Major Facilitator Superfamily; The Major Facilitator Superfamily (MFS) is a large and diverse group of secondary transporters that includes uniporters, symporters, and antiporters. MFS proteins facilitate the transport across cytoplasmic or internal membranes of a variety of substrates including ions, sugar phosphates, drugs, neurotransmitters, nucleosides, amino acids, and peptides. They do so using the electrochemical potential of the transported substrates. Uniporters transport a single substrate, while symporters and antiporters transport two substrates in the same or in opposite directions, respectively, across membranes. MFS proteins are typically 400 to 600 amino acids in length, and the majority contain 12 transmembrane alpha helices (TMs) connected by hydrophilic loops. The N- and C-terminal halves of these proteins display weak similarity and may be the result of a gene duplication/fusion event. Based on kinetic studies and the structures of a few bacterial superfamily members, GlpT (glycerol-3-phosphate transporter), LacY (lactose permease), and EmrD (multidrug transporter), MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement. Bacterial members function primarily for nutrient uptake, and as drug-efflux pumps to confer antibiotic resistance. Some MFS proteins have medical significance in humans such as the glucose transporter Glut4, which is impaired in type II diabetes, and glucose-6-phosphate transporter (G6PT), which causes glycogen storage disease when mutated.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAGVQQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALALLEQLPWMSYLSIVAIF 80
Cdd:cd17431 281 STSIFEKAGVQQPVYATIGAGVVNTIFTVVSLFLVERAGRRTLHLIGLGGMAICAILMTIALLLLEGYPWMSYVSIVAIF 360

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 14268550  81 GFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCFQ 130
Cdd:cd17431 361 GFVAFFEIGPGPIPWFIVAELFSQGPRPAAMAVAGFSNWTSNFIVGMCFQ 410

Class 1 Glucose transporters (GLUTs) of the Major Facilitator Superfamily; GLUTs, also called Solute carrier family 2, facilitated glucose transporters (SLC2A), are a family of proteins that facilitate the transport of hexoses such as glucose and fructose. There are fourteen GLUTs found in humans; they display different substrate specificities and tissue expression. They have been categorized into three classes based on sequence similarity: Class 1 (GLUTs 1-4, 14); Class 2 (GLUTs 5, 7, 9, and 11); and Class 3 (GLUTs 6, 8, 10, 12, and HMIT). GLUTs 1-4 are well-established as glucose and/or fructose transporters in various tissues and cell types. GLUT1, also called solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), displays broad substrate specificity and can transport a wide range of pentoses and hexoses including glucose, galactose, mannose, and glucosamine. It is found in the brain, erythrocytes, and in many fetal tissues. GLUT2 (or SLC2A2) is found in the liver, islet of Langerhans, intestine, and kidney, and is the isoform that likely mediates the bidirectional transfer of glucose across the plasma membrane of hepatocytes and is responsible for uptake of glucose by beta cells. GLUT3 (or SLC2A3) is found in the brain and can mediates the uptake of glucose, 2-deoxyglucose, galactose, mannose, xylose and fucose, and dehydroascorbate. GLUT4 (or SLC2A4) is an insulin-regulated facilitative glucose transporter found in adipose tissues, and in skeletal and cardiac muscle. GLUT14 (or SLC2A14) is an orphan transporter expressed mainly in the testis. GLUT proteins are comprised of about 500 amino acid residues, possess a single N-linked oligosaccharide, and have 12 transmembrane segments. They belong to the Glucose transporter -like (GLUT-like) family of the Major Facilitator Superfamily (MFS) of membrane transport proteins. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAGVQQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALALLEQLPWMSYLSIVAIF 80
Cdd:cd17431 281 STSIFEKAGVQQPVYATIGAGVVNTIFTVVSLFLVERAGRRTLHLIGLGGMAICAILMTIALLLLEGYPWMSYVSIVAIF 360

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 14268550  81 GFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCFQ 130
Cdd:cd17431 361 GFVAFFEIGPGPIPWFIVAELFSQGPRPAAMAVAGFSNWTSNFIVGMCFQ 410

MFS transporter, sugar porter (SP) family; This model represent the sugar porter subfamily of the major facilitator superfamily (pfam00083) [Transport and binding proteins, Carbohydrates, organic alcohols, and acids]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550     1 STSIFEKAGVQ--QPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALA--LLEQLPWMSYLSI 76
Cdd:TIGR00879 307 SPTIFENAGVStdHAFLVSIIVGAVNFAFTFVAIFLVDRFGRRPLLLIGAAGMAICLFVLGILGAsfVTGSSKSSGNVAI 386

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 14268550    77 VAIFGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCF 129
Cdd:TIGR00879 387 VFILLFIAFFAMGWGPVPWVIVSEIFPLSLRPKGISIAVAANWLANFIVGFLF 439

Class 1 Glucose transporters (GLUTs) of the Major Facilitator Superfamily; GLUTs, also called Solute carrier family 2, facilitated glucose transporters (SLC2A), are a family of proteins that facilitate the transport of hexoses such as glucose and fructose. There are fourteen GLUTs found in humans; they display different substrate specificities and tissue expression. They have been categorized into three classes based on sequence similarity: Class 1 (GLUTs 1-4, 14); Class 2 (GLUTs 5, 7, 9, and 11); and Class 3 (GLUTs 6, 8, 10, 12, and HMIT). GLUTs 1-4 are well-established as glucose and/or fructose transporters in various tissues and cell types. GLUT1, also called solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), displays broad substrate specificity and can transport a wide range of pentoses and hexoses including glucose, galactose, mannose, and glucosamine. It is found in the brain, erythrocytes, and in many fetal tissues. GLUT2 (or SLC2A2) is found in the liver, islet of Langerhans, intestine, and kidney, and is the isoform that likely mediates the bidirectional transfer of glucose across the plasma membrane of hepatocytes and is responsible for uptake of glucose by beta cells. GLUT3 (or SLC2A3) is found in the brain and can mediates the uptake of glucose, 2-deoxyglucose, galactose, mannose, xylose and fucose, and dehydroascorbate. GLUT4 (or SLC2A4) is an insulin-regulated facilitative glucose transporter found in adipose tissues, and in skeletal and cardiac muscle. GLUT14 (or SLC2A14) is an orphan transporter expressed mainly in the testis. GLUT proteins are comprised of about 500 amino acid residues, possess a single N-linked oligosaccharide, and have 12 transmembrane segments. They belong to the Glucose transporter -like (GLUT-like) family of the Major Facilitator Superfamily (MFS) of membrane transport proteins. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAGVQQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALALLEQLPWMSYLSIVAIF 80
Cdd:cd17431 281 STSIFEKAGVQQPVYATIGAGVVNTIFTVVSLFLVERAGRRTLHLIGLGGMAICAILMTIALLLLEGYPWMSYVSIVAIF 360

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 14268550  81 GFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCFQ 130
Cdd:cd17431 361 GFVAFFEIGPGPIPWFIVAELFSQGPRPAAMAVAGFSNWTSNFIVGMCFQ 410

Sugar (and other) transporter;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550     1 STSIFEKAGVQQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTI-ALALLEQLPWMSYLSIVAI 79
Cdd:pfam00083 277 STTIFENLGLSDSFLVTIIVGVVNFVFTFIAIFLVDRFGRRPLLLLGAAGMAICFVILGIvALLGVSKSDWAGIVAIVFI 356

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 14268550    80 FGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCFQ 130
Cdd:pfam00083 357 ALFIAFFAMGWGPVPWVIVSELFPLSVRSKAMALATAANWLANFLIGFLFP 407

Glucose transporters (GLUTs) and other similar sugar transporters of the Major Facilitator Superfamily; This family is composed of glucose transporters (GLUTs) and other sugar transporters including fungal hexose transporters (HXT), bacterial xylose transporter (XylE), plant sugar transport proteins (STP) and polyol transporters (PLT), H(+)-myo-inositol cotransporter (HMIT), and similar proteins. GLUTs, also called Solute carrier family 2, facilitated glucose transporters (SLC2A), are a family of proteins that facilitate the transport of hexoses such as glucose and fructose. There are fourteen GLUTs found in humans; they display different substrate specificities and tissue expression. They have been categorized into three classes based on sequence similarity: Class 1 (GLUTs 1-4, 14); Class 2 (GLUTs 5, 7, 9, and 11); and Class 3 (GLUTs 6, 8, 10, 12, and HMIT). GLUT proteins are comprised of about 500 amino acid residues, possess a single N-linked oligosaccharide, and have 12 transmembrane segments. The GLUT-like family belongs to the Major Facilitator Superfamily (MFS) of membrane transport proteins, which are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAG-VQQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALALLEQLPWMSYLSIVAI 79
Cdd:cd17315 203 APTIFKSAGgGTASILASIIVGVVNLLATLVAIRLVDKVGRRPLLLIGFAGMAASLLLLAIAFLLPALAKAAGWLALLGI 282

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 14268550  80 FGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCF 129
Cdd:cd17315 283 LLYIAAFAMGAGPVPWLLLSEIFPLRIRGKGMAIATLVNWIFNFIVGLTF 332

D-xylose-proton symporter and similar transporters of the Major Facilitator Superfamily; This subfamily includes bacterial transporters such as D-xylose-proton symporter (XylE or XylT), arabinose-proton symporter (AraE), galactose-proton symporter (GalP), major myo-inositol transporter IolT, glucose transport protein, putative metabolite transport proteins YfiG, YncC, and YwtG, and similar proteins. The symporters XylE, AraE, and GalP facilitate the uptake of D-xylose, arabinose, and galactose, respectively, across the boundary membrane with the concomitant transport of protons into the cell. IolT is involved in polyol metabolism and myo-inositol degradation into acetyl-CoA. The XylE-like subfamily belongs to the Glucose transporter -like (GLUT-like) family of the Major Facilitator Superfamily (MFS) of membrane transport proteins. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAGV--QQPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALALLEQLPWMSYLSIVA 78
Cdd:cd17359 220 GPEIFQNAGFseNAALLQTIGIGVVNVIFTIIAILLVDKVGRKPLLLIGSIGMAISLLLIGTAFYFAPGSQASGIVALVL 299

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 14268550  79 IFGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCF 129
Cdd:cd17359 300 ILLFVAFFAMSWGPVTWVLLSEIFPNRIRGLAMGIAVFFLWIANFLVSLTF 350

Glucose transporter (GLUT) types 6 and 8, Class 3 GLUTs, and similar transporters of the Major Facilitator Superfamily; This subfamily is composed of glucose transporter type 6 (GLUT6), GLUT8, plant early dehydration-induced gene ERD6-like proteins, and similar insect proteins including facilitated trehalose transporter Tret1-1. GLUTs, also called Solute carrier family 2, facilitated glucose transporters (SLC2A), are a family of proteins that facilitate the transport of hexoses such as glucose and fructose. There are fourteen GLUTs found in humans; they display different substrate specificities and tissue expression. They have been categorized into three classes based on sequence similarity: Class 1 (GLUTs 1-4, 14); Class 2 (GLUTs 5, 7, 9, and 11); and Class 3 (GLUTs 6, 8, 10, 12, and HMIT). Insect Tret1-1 is a low-capacity facilitative transporter for trehalose that mediates the transport of trehalose synthesized in the fat body and the incorporation of trehalose into other tissues that require a carbon source. GLUT proteins are comprised of about 500 amino acid residues, possess a single N-linked oligosaccharide, and have 12 transmembrane segments. They belong to the Glucose transporter -like (GLUT-like) family of the Major Facilitator Superfamily (MFS) of membrane transport proteins. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAGVQ-QPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIALALLEQLPWMSYLSIVAI 79
Cdd:cd17358 263 ASSIFDEAGSGlDPNTATIIIGVVQVVGTLVATLLVDRLGRRPLLLVSAIGMGIGLLALGLYFYLQEHGALLSSVSWLPL 342

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 14268550  80 FG---FVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCFQ 130
Cdd:cd17358 343 VGlviYIISFSIGLGPLPWVIMSEIFPAKIKGLAGSLVTLVNWLFAFIVTKTFP 396

H(+)-myo-inositol cotransporter and similar transporters of the Major Facilitator Superfamily; This subfamily is composed of myo-inositol/inositol transporters and similar transporters from vertebrates, plant, and fungi. The human protein is called H(+)-myo-inositol cotransporter/Proton myo-inositol cotransporter (HMIT), or H(+)-myo-inositol symporter, or Solute carrier family 2 member 13 (SLC2A13). HMIT is classified as a Class 3 GLUT (glucose transporter) based on sequence similarity with GLUTs, but it does not transport glucose. It specifically transports myo-inositol and is expressed predominantly in the brain, with high expression in the hippocampus, hypothalamus, cerebellum and brainstem. HMIT may be involved in regulating processes that require high levels of myo-inositol or its phosphorylated derivatives, such as membrane recycling, growth cone dynamics, and synaptic vesicle exocytosis. Arabidopsis Inositol transporter 4 (AtINT4) mediates high-affinity H+ symport of myo-inositol across the plasma membrane. The HMIT-like subfamily belongs to the Glucose transporter -like (GLUT-like) family of the Major Facilitator Superfamily (MFS) of membrane transport proteins. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAGVQQPVYATIGSGIV---NTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIalalleqlpwmsYLSIV 77
Cdd:cd17360 210 SATILQMAGFKDNQNAIWLSLIVagtNFIFTIVGMYLIDKFGRRKLLLISLFGVIVALVVLAV------------WLALV 277

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 14268550  78 AIFGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCF 129
Cdd:cd17360 278 GLILYLAFFAPGMGPVPWTVNSEIYPLWARGTGGGCAAAVNWVFNLLVSQTF 329

Fungal Hexose transporter subfamily of the Major Facilitator Superfamily of transporters and similar proteins; The fungal hexose transporter (HXT) subfamily is comprised of functionally redundant proteins that function mainly in the transport of glucose, as well as other sugars such as galactose and fructose. Saccharomyces cerevisiae has 20 genes that encode proteins in this family (HXT1 to HXT17, GAL2, SNF3, and RGT2). Seven of these (HXT1-7) encode functional glucose transporters. Gal2p is a galactose transporter, while Rgt2p and Snf3p act as cell surface glucose receptors that initiate signal transduction in response to glucose, functioning in an induction pathway responsible for glucose uptake. Rgt2p is activated by high levels of glucose and stimulates expression of low affinity glucose transporters such as Hxt1p and Hxt3p, while Snf3p generates a glucose signal in response to low levels of glucose, stimulating the expression of high affinity glucose transporters such as Hxt2p and Hxt4p. Schizosaccharomyces pombe contains eight GHT genes (GHT1-8) belonging to this family. Ght1, Ght2, and Ght5 are high-affinity glucose transporters; Ght3 is a high-affinity gluconate transporter; and Ght6 high-affinity fructose transporter. The substrate specificities for Ght4, Ght7, and Ght8 remain undetermined. The HXT subfamily belongs to the Glucose transporter -like (GLUT-like) family of the Major Facilitator Superfamily (MFS) of membrane transport proteins. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAGVQQ--PVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGC----AILMTIALALLEQLPWMSYL 74
Cdd:cd17356 220 GTTIFQSTGLTGssPLLTSIILYIVNFVSTIPGLFFVDKFGRRTCLLIGAAGMSIClfiyAAVGVRYLIPNPQSGTSNKS 299

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 14268550  75 S----IVAIFGFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGM 127
Cdd:cd17356 300 AgngmIVFICLFIFSFATTWGPIAWVYVAEVFPLRVRSKGMALATAFNWLWNFLISF 356

Glucose transporter type 12 (GLUT12), a Class 3 GLUT, of the Major Facilitator Superfamily of transporters; Glucose transporter type 12 (GLUT12) is also called Solute carrier family 2, facilitated glucose transporter member 12 (SLC2A12). It is a facilitative glucose transporter, classified as a Class 3 GLUT, and is expressed in the heart, skeletal muscle, prostate, and small intestine, and is highly upregulated in breast ductal cell carcinoma. It plays a role as a secondary insulin-sensitive glucose transporter in insulin-dependent tissues. The GLUT12 subfamily belongs to the Glucose transporter -like (GLUT-like) family of the Major Facilitator Superfamily (MFS) of membrane transport proteins. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550  16 ATIGSGIVNTAFTVVSLFVVERAGRRTLHLIGLAGMAGCAILMTIalalleqlpwmsYLSIVAIFGFVAFFEVGPGPIPW 95
Cdd:cd17435 233 ASTGVGVVKVVSTIPAIFLVDKVGSKTFLCIGSSVMAVSLVTMGL------------WLSLASLLVYVAAFSIGLGPMPW 300

                        90       100       110
                ....*....|....*....|....*....|....
gi 14268550  96 FIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCF 129
Cdd:cd17435 301 LVLSEIFPGGIRGRAMALTSSMNWGINLLISLTF 334

Glucose transporter type 10 (GLUT10), a Class 3 GLUT, of the Major Facilitator Superfamily of transporters; Glucose transporter type 10 (GLUT10) is also called Solute carrier family 2, facilitated glucose transporter member 10 (SLC2A10). It is classified as a Class 3 GLUT and is a facilitative glucose transporter that exhibits a wide tissue distribution. It is expressed in pancreas, placenta, heart, lung, liver, brain, fat, muscle, and kidney. GLUT10 facilitates the transport of dehydroascorbic acid (DHA), the oxidized form of vitamin C, into mitochondria, and also increases cellular uptake of DHA, which in turn protects cells against oxidative stress. Loss-of-function mutations in SLC2A10 cause arterial tortuosity syndrome (ATS), an autosomal recessive connective tissue disorder characterized by twisting and lengthening of the major arteries, hypermobility of the joints, and laxity of skin. The GLUT10 subfamily belongs to the Glucose transporter -like (GLUT-like) family of the Major Facilitator Superfamily (MFS) of membrane transport proteins. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 14268550   1 STSIFEKAGVQ---QPVYATIGSGIVNTAFTVVSLFVVERAGRRTLHLiglagmAGCaILMTIALALLEQlpWMSYLSIV 77
Cdd:cd17436 215 ASTIFRSVGFQsnsSAVLASVGLGVVKVIATLLAMLFADRAGRRSLLI------AGC-SVMAVSVSGIGL--WITLLCLM 285

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 14268550  78 AifgFVAFFEVGPGPIPWFIVAELFSQGPRPAAIAVAGFSNWTSNFIVGMCF 129
Cdd:cd17436 286 A---FVSAFSIGFGPMTWLVLSEIYPADIRGRAFSFCNSFNWAANLLITLSF 334