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TCID System Name Disease OMIM

The erythrocyte/brain hexose facilitator, glucose transporter-1, Gtr1. SLC2a1 or Glut1. Transports D-glucose, dehydroascorbate, arsenite and the flavonone, quercetin, via one pathway and water via a distinct channel. Sugar transport has been suggested to function via a sliding mechanism involving several sugar binding sites (Cunningham et al., 2006). Glut1 is the receptor for human T-cell leukemia virus (HTLV)) (Manel et al., 2003). The orientation of the 12 TMSs and the conformation of the exofacial glucose binding site of GLUT1 have been proposed (Mueckler and Makepeace 2004). It is regulated by stomatin (TC# 8.A.21) to take up dehydroascorbate (Montel-Hagen et al., 2008). Mutations cause Glut1 deficiency syndrome, a human encephalopathy that results from decreased glucose flux through the blood brain barrier (Pascual et al., 2008).  Mueckler and Makepeace (2009) have presented a model of the exofacial substrate-binding site and helical folding of Glut1. Glut1, 2, 4 and 9 are functional both in the plasma membrane and the endoplasmic reticulum (Takanaga and Frommer, 2010). Glut1 is down-regulated in the brains of Alzheimer's disease patients (Liu et al., 2008b). Metabolic stress rapidly stimulates blood-brain barrier endothelial cell sugar transport by acute up-regulation of plasma membrane GLUT1 levels, possibly involving an AMP-activated kinase activity (Cura and Carruthers, 2010). Serves as a receptor for neuropilin-1 (923aas; 2 TMSs; O14786) and heparan sulfate proteoglycans (HSPGs) (Hoshino, 2012). Glut1 has a nucleotide binding site, and nucleotide binding affects transport activity (Yao and Bajjalieh 2009).  The protein serves as a receptor for dermatin and β-adducin which help link the spectrin-actin junctional complex to the erythrocyte plasma membrane (Khan et al. 2008).  May play a role in paroxysmal dyskinesias (Erro et al. 2017). GLUT1 mediates infection of CD4+ lymphocytes by human T cell leukemia virus type 1 (Jin et al. 2006). Mutations in disordered regions can cause disease by introducing dileucine motifs, For example, mutations that are causative of GLUT1 deficiency syndrome are of this type, and the mutated protein mislocalizes to intracellular compartments (Meyer et al. 2018). Glucose transits along a transmembrane pathway through significant rotational motions while maintaining hydrogen bonds with the protein (Galochkina et al. 2019). It is phosphoryated by protein kinase C-B (TC# 8.A.104.1.4) (Lee et al. 2015). GLUT1-mediated exchange of fluorosugars has been studied (Shishmarev et al. 2018). Resveratrol and soy isoflavones alone and in combination improve the learning and memory of aging rats. The mechanism may be related to up-regulating the expression of GLUT1 and GLUT3 genes in the hippocampus (Zhang et al. 2020). The pore diameters of the transmembrane glucose transporters of all Class I GLUT proteins are constricted upon depletion of unsaturated fatty acids in the membranes (Weijers 2020). Diclofenac inhibits tumor cell glycolysis and growth by decreasing GLUT1 expression (Yang et al. 2021). Almost the entire populations of Glut1 and three other transmembrane proteins are immobilized by either the incorporation within large multiprotein complexes or entrapment within the protein network of the cortical spectrin cytoskeleton (Kodippili et al. 2020). This system is required for hepatocellular carcinoma proliferation and metastasis (Fang et al. 2021). The main triggers FoR activation of transport are located within the solvent accessible linker regions in the extramembranous zones (Gonzalez-Resines et al. 2021). DHHC9-mediated GLUT1 S-palmitoylation is requuired for plasma membrane localization and promotes glioblastoma glycolysis and tumorigenesis (Zhang et al. 2021). An ancient family of arrestin-fold proteins, termed alpha-arrestins, have conserved roles in regulating nutrient transporter trafficking and cellular metabolism as adaptor proteins. One alpha-arrestin, TXNIP (thioredoxin-interacting protein), is known to regulate myocardial glucose uptake, but the in vivo role of the related alpha-arrestin, ARRDC4 (arrestin domain-containing protein 4), was unknown. Interactions of ARRDC4 with GLUT1 prove to mediate metabolic stress in the ischemic heart (Nakayama et al. 2022). Mercury (Hg2+) decreased membrane deformability, impairing RBC capacity to deal with the shear forces in the circulation, increasing membrane fragmentation, and affecting transport (Notariale et al. 2022). GLUT-1 and GLUT-3 play important roles in the development of some types of malignant tumors, including glioblastoma, and expression of both is regulated by miRNAs (Beylerli et al. 2022). Glucose uptake inhibitors via Glut1 are potential anticancer agents (Hung et al. 2022). GLUT1 deficiency syndrome (GLUT1DS1) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly, and movement disorders (e.g., spasticity and dystonia) (Mauri et al. 2022). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly, these variants (~2 dozen) arise de novo, resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described (Mauri et al. 2022). Fluoride exposure affects the expression of glucose transporters (GLUT1 and 3) and ATP synthesis (Chen et al. 2023). GLUT1 is necessary for the flexor digitorum brevis (FDB) to survive hypoxia, but overexpression of GLUT1 was insufficient to rescue other skeletal muscles from hypoxic damage (Amorese et al. 2023). The role of GLUT inhibitors, micro-RNAs, and long non-coding RNAs that aid in inhibiting glucose uptake by cancer cells have been discussed as potential theraputics (Chamarthy and Mekala 2023). GLUT1 overexpression in tumor cells is a potential target for drug therapy (Zhao et al. 2023). HSP90B1-mediated plasma membrane localization of GLUT1 promotes radioresistance of glioblastomas (Li et al. 2023).  The core genes (Fgf2, Pdgfra, Ptpn11, Slc2a1) are highly expressed in sevoflurane anesthesia brain tissue samples. The 4 core genes (Fgf2, Pdgfra, Ptpn11, and Slc2a1) are associated with neurodegenerative diseases, brain injuries, memory disorders, cognitive disorders, neurotoxicity, drug-induced abnormalities, neurological disorders, developmental disorders, and intellectual disabilities. Fgf2 and Ptpn11 are highly expressed in brain tissue after sevoflurane anesthesia, the higher the expression level of Fgf2 and Ptpn11, the worse the prognosis (Zhang and Xu 2023). Target separation and potential anticancer activity of withanolide-based glucose transporter protein 1 inhibitors from Physalis angulata var. villosa have been evaluated (Zhang et al. 2023).  PIGT is a subunit of the glycosylphosphatidylinositol transamidase which is involved in tumorigenesis and invasiveness.  PIGT promotes cell growth, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking (Tan et al. 2024).  PDGF-stimulated glucose uptake via Glut1 has been reported to be dependent on receptor/transporter endocytosis (Tsutsumi et al. 2024).

GLUT1 deficiency syndrome 1 (GLUT1DS1) 606777

Glucosamine/glucose/fructose uniporter, Glut-2, Glut2 or ATG9A; it may also transport dehydroascorbate (Mardones et al., 2011Maulén et al., 2003), and cotransports water against an osmotic gradient (Naftalin, 2008).  Mutations may give rise to the rare autosomal recessive Fanconi-Bickel syndrome (Batool et al. 2019). It mediates intestinal transport of quercetrin (Li et al. 2020) and can transport the drug gastrodin, a seditive with a strcture of a phenolic glucoside (Huang et al. 2023). It also functions in autophagy. The cryoEM structure of the human ATG9A isoform at 2.9-Å resolution has been solved (Guardia et al. 2020). The structure reveals a fold with a homotrimeric domain-swapped architecture, multiple membrane spans, and a network of branched cavities, consistent with ATG9A being a membrane transporter. Mutational analyses support a role for the cavities in the functions of ATG9A. Structure-guided molecular simulations predict that ATG9A causes membrane bending, explaining the localization of this protein to small vesicles and highly curved edges of growing autophagosomes (Guardia et al. 2020). Both GLUT2 and GLUT3 have been expressed in yeast and exhibit most of the characteristics of the proteins expressed in humans (Schmidl et al. 2020). Autophagy is a highly conserved pathway that the cell uses to maintain homeostasis, degrade damaged organelles, combat invading pathogens, and survive pathological conditions. A set of proteins, called ATG proteins, comprise the core autophagy machinery and work together in a defined hierarchy. ATG9A vesicles are at the heart of autophagy, as they control the rapid de novo synthesis of an organelle called the phagophore. ATG9A is present in different membrane compartments (van Vliet et al. 2023).  Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression (Morrice et al. 2023).


Fanconi-Bickel syndrome (FBS) 227810
2.A.1.1.59 The glucose transporter, GLUT10, was originally believed to be responsible for Type 2 diabetes. It is now believed to be responsible for arterial tortuosity, a rare autosomal recessive connective tissue disease (Callewaert et al., 2007). GLUT10 transports glucose and 2-deoxy glucose (Km=0.3 mM), and is inhibited by galactose and phloretin (Coucke et al., 2006). Arterial tortuosity syndrome (ATS) 208050

The kidney basolateral urate efflux transporter (SLC2A9, URATv1 or GLUT9) (orthologue of 2.A.1.1.47) (Anzai et al., 2008). Human SLC2A9a and SLC2A9b isoforms mediate electrogenic transport of urate with different characteristics in the presence of hexoses (Witkowska et al., 2012).  It transports hexoses as well as urate, the latter by a uniport mechanism, thus catalyzing uptake as well as efflux. The ITM2B protein Q9Y287; 266 aas and 1 TMS) inhibits urate uptake and stimulates efflux (Mandal and Mount 2019). GLUT9's transcription is regulated by a hepatocyte nuclear factor, HNF4α (Prestin et al. 2014). Residues involved in urate transport have been identified (Long et al. 2017). Pathogenic variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) can give rise to renal hypouricemia (Perdomo-Ramirez et al. 2023).

Hypouricemia renal 2 (RHUC2) 612076

Insulin-responsive facilitative glucose transporter in skeletal and cardiac muscle, adipose, and other tissues, Glut4 (GTR4; SLC2A4; 509aas). Defects in Glut4 cause noninsulin-dependent diabetes mellitus (NIDDM). Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor (Gonzalez et al., 2011). The first luminal loop confers insulin responsiveness to GLUT4 (Kim and Kandror, 2012). Exercise increases Glut4 synthesis in a process involving several protein kinases, the Glut4 enhancer factor (GEF; SLC2A4 regulator; Q9NR83), and the myocyte enhancing factor 2 (MEF2; NP_001139257). (McGee and Hargreaves 2006; Wright 2007; Zorzano et al. 2005). monoclonal antibodies against the GLUT4 inward-open and outward-open states have been isoated (Tucker et al. 2018). It is phosphoryated by protein kinase C-β, PRKCB or PKCB (Lee et al. 2015). Insulin-induced GLUT4 transport is observed in the heart and brain in addition to the skeletal muscle and adipocytes, and hormones other than insulin can enhance GLUT4 transport (Wang et al. 2020). Prolonged preoperative fasting induces postoperative insulin resistance by ER-stress mediated Glut4 down-regulation in skeletal muscle (Lin et al. 2021). GLUT4 is the primary glucose transporter in adipose and skeletal muscle tissues, and its cellular trafficking is regulated by insulin signaling. Failed or reduced plasma membrane localization of GLUT4 is associated with diabetes. The cryo-EM structures of human GLUT4 bound to a small molecule inhibitor cytochalasin B (CCB) at resolutions of 3.3 Å which exhibits an inward-open conformation. The cryo-EM structure reveals an extracellular glycosylation site and an intracellular helix that is invisible in the crystal structure of GLUT1 (Yuan et al. 2022). Tectorigenin targets PKACα to promote GLUT4 expression in skeletal muscle and improve insulin resistance in vitro and in vivo (Yao et al. 2023). Key molecular players in insulin resistance (IR) are the insulin receptor and glucose transporter 4, and certain natural products, such as lipids, phenols, terpenes, antibiotics and alkaloids have beneficial effects on IR which are named "membrane-active immunomodulators" (MAIMs) (Izbicka and Streeper 2023). An example is the medium chain fatty acid ester diethyl azelate (DEA), which increases the fluidity of plasma membranes with subsequent downstream effects on cellular signaling and improves the symptoms of IR. The intracellular helical bundle of human glucose transporter GLUT4 is important for complex formation with ASP (Huang et al. 2023). Diabetes-induced electrophysiological alterations on neurosomes in ganglia of the peripheral nervous system have been reported (Leal-Cardoso et al. 2023). Regulated dynamic subcellular GLUT4 localization has been revealed by proximal proteome mapping in human muscle cells (Ray et al. 2023). In goats, this system is closely associate with lipid metabolism (Zhang et al. 2024).

Diabetes mellitus, non-insulin-dependent (NIDDM) 125853

The low affinity proton-linked monocarboxylate (lactate, pyruvate, mevalonate, branched chain oxo acids, β-hydroxybutyrate, γ-hydroxybutyrate, butyrate, acetoacetate, acetate and formate, succinate) uptake/efflux porter (Moschen et al. 2012; Reddy et al. 2020). pH-gated succinate secretion regulates muscle remodeling in response to exercise (Reddy et al. 2020). The structural basis of MCT1 inhibition by anti-cancer drugs has been considered (Wang et al. 2020). MCT1 also transports anti-tumor alkylating agents, 3-bromopyruvate and dichloroacetate (Cooper et al. 1989; Su et al. 2016; Bailey et al. 2019) as well as artemisinin (Girardi et al. 2020). Activity is stimulated by direct interaction with carbonic anhydrase isoform II (Becker et al., 2005). This transporter interacts physically with the chaperone protein Basigin (CD147; TC #8.A.23.1.1) which is required both for targetting to the plasma membrane and for activity. Mct-2 uses a different chaperone protein, GP70. Mct-1 also transports the methionine hydroxy analogue 2-hydroxy (4-methylthio) butanate (Martin-Venegas et al., 2007; Becker and Deitmer, 2008). MCT1, 3 and 4 require the ancillary protein, basigin (P35613; 8.A.23.1.1) for plasma membrane localization (Ovens et al., 2010).  It partially localizes to the peroxysomal membrane (Visser et al. 2007). MCT1 is regulated by CD147 proteins, and this association is important for lactate export and cell proliferation in certain cancer cells (Walters et al. 2013).  It is upregulated in some cancers and maintains the metabolic phenotype of these cancer cells by mediating lactate efflux together with a proton, promoting pH homeostasis (Baltazar et al. 2014). MCT-1 functions as a positive regulator of osteoblast differentiation via suppression of p53 (Sasa et al. 2018). It plays a role in aggressive breast cancer subtypes (Li et al. 2018) as well as other cancers (Park et al. 2018).  The SLC16A1 gene is a potential marker to predict race performance in Arabian horses (Ropka-Molik et al. 2019). MCT1 is a negative regulator and MCT2 and a positive regulator of osteoclast differentiation, while MCT2 is required for bone resorption by osteoclasts (Imai et al. 2019). MCTs 1 and 4 are present in increased amounts in solid tumors, and inhibitors as potential therapeutics have been reviewed (Puri and Juvale 2020). Interleukin-1beta induces monocarboxylate transporter-1 in an oxygen tension-dependent manner (Tanaka et al. 2022). Substrate protonation is a pivotal step in the mechanisms of several MCT-unrelated weak acid translocating proteins, but utilization of the proton binding and transfer capabilities of the transporter-bound substrate is probably a universal theme for weak acid anion/H+ cotransport (Geistlinger et al. 2023). This transporter is over expressed in breast cancer (Arponen et al. 2023). Fasting upregulates MCT1 at the rat blood-brain barrier through PPAR δ activation (Chasseigneaux et al. 2024).  The anticancer effect of androgen deprivation therapy can be enhanced by an MCT1 inhibitor in prostate cancer cells (Kim et al. 2024).

Symptomatic deficiency in lactate transport (SDLT) 245340

MCT8 (SLC16a2) homodimeric monocarboxylate thyroid hormone transporter 8 of 613 or 539 aas and 12 TMSs (Visser et al. 2009; Arjona et al., 2011).  It is the X-linked mental retardation Allan-Herndon-Dudley syndrome (AHDS) (a severe psychomotor retardation syndrome) protein (Schweizer and Köhrle 2012; Boccone et al. 2010; Johannes et al. 2016). Lack of MCT8 function produces serious neurological disturbances, most likely due to impaired transport of thyroid hormones across brain barriers during development, resulting in severe brain hypothyroidism (Grijota-Martínez et al. 2020). Arg residues important for function have been identified (Groeneweg et al. 2013).  Thyroid hormone (TH) transporters in the brain and across the blood brain barrier have been reviewed (Wirth et al. 2014; Bernal et al. 2015). The product facilitates both TH uptake and efflux across the cell membrane. The disease goes together with low serum T4 and high T3 levels. The mechanisms underlying MCT8-deficient brain development in various animal models including humans has been reviewed (Vancamp and Darras 2017). Together with OATP1C1 (TC# 2.A.60.1.15), MCT8 controls skeletal muscle regeneration (Mayerl et al. 2018).  Deafness and loss of cochlear hair cells occurs in the absence of thyroid hormone transporters, Slc16a2 (Mct8) and Slc16a10 (Mct10) (Sharlin et al. 2018). Stable levels of MCT8 protein in endothelial cells of the blood-brain barrier, choroid plexus epithelial cells and tanycytes during postnatal development has been demonstrated (Wilpert et al. 2020). Oligomerization involves noncovalent interactions between the N-terminal halves of MCT8 proteins (Groeneweg et al. 2020). Genetic variants in MCT8, cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency (van Geest et al. 2020). Shaji 2021 identified natural inhibitors against MCT8. Emodin exhibited the best binding energy of -8.6 kcal/mol followed by helenaquinol, cercosporamide and resveratrol. Emodin and helenaquinol exhibit high binding energy. Cercosporamide and resveratrol exhibited higher binding energy than triac and desipramine and showed the binding energy similar to silychristin. Thus, these compounds could be promising candidates for further evaluation for AHDS prevention. MCT8 deficiency induces severe X-linked psychomotor retardation (Iwayama et al. 2021). It is common and severe in homozygous males (one X chromosome) but mild in heterozygous females (XX) (Dumitrescu et al. 2004). Thyroid normone transporters MCT8 and OATP1C1 are expressed in pyramidal neurons and interneurons in the adult motor cortex of human and macaque brains (Wang et al. 2023). Thyroid hormone transporters MCT8 and OATP1C1 are expressed in projection neurons and interneurons of basal ganglia and motor thalamus in adult human brains (Wang et al. 2023). MCT8 plays a vital role in maintaining brain thyroid hormone homeostasis. This transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders as well as BBB leakage (Guillén-Yunta et al. 2023). A novel SLC16A2 gene mutation produced a rare case of delayed myelination with dysthyroidism, v Allan-Herndon-Dudley syndrome (Mahesan et al. 2023). MCT8 inhibitors include methylmercury, bisphenol-AF and bisphenol-Z as well as previously known MCT8 inhibitors (Wagenaars et al. 2024).

Monocarboxylate transporter 8 deficiency (MCT8 deficiency) 300523
2.A.1.13.13 solute carrier family 16, member 11 (monocarboxylic acid transporter 11) Diabetes mellitus, non-insulin-dependent (NIDDM) 125853

Solute carrier family 16, member 12, SLC16A12, or monocarboxylic acid transporter 12; MCT12. Facilitative monocarboxylate transporter that mediates creatine transport across the plasma membrane (Abplanalp et al. 2013; Takahashi et al. 2020). It is the cataract and glucosuria associated monocarboxylate transporter.

Cataract, juvenile, with microcornea and glucosuria (CJMG) 612018
2.A.1.13.17 Monocarboxylate transporter 13 (MCT 13) (Solute carrier family 16 member 13) Diabetes mellitus, non-insulin-dependent (NIDDM) 125853

Lysosomal sialate transporter (Salla disease and infantile sialate storage disease protein, Sialin, of 419 aas and 12 TMSs (Morin et al., 2004)). Also transports glucuronic acid and aspartate. Structure-function studies have identify crucial residues and substrate-induced conformational changes (Courville et al., 2010). Also called SLC17A5. The substrate binding pocket has been identified based on modeling studies (Pietrancosta et al., 2012).  NAAG (N-acetylaspartylglutamate) an abundant neuropeptide in the vertebrate nervous system that is released from synaptic terminals in a calcium-dependent manner and acts as an agonist at the type II metabotropic glutamate receptor mGluR3, is transported into synaptic vesicles before it is secreted. Lodder-Gadaczek et al. 2013 demonstrate that vesicular uptake of NAAG and the related peptide NAAG2 (N-acetylaspartylglutamylglutamate) is mediated by sialin (SLC17A5). Sialin is probably the only vesicular transporter for NAAG and NAAG2, because transport of both peptides was not detectable in vesicles isolated from sialin-deficient mice.  Sialin also transports nitrate in the plasma membrane of salivary glands (Qin et al. 2012). Sialin interacts with nitrate and participates in the regulation of NO production and cell biological functions for body homeostasis (Wang and Qin 2022). Sialin mediates the flux of sialic acid from lysosomes to the cytoplasm (Li et al. 2022). Altered sialin mRNA expression in the main tissues of male type 2 diabetes rats has been documented (Yousefzadeh et al. 2023).  Base editing corrects the common Salla disease SLC17A5 c.115C>T variant (Harb et al. 2023).

Salla disease (SD) 604369

The vesicular purine nucleotide (ADP, ATP, GTP) transporter, VNUT or SLC17A9. It is found in synaptic vesicles and chromafin granules (Sawada et al., 2008)) and is associated with disseminated superficial actinic porokeratosis (DSAP), a rare autosomal dominant genodermatosis (Cui et al. 2014). It plays a key role in purinergic signaling through its ability to transport nucleotides using the pmf. It catalyzes Cl--dependent transport activity involving essential arginines in the transmembrane region. Ketoacids inhibit these transporters through modulation of Cl- activation, but Cl- and the arginine residues are not important for ATP binding (Iwai et al. 2019). High expression of SLC17A9 correlates with a poor prognosis for colorectal cancer (Yang et al. 2019).

Porokeratosis 8, disseminated superficial actinic type (POROK8) 616063
Vesicular glutamate transporter 3 (VGluT3) (Solute carrier family 17 member 8). Loss in mice produces circadian-dependent hyperdopaminergia and amiliorates motor disfunction and dopa-mediated dyskinesias in a model of Parkinson's Disease (Divito et al. 2015). VGLUT3 is expressed selectively in the inner hair cells (IHCs) and transports the neurotransmitter glutamate into synaptic vesicles. Mutation of the SLC17A8 gene is associated with DFNA25 (deafness, autosomal dominant 25), a non-syndromic hearing loss (ADNSHL) in humans (Ryu et al. 2016). Glut3 contributes to stress response and related psychopathologies (Horváth et al. 2018). An adeno-associated virus carrying the Slc17a8 gene restored vesicular Glut3 in the inner hair cells of the cochlea, thereby rescuing loss in mice that lacked Glut3 (Mathiesen et al. 2023).
Deafness, autosomal dominant, 25 (DFNA25) 605583

The apical proximal tubular renal urate:anion exchanger, URAT1 (Slc22a12).  Catalyzes Na+-independent anion efflux (secretion) and reabsorption (Eraly et al., 2003a,b; Anzai and Endou, 2011; Prestin et al. 2014)  Regulated by the PDZK1 protein; Anzai et al., 2004). Also transports orotate, a precursor of pyrimidine biosynthesis (Miura et al., 2011). Mutations in URAT1 cause hereditary renal hypouricemia/gaut.  Residues involved in urea and inhibitor binding have been identified (Tan et al. 2016). Mutations can cause renal hypouricemia (RHUC), a heterogeneous genetic disorder that is characterized by decreased serum uric acid concentrations and increased fractional excretion of uric acid (Zhou et al. 2018; Kaynar et al. 2022). Mutation in transmembrane domain 8 of the human urate transporter 1 (residue K393) disrupts uric acid recognition and transport (Lan et al. 2022). Pathogenic variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) can give rise to renal hypouricemia (Perdomo-Ramirez et al. 2023). Biphenyl carboxylic acid derivatives are potent URAT1 inhibitors (Hou et al. 2023).

Hypouricemia renal 1 (RHUC1) 220150

The polyspecific organic cation (L- and D-carnitine, butyryl-L-carnitine, acetyl carnitine, γ-butyro-betaine, glycinebetaine, β-lactam antibiotics with a quaternary nitrogen such as cephaloridine, and others):Na+ symporter, OCTN2 (SLC22A5). Carnitine is transporter with high affinity (2 - 20 μM0 (Ingoglia et al. 2015). Associated with Crohn''s disease (Barton et al., 2005) as well as primary carnitine deficiency.  The protein is glycosylated on extracytoplasmic asparagines, and these residues are in a region important for function and turnover (Filippo et al. 2011).  OCTN2 maintains the carnitine homeostasis, resulting from intestinal absorption, distribution to tissues, and renal excretion/reabsorption (Pochini et al. 2013).  OCTN1 and OCTN2 are associated with several pathologies, such as inflammatory bowel disease, primary carnitine deficiency, diabetes, neurological disorders, and cancer.  OCTN2 is activated in a process dependent on Caveolin1 (Q03135) which interacts directly with OCTN2 and by protein kinase C which does not phosphorylate OCTN2 directly (Czeredys et al. 2013). Cholesterol stimulates the cellular uptake of L-carnitine by the carnitine/organic cation transporter novel 2 (OCTN2) (Zhang et al. 2020). A dataset of OCTN2 variant functions and localization has been created, revealing important disease-causing mechanisms (Koleske et al. 2022).  Primary carnitine deficiency (PCD) is caused by pathogenic variants of the SLC22A5 gene, which encodes a high affinity carnitine transporter. Carnitine is essential for the transport of acyl-CoA, produced from fatty acids, into the mitochondria where they are oxidised to produce energy (Khries et al. 2023). OctN2 transports doxorubicin (Yi et al. 2023). A novel pathogenic variant in the carnitine transporter gene, SLC22A5, is associated with metabolic carnitine deficiency and cardiomyopathy features (Jolfayi et al. 2024).

Systemic primary carnitine deficiency (CDSP) 212140

MDR pump, SLC22A18 in lung cancer cells (Lei et al., 2012). It has 424 aas and 12 TMSs. Allelic loss in the absence of mutations in the polyspecific transporter gene BWR1A on 11p15.5 in hepatoblastoma has been shown (Albrecht et al. 2004).

Lung cancer (LNCR) 211980

NCL7 or MFSD8. Neuronal ceroid lipofuscinosis, NCL, a neuro-degenerative genetic disease, is caused by mutations in at least 8 different human genes, one of which, CLN7 (MFSD8), is associated with late infantile NCL. CLN7 is localized to lysosomes (Sharifi et al., 2010).  Loss of this putative lysosomal transporter in the brain leads to lysosomal dysfunction, impaired constitutive autophagy and neurodegeneration late in the disease (Brandenstein et al. 2015). An in-frame deletion in the MFSD8 gene gave rise to neuronal ceroid lipofuscinosis type 7 (Hosseini Bereshneh and Garshasbi 2018). In D. discoideum, it interacts with cathepsin D (CtsD), as well as human orthologs of CLN3 (Cln3) and CLN5 (Cln5) (Huber et al. 2020). In humans the defect can also affect cardiac conducting cells and cardiomyocytes as well as basophilic degeneration of myocardium. (Iannaccone Farkašová et al. 2019).  Moreover, loss of Mfsd8 alters the secretome during Dictyostelium aggregation (Huber et al. 2023).

Ceroid lipofuscinosis, neuronal, 7 (CLN7) 610951

The endoplasmic reticular/Golgi acetyl-CoA:CoA antiporter 1, ACATN/ACATN1 (SLC33A1).  Allows acetylation of sialic acid residues in gangliosides and lysine residues in membrane proteins.  It is associated with neurodegenerative disorders such as sporadic amyotrophic laterial sclerosis (ALS) and Spastic Paraplegia 42, and it is essential for motor neuron viability (Hirabayashi et al. 2013). Abnormal concentrations of acetylated amino acids in cerebrospinal fluid are observed in acetyl-CoA transporter deficiency (Šikić et al. 2022).

Spastic paraplegia 42, autosomal dominant (SPG42) 612539

Cell surface receptor (C-receptor) for anemia-inducing feline leukemia virus subgroup C (FLCVR, Slc49A1 or Mfsd7d) of 555 aas and 12 TMSs. It may function in choline transport (Kenny et al. 2023) or haem export in haemopoietic cells (Latunde-Dada et al., 2006Khan and Quigley, 2011) and may cause Diamond-Blackfan anemia when defective (Keel et al., 2008). Mutations of FLVCR1 in posterior column ataxia and retinitis pigmentosa result in the loss of heme export activity (Yanatori et al., 2012). Heme accumulation causes toxicity (Khan and Quigley 2018).  FLVCR1 is co-induced upon iron insufficiency in the placenta with the LDL receptor-related protein 1 (LRP1) heme receptor, and these two proteins may be important for neonatal iron status (Cao et al. 2014).  FLVCR1 is required for erythroid and αβ-, CD4 and CD8 T- cell development (Philip et al. 2015). A splice-site variant of FLVCR1 produces retinitis pigmentosa without posterior column ataxia (Yusuf et al. 2018). Protocols suitable for purification of FLVCR1a, antibody generation and structural characterization of the transporter have been reported (Chiabrando et al. 2020). FLVCR1-related disease is a rare cause of retinitis pigmentosa and hereditary sensory autonomic neuropathy (Grudzinska Pechhacker et al. 2020). More recently, integrative genetic analyses identified FLVCR1 as a plasma-membrane choline transporter in mammals (Kenny et al. 2023).

Posterior column ataxia with retinitis pigmentosa (PCARP) 609033

The Fowler syndrome-associated protein, feline leukemia virus subgroup C receptor-related protein 2, FLVCR2, or SLC49A2, is probably a heme importer (Duffy et al., 2010). Mutations of SLC49A2  are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain (Khan and Quigley 2018).

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH) 225790

Microsomal (ER/Golgi) glucose-6-P:Pi antiporter (glycogen storage disease (GSD1b and 1c); Gierke''s disease protein) (SLC37A2 in mice, associated with white adipose tissue obesity and expressed at high levels in macrophage) (4 isoforms present in humans (Chen et al., 2008)).  SLC37A1 and A2 can not substitute for A4.  91 mutations have been observed in human patients (Chou and Mansfield 2014).  Inhibited by cholorogenic acid although SLC37A1 and A2 are not.  SLC37A3 had not been characterized by 2014 (Chou and Mansfield 2014).

Glycogen storage disease 1B (GSD1B) 232220

The apical intestinal and choroid plexus proton-coupled, high affinity folate transporter, the hereditary folate malabsorption (HFM) protein, PCFT/HCP1 (Shin et al. 2010).  Also reported to mediate heme-iron uptake from the gut lumen with duodenal epithelial cells (Shayeghi et al., 2005; Latunde-Dada et al., 2006; Subramanian et al., 2008, Shin et al., 2012b), but it shows a higher affinity for folate than heme) (Qiu et al., 2006). Responsible for folate uptake by choroid plexus epithelial cells (Wollack et al., 2007) and placenta (Yasuda et al., 2008). The rat orthologue (Q5EBA8) catalyzes H+-dependent folate uptake in the intestine (Inoue et al., 2008; Zhao and Goldman, 2007; Qiu et al., 2006; Shin et al., 2012). Evidence for a 12 TMS topology with a renetrant loop between TMSs 2 and 3 has been presented (Zhao et al., 2010; Qiu et al., 2006; Zhao et al., 2011; Wilson et al. 2014).  Downregulated in Chronic Kidney Disease (CKD) in heart, liver, and brain, causing malabsorption (Bukhari et al., 2011). An IGXXG motif in TMS5 is important for folate binding and a GXXXG motif is involved in dimerization (Zhao et al., 2012). It is inhibited by bicarbonate, bisulfite, nitrite and other anions (Zhao et al. 2013).  Its role in antifolate cancer chemotherapy has been reviewed (Matherly et al. 2014). TMSs 3 and 6 may provide critical interfaces for formation of hPCFT oligomers, facilitated by the GXXXG motifs in TMS2 and TMS4 (Wilson et al. 2015).  The extracellular gate has been identified (Zhao et al. 2016), and mechanistic aspects have been considered (Date et al. 2016). Residues in the seventh and eighth TMSs play roles in the translocation pathway and folate binding (Aluri et al. 2017). The mutation, N411K-PCFT, is responsible for HFM (Aluri et al. 2018). PCFT is ubiquitously expressed in solid tumors to which it delivers antifolates, particularly pemetrexed, into cancer cells in a concentrative fashion (Zhao et al. 2018). Substitutions have been identified that lock and unlock PCFT into an inward-open conformation (Aluri et al. 2019). The nanodisc lipid composition influences the cell-free expression of PCFT (Do et al. 2021). Iron deficiency promotes hepatocellular carcinoma metastasis, and the loss of SLC46A1 expression leads to iron deficiency in liver tumor tissues (Wang et al. 2022). Cell-free expression of PCFT in the presence of nanodiscs has been reported (Do and Jansen 2022). Biological and therapeutic applications of the proton-coupled folate transporter have been reviewed (Matherly et al. 2022).

Hereditary folate malabsorption (HFM) 229050

Na+:glucose co-transporter of 672 aas and about 14 TMSs, SGLT2. It has a Na+ to glucose coupling ratio of 1:1 (Brown et al. 2019). Efficient substrate transport in the mammalian kidney is provided by the concerted action of a low affinity high capacity and a high affinity low capacity Na+/glucose cotransporter arranged in series along kidney proximal tubules. Inhibitors are antidiabetic agents (Li 2019; Singh and Singh 2020). They are also useful as theraputic agents of non-alcoholic fatty liver disease and chronic kidney disease (Kanbay et al. 2020). Marein, an active component of the Coreopsis tinctoria Nutt plant, ameliorates diabetic nephropathy by inhibiting renal sodium glucose transporter 2 and activating the AMPK signaling pathway (Guo et al. 2020). NHE-3 (TC# 2.A.53.2.18) was markedly downregulated, while the Na+-HCO3--cotransporter (NBC-1; TC# 2.A.31.2.12) and SGLT2 were upregulated after kidney transplantation (Velic et al. 2004). Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes. Niu et al. 2021 determined the cryogenic electron microscopic structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to a resolution of 2.95 Å. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle (Niu et al. 2021). There is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker, linagliptin, are used (Xiong et al. 2022). Canagliflozin, dapagliflozin and ipragliflozin significantly inhibit the growth of different cancer cell lines in the micromolar range; SGLT2 inhibitors have antiproliferation, anti-tumorigenesis, and anti-migration effects and may induce apoptosis in cancer cells. Treatment with SGLT2 inhibitors also results in the downregulation of selected genes (Bardaweel and Issa 2022). SGLT2 inhibitor treatment results in symptomatic and functional well-being, especially in relieving pain (Calderon-Rivera et al. 2022). Effects of SGLT2 inhibitors affect the heart and kidney to promote autophagic flux, nutrient deprivation signaling and transmembrane sodium transport (Zannad et al. 2022). Empagliflozin (EMPA), mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects (Scisciola et al. 2023). A diversifiable synthetic platform for the discovery of new carbasugar SGLT2 inhibitors using azide-alkyne click chemistry has been described (Kitamura et al. 2023). SGLT2 is inhibited by empagliflozin (Raven et al. 2023). SGLT2 inhibitors not only suppress hyperglycemia but also reduce renal, heart, and cardiovascular diseases (Unno et al. 2023). In fact, SGLT2 may also be related to other functions, such as bone metabolism, longevity, and cognitive functions based on mouse models (Unno et al. 2023). Complex effects of different SGLT2 inhibitors on alphaKlotho gene expression (see TC family 8.A.49) and protein secretion in renal MDCK and HK-2 cells have been observed (Wolf et al. 2023). Ferulic acid-grafted chitosan (FA-g-CS) stimulates the transmembrane transport of anthocyanins by SGLT1 and GLUT2 (Ma et al. 2022). SGLT2 Inhibitors are potential anticancer agents (Basak et al. 2023). Analyses of the effects of SGLT2 inhibitors on renal tubular sodium, water and chloride homeostasis as well as their roles in influencing heart failure outcomes has appeared (Packer et al. 2023).  The SGLT2 inhibitor, empagliflozin, alleviates cardiac remodeling and contractile anomalies in a FUNDC1-dependent manner in experimental Parkinson's disease (Yu et al. 2023). Type 2 diabetes guidance proposes offering SGLT2-inhibitor therapy to people with established atherosclerotic cardiovascular disease (ASCVD) or heart failure, but this suggestion has been questioned (Young et al. 2023). SGLT2 inhibition in a non-diabetic rat model of salt-sensitive hypertension blunts the development of salt-induced hypertension independent of sex (Kravtsova et al. 2023).

Renal glucosuria (GLYS1) 233100
Developed by Vamsee Reddy, 2015