides as well as derivatives of antifungal agents, such as chlorotetaine and lysyl-cholortetaine (Liu et al. 2018).

PTR22 of Candida albicans (Yeast)

Dual affinity Nitrate/Chlorate symporter, Nrt1.1; CHL1 of 590 aas and 12 TMSs in a 6 + 6 TMS arrangement (Martin et al., 2008).  The low affinity form is a homo-dimer and has Thr101 in the non-phosphorylated form; the high affinty form (0.1 micromolar K_m) is a monomer and has Thr101 phosphorylated (Sun and Zheng 2015). Rehmannia glutinosa (Chinese foxglove) has 18 ntr1 genes encoding proteins of 419 to 601 aas with 7 - 12 TMSs. They are found primarily in the plasma membranes of various plant tissues (Gu et al. 2021).

Plants

Ntr1.1/CHL1 of Arabidopsis thaliana

solute carrier family 15, member 5.  Function unknown as of 1/17, but probably a di- and tri-peptide uptake porter (Verri et al. 2016). The tissue expression profile has been reported (Sreedharan et al. 2011).

Animals

SLC15A5 of Homo sapiens

Solute carrier family 15 member 4 (Peptide transporter 4) (Peptide/histidine transporter 1) (hPHT1; SLC15A4; ) is present in immune cells (Verri et al. 2016). It is a proton-coupled amino-acid transporter that mediates the transmembrane transport of L-histidine and some di- and tripeptides from inside the lysosome to the cytosol, and plays a key role in innate immune responses (Bhardwaj et al. 2006, Kobayashi et al. 2014, Song et al. 2018). It is able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans peptides (Song et al. 2018; Oppermann et al. 2019). Transport activity is pH-dependent and maximized in the acidic lysosomal environment. It is involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycan fragments across the endolysosomal membrane: it catalyzes the transport of certain bacterial peptidoglycan-derived peptides, such as muramyl dipeptide, the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand (Kobayashi et al. 2014, Song et al. 2018). Byrnes et al. 2022 reviewed three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. PHT1 is a histidine/oligopeptide transporter with an essential role in Toll-like receptor innate immune responses. It can act as a receptor by recruiting the adaptor protein TASL which leads to type I interferon production via IRF5 (Custódio et al. 2023). Persistent stimulation of this signalling pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). The authors presented the Cryo-EM structure of PHT1 stabilized in the outward-open conformation and proposed a model of the PHT1-TASL complex, in which the first 16 N-terminal TASL residues that fold into a helical structure that binds in the central cavity of the inward-open conformation of PHT1. This work suggests the molecular basis of PHT1/TASL mediated type I interferon production (Custódio et al. 2023). PHT1 substrate selectivity, as well as the transport kinetics of the identified substrates have been characterized (Pujol-Giménez et al. 2024).

Animals

SLC15A4 of Homo sapiens

Putative peptide/nitrate transporter At3g25280

Plants

At3g25280 of Arabidopsis thaliana

Nitrate transporter 1.6

Plants

NRT1.6 of Arabidopsis thaliana

Nitrate transporter 1.7

Plants

NRT1.7 of Arabidopsis thaliana

Nitrate transporter 1.2 (Nitrate transporter NTL1; NRT1:2; PRT family protein 4.6; NPF4.6; AIT1).  Low-affinity proton-dependent nitrate transporter involved in constitutive nitrate uptake but not histidine or dipeptides transport. Involved in (+)-abscisic acid (ABA) transport, but not in gibberellin, indole-3-acetic acid or jasmonic acid import; ABA and nitrate do not compete for substrate uptake (Kanno et al. 2013). Arabidopsis NPF4.6 and NPF5.1 control the leaf stomatal aperture by regulating abscisic acid transport (Shimizu et al. 2021). NPF4.6 is expressed in vascular tissues and guard cells, and it positively regulates stomatal closure in leaves (Shimizu et al. 2021).

Plants

NRT1.2 of Arabidopsis thaliana

Transporter for glucosinolates, GTR1, (aliphatic but not indole glucosinolates such as 4-methylthiobutyl glucosinolate, major defence compounds, translocated to seeds on maturation) as well as gibberellic acid and jasmonoyl-L-isoleucine, GTR1 or NPF2.10, of 636 aas and 12 TMSs (Nour-Eldin et al. 2012; Ishimaru et al. 2017). Regulated at the transcriptional level, but also postranslationally.  Dimerization of GTR1, possibly induced by dephosphorylation of a Thr residue, regulates its plasma membrane localization, leading to increased transport of glucosinolates and gibberellic acid (Ishimaru et al. 2017). Homologues have been found and characterized in Chinese kale (Jiang et al. 2019).

Plants

GTR1 of Arabidopsis thaliana

Nitrate transporter 1.4

Plants

NRT1.4 of Arabidopsis thaliana

Nitrate transporter 1.5

Plants

NRT1.5 of Arabidopsis thaliana

Histidine or peptide:H⁺ symporter of 585 aas and 12 TMSs. It mediates the transport of di- and tripeptides with high affinity, low capacity (Rentsch et al. 1995).

Plants

PTR2-B (NTR1) of Arabidopsis thaliana

High-affinity, proton-dependent glucosinolate-specific transporter-2, GTP2 or NPF2.11. Involved in apoplasmic phloem-loading of glucosinolates and in bidirectional long-distance transport of aliphatic but not indole glucosinolates. May be involved in removal of glucosinolates from the xylem in roots (Nour-Eldin et al. 2012; Andersen et al. 2013).

Plants

GTR2 of Arabidopsis thaliana

Low affinity nitrate transporter, Nrt1, of 584 aas and 13 putative TMSs.  Two splice variants, Ntr1.1a and Ntr1.1b, have been identified.  Under low nitrogen condition, Nrt1.1b accumulates more nitrogen in plants and improves rice growth, but Ntr1.1a had no such effect (Fan et al. 2015). The absorption and long-distance distribution/transport of nitrate is mediated by NRT1.1B in tabacco (Wu et al. 2023).

Ntr1 of Oryza sativa (Rice)

Uncharacterized peptide transport protein of 609 aas and 12 TMSs, PTR3-A.

PTR3-

aof Aegilops tauschii (Tausch's goatgrass) (Aegilops squarrosa)

Protein NRT1, PTR FAMILY 5.1, NPF5.1 of 583 aas and 12 TMSs in a 6 + 6 TMS arrangement. Mutants defective in NPF5.1 had a higher leaf surface temperature compared to the wild type and, NPF5.1 mediated cellular abscisic acid (ABA) uptake when expressed in a heterologous yeast system (Shimizu et al. 2021). An NRT  protein (NPF) from wheat (Triticum aestivum) has been identified and partiallly characterized (Kumar et al. 2022).

NPF5.1 of Arabidopsis thaliana (Mouse-ear cress)

NRT1.13; NPF4.4; PTR family 4.4 of 601 aas and 12 or 13 TMSs in a 6 or 7 + 6 TMS arrangement. In contrast to most NRT1 transporters, NRT1.13 does not have the conserved proline residue between TMSs 10 and 11, an essential residue for nitrate transport activity in CHL1/NRT1.1/NPF6.3 ( TC# 2.A.17.3.1). NRT1.13 showed no nitrate transport activity, but when Ser487 at the corresponding position was converted to proline, NRT1.13 S487P gained nitrate uptake activity, suggesting that wild-type NRT1.13 cannot transport nitrate but can bind it (Chen et al. 2021). Subcellular localization  indicated that NRT1.13 is a plasma membrane protein expressed at the parenchyma cells next to xylem in the petioles and the stem nodes. When plants were grown with a normal concentration of nitrate, the nrt1.13 mutant showed no severe growth phenotype, but when grown under low-nitrate conditions, nrt1.13 showed delayed flowering, increased node number, retarded branch outgrowth, and reduced lateral nitrate allocation to nodes. This suggested that NRT1.13 is required for low-nitrate acclimation and that internal nitrate is monitored near the xylem by NRT1.13 to regulate shoot architecture and flowering time.

Ntr1.13 of Arabidopsis thaliana

Protein NRT1/ PTR FAMILY 5.8, NPF5.8 or NAEZT1, of 552 aas and 11 or 12 TMSs.  NAET1 and NAET2, function as nicotianamide (nicotinamide NA) transporters required for translocation of both iron and copper to seeds. Chao et al. 2021 showed that NAET1 and NAET2 are predominantly expressed in the shoot and root vascular tissues and mediate secretion of NA out of the cells, resembling the release of neurotransmitters from animal synaptic vesicles (Chao et al. 2021).

NPF5.8 of Arabidopsis thaliana (Mouse-ear cress)

Nicotinamine efflux porter of 563 aas and 11 or 12 TMSs. NAET1 and NAET2 function as a nicotianamide (nicotinamide NA) transporters required for translocation of both iron and copper to seeds. Chao et al. 2021 showed that NAET1 and NAET2 are predominantly expressed in the shoot and root vascular tissues and mediate secretion of NA out of cells, resembling the release of neurotransmitters from animal synaptic vesicles.

NAET2 of Arabidopsis thaliana (Mouse-ear cress)

Vacuolar (tonoplast) glycerate transporter AtNPF8.4 or Npf8.4, of 545 aas and 11 or 12 TMSs.  It facilitates shuttling of glycerate between peroxysomes and chloroplasts (Lin and Tsay 2023). It is a tonoplast glycerate uptake system that plays a role of photorespiration in C/N balance (Lin and Tsay 2023).

NPF8.4 of Arabidopsis thaliana

Nitrate (chlorate) or histidine:H⁺ symporter of 589 aas and 12 TMSs, Ntr1. Its structural gene is specifically expressed in the floral nectaries of Brassica species (Song et al. 2000).

Plants

RCH2 of Brassica napus

The nitrate excretion transporter1, NaxT1, og 558 aas and 13 TMSs in a 7 + 6 TMS arrangement (in the plasma membranes of plant cells).

Plants

NaxT1 of Arabidopsis thaliana (Q9M1E2)

The root dipeptide/tripeptide transporter, PTRI (Komarova et al., 2008). Transport is electrogenic and dependent on protons. Leak currents are inhibited by Phe-Ala when this peptide binds at the active site with high affinity (Hammes et al., 2010).

Plants

PTR1 of Arabidopsis thaliana (Q9M390)

The germinating pollen dipeptide/tripeptide transporter, PTR5 (Komarova et al., 2008). Transport is electrogenic and dependent on protons. Leak currents are inhibited by Phe-Ala when this peptide binds at the active site with high affinity (Hammes et al., 2010).

Plants

PTR5 of Arabidopsis thaliana (Q0WR84)

solute carrier family 15, member 3, SLC15A3, OCTP, PHT2, PHT3, of 581 aas and 12 TMSs in a 3 + 3 + 3 + 3 TMS arrangement. It is a histidine + di- and tri-peptide uptake transporter in immune cells (Verri et al. 2016). The functions, regulation and pathophysiology of PHT2 and PHT1, specifically in immunoregulation have been reviewed (Dong et al. 2023). 

Animals

SLC15A3 of Homo sapiens

Peptide:H⁺ symporter (transports cationic, neutral and anionic dipeptides including glycylsarcosine (gly-sar) (Søndergaard et al., 2008) as well as anserine (β-alanyl-1-N-methyl-L-histidine) and carnosine (β-alanyl-L-histidine) (Geissler et al., 2010); also transports β-lactam antibiotics, the antitumor agent, bestatin, and various protease inhibitors). It is competitively inhibited by L-4,4'-biphenylalanyl-L-proline (Bip-Pro) with ~10-20µM affinity. Inhibitors/substrates include cefadroxil, Ala-4-nitroanilide and δ-aminolevulinic acid (Knutter et al., 2007). The intracellular loop linking transmembrane domains 6 and 7 of the human dipeptide transporter hPEPT1 includes two amphipathic alpha-helices, with net positive and negative charges which interact and influence conformational changes of hPEPT1 during and after glycylsarcosine transport (Xu et al., 2010).  The rabbit orthologue provides the main pathway for dietary nitrogen uptake. Five tyrosyl residues are important for function and/or substrate binding (Pieri et al. 2009).  Human PepT1 is modified by N-glycosylation, and all six asparagine residues in the large extracellular loop between transmembrane domains 9 and 10 are subject to N-glycosylation (Chan et al. 2016). Lat1 transports 26 biologically active ultrashort peptides (USPs) into cells as is also true of LAT2 and PEPT1 (Khavinson et al. 2023). The sizes and structures of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analyses of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters was considered (Khavinson et al. 2023). The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the previously known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp^- or Glu^- amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide were found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters (Khavinson et al. 2023).

Animals

PepT1 of Rattus norvegicus

Peptide transporter, Pep1, also called CptB, Opt-2 and Pep-2.  It is of 835 aas and 11 TMSs.  It transports di-, tri- and tetra-peptides including phenylalanylmethionylarginylphenylalaninamide (FMRFamide) and N-acetylaspartylglutamate, both neuropeptides found throughout the animal kingdom. In contrast to CptA (TC# 2.A.17.4.3), CptB has low-affinity for its substrates (Fei et al. 1998). 

CptB of Caenorhabditis elegans

The tonoplast localized protein PtNPF1 participates in the regulation of nitrogen response in diatoms (phytoplankton). It has 775 aas and 12 TMSs in a 6 + 6 TMS arrangement.  PtNPF1 is presumably involved in modulating intracellular nitrogen fluxes, managing intracellular nutrient availability. This ability might allow diatoms to fine-tune the assimilation, storage and reallocation of nitrate, conferring upon them a strong advantage in oligotrophic environments (Santin et al. 2023).

PtNPF1 of Phaeodactylum tricornutum

High affinity oligopeptide transporter, CPTA. It transports di-, tri- and tetra peptides with low specificity. Neuropeptides (FMRF-amide and N-acetyl-Asp-Glu) are also transported (Fei et al. 1998).

Animals

CPTA of Caenorhabditis elegans

The renal brush-border electrogenic, proton-coupled, broad specificity, high affinity, peptide transporter, PepT2 (Rubio-Aliaga et al., 2000). It is competitively inhibited by L-4,4'-Biphenylalanyl-L-Proline (Bip-Pro) with ~10-20µM affinity. Inhibitor/substrates includes cefadroxil, Ala-4-nitroanilide and delta-aminolevulinic acid (Knutter et al., 2007).  It transports the fluorescent tracer-dipeptide beta-Ala-Lys-Nepsilon-7-amino-4-methyl-coumarin-3-acetic acid (Ala-Lys-AMCA). Whole-mount preparations from mouse, rat, and guinea pig stomach and small and large intestine were incubated with Ala-Lys-AMCA in the presence or absence of the uptake-inhibitors L-histidine, D-phenylalanyl-L-alanine (D-Phe-Ala), glycyl-L-sarcosine (Gly-Sar), glycyl-L-glutamine (Gly-Gln), benzylpenicillin, and cefadroxil. Fluorescence microscopy revealed that Ala-Lys-AMCA specifically accumulated in both ganglionic layers of the enteric nervous system (ENS) in all regions and species studied (Rühl et al. 2005). This could be inhibited by Gly-Sar, D-Phe-Ala, Gly-Gln, and cefadroxil, but not by free histidine and benzylpenicillin, indicating uptake via PEPT2. Accordingly, dipeptide uptake was completely abolished in PEPT2-deficient mice.

Animals

PepT2 of Mus musculus (Q9ES07)

Oligopeptide transporter, PepT1 (Slc15A1b) (Bucking and Schulte, 2012) (expressed in freshwater acclimated fish)

Animals

PepT1b of Fundulus heteroclitus (H2DJV9)

Di-/Tri-peptide porter. 3-d structure (PDB: 2XUT) known revealing a probable alternating access mechanism of transport (Newstead et al., 2011).  A second structure shows the protein in an inward open conformation with the peptidommetic, alafosfalin, bound (Guettou et al. 2013). Appears to take up glutathione (Deutschbauer et al. 2011).

Bacteria

Di-/Tri-peptide permease of Shewanella oneidensis (Q8EKT7)

Solute carrier family 15 member 2 (Kidney H⁺:peptide cotransporter) (Oligopeptide transporter, kidney isoform) (Peptide transporter 2, PEPT2) (Verri et al. 2016). Transports opioid peptides (Ganapathy and Miyauchi 2005). It is an electrogenic uphill peptide and peptidomimetic drug transporter, coupling of substrate translocation to a transmembrane electrochemical proton gradient serving as the driving force. In human airways, PEPT2 is localized to bronchial epithelium and alveolar type II pneumocytes, and transport studies revealed that both peptides and peptidomimetic drugs such as antibiotic, antiviral, and antineoplastic drugs are carried by the system. PEPT2 is also responsible for the transport of delta-aminolevulinic acid, which is used for photodynamic therapy and the diagnostics of pulmonary neoplasms (Groneberg et al. 2004). PepT2 in mammals plays essential roles in the reabsorption and conservation of peptide-bound amino acids in the kidney and in maintaining neuropeptide homeostasis in the brain. It is also responsible for the absorption and disposing of peptide-like drugs, including angiotensin-converting enzyme inhibitors, β-lactam antibiotics and antiviral prodrugs. Understanding the structure, function and regulation of PepT2 is of emerging interest in nutrition, medical and pharmacological research. Wang et al. 2022 provided an overview of the structure, substrate preferences and localizations of PepT2 in mammals. As PepT2 is expressed in various organs, its functions in the liver, kidney, brain, heart, lung and mammary gland have been addressed. Regulatory factors that affect the expression and function of PepT2, such as transcriptional activation and posttranslational modification, are also discussed (Wang et al. 2022). Lichtinger et al. 2024 established a mechanistic link between proton binding and peptide recognition, revealing key details underpining secondary active transport in POTs.

Animals

SLC15A2 of Homo sapiens

Solute carrier family 15 member 1 (Intestinal H⁺:peptide cotransporter) (Oligopeptide transporter, small intestine isoform) (Peptide transporter 1, PepT1).  Takes up oligopeptides of 2 to 4 amino acids with a preference for dipeptides, a major route for the absorption of protein digestion end-products. PepT1 is modified by N-glycosylation, and all six asparagine residues in the large extracellular loop between TMSs 9 and 10 are subject to N-glycosylation.  This allows proper association with the plasma membrane and/or stabilization (Chan et al. 2016). Transports opioid peptides (Ganapathy and Miyauchi 2005), can serve as a druh importer and plays a role in inflammatory bowel diseases (Viennois et al. 2018). PEPT1 is upregulated in kidney cancer cell lines, with little expression in normal pancreas. PEPT1 is essential for the growth of pancreatic cancer cells and is therefore a viable drug target (Schniers et al. 2021). Mutation of arginine 282 to glutamate uncouples the movement of peptides and protons by the rabbit PepT1 (Meredith 2004). The structure of the horse ortholog shows that the extracellular domain between TMSs 9 and 10 bridges the NTD and CTD by interacting with TMS1. Deletion of ECD or mutations to the ECD-TMS1 interface impairs transport activity (Shen et al. 2022).

Animals

PepT1 of Homo sapiens