ProGT3 (Toxin A)
| ProGT ID | ProGT3 (Toxin A) |
| Organism Information | |
| Organism Name | Clostridium difficile VPI 10463 |
| Clinical Implication | Pathogenic |
| Domain | Bacteria |
| Phylum | Firmicutes |
| Classification | Family: Clostridiaceae Order: Clostridiales Class: Clostridia Phylum: Firmicutes |
| Taxonomic ID (NCBI) | 1496 |
| Genome Information | |
| Gene Information | |
| Gene Name | toxA |
| NCBI Reference Sequence | X51797 |
| Protein information | |
| Protein Name | Toxin AÂ |
| UniProtKB/ SwissProt ID | P16154 |
| NCBI Ref Seq | WP_009902072.1 |
| UniProtKB Sequence | >sp|P16154|TOXA_CLODI Toxin A OS=Clostridioides difficile GN=toxA PE=1 SV=2 MSLISKEELIKLAYSIRPRENEYKTILTNLDEYNKLTTNNNENKYLQLKKLNESIDVFMN KYKTSSRNRALSNLKKDILKEVILIKNSNTSPVEKNLHFVWIGGEVSDIALEYIKQWADI NAEYNIKLWYDSEAFLVNTLKKAIVESSTTEALQLLEEEIQNPQFDNMKFYKKRMEFIYD RQKRFINYYKSQINKPTVPTIDDIIKSHLVSEYNRDETVLESYRTNSLRKINSNHGIDIR ANSLFTEQELLNIYSQELLNRGNLAAASDIVRLLALKNFGGVYLDVDMLPGIHSDLFKTI SRPSSIGLDRWEMIKLEAIMKYKKYINNYTSENFDKLDQQLKDNFKLIIESKSEKSEIFS KLENLNVSDLEIKIAFALGSVINQALISKQGSYLTNLVIEQVKNRYQFLNQHLNPAIESD NNFTDTTKIFHDSLFNSATAENSMFLTKIAPYLQVGFMPEARSTISLSGPGAYASAYYDF INLQENTIEKTLKASDLIEFKFPENNLSQLTEQEINSLWSFDQASAKYQFEKYVRDYTGG SLSEDNGVDFNKNTALDKNYLLNNKIPSNNVEEAGSKNYVHYIIQLQGDDISYEATCNLF SKNPKNSIIIQRNMNESAKSYFLSDDGESILELNKYRIPERLKNKEKVKVTFIGHGKDEF NTSEFARLSVDSLSNEISSFLDTIKLDISPKNVEVNLLGCNMFSYDFNVEETYPGKLLLS IMDKITSTLPDVNKNSITIGANQYEVRINSEGRKELLAHSGKWINKEEAIMSDLSSKEYI FFDSIDNKLKAKSKNIPGLASISEDIKTLLLDASVSPDTKFILNNLKLNIESSIGDYIYY EKLEPVKNIIHNSIDDLIDEFNLLENVSDELYELKKLNNLDEKYLISFEDISKNNSTYSV RFINKSNGESVYVETEKEIFSKYSEHITKEISTIKNSIITDVNGNLLDNIQLDHTSQVNT LNAAFFIQSLIDYSSNKDVLNDLSTSVKVQLYAQLFSTGLNTIYDSIQLVNLISNAVNDT INVLPTITEGIPIVSTILDGINLGAAIKELLDEHDPLLKKELEAKVGVLAINMSLSIAAT VASIVGIGAEVTIFLLPIAGISAGIPSLVNNELILHDKATSVVNYFNHLSESKKYGPLKT EDDKILVPIDDLVISEIDFNNNSIKLGTCNILAMEGGSGHTVTGNIDHFFSSPSISSHIP SLSIYSAIGIETENLDFSKKIMMLPNAPSRVFWWETGAVPGLRSLENDGTRLLDSIRDLY PGKFYWRFYAFFDYAITTLKPVYEDTNIKIKLDKDTRNFIMPTITTNEIRNKLSYSFDGA GGTYSLLLSSYPISTNINLSKDDLWIFNIDNEVREISIENGTIKKGKLIKDVLSKIDINK NKLIIGNQTIDFSGDIDNKDRYIFLTCELDDKISLIIEINLVAKSYSLLLSGDKNYLISN LSNTIEKINTLGLDSKNIAYNYTDESNNKYFGAISKTSQKSIIHYKKDSKNILEFYNDST LEFNSKDFIAEDINVFMKDDINTITGKYYVDNNTDKSIDFSISLVSKNQVKVNGLYLNES VYSSYLDFVKNSDGHHNTSNFMNLFLDNISFWKLFGFENINFVIDKYFTLVGKTNLGYVE FICDNNKNIDIYFGEWKTSSSKSTIFSGNGRNVVVEPIYNPDTGEDISTSLDFSYEPLYG IDRYINKVLIAPDLYTSLININTNYYSNEYYPEIIVLNPNTFHKKVNINLDSSSFEYKWS TEGSDFILVRYLEESNKKILQKIRIKGILSNTQSFNKMSIDFKDIKKLSLGYIMSNFKSF NSENELDRDHLGFKIIDNKTYYYDEDSKLVKGLININNSLFYFDPIEFNLVTGWQTINGK KYYFDINTGAALTSYKIINGKHFYFNNDGVMQLGVFKGPDGFEYFAPANTQNNNIEGQAI VYQSKFLTLNGKKYYFDNNSKAVTGWRIINNEKYYFNPNNAIAAVGLQVIDNNKYYFNPD TAIISKGWQTVNGSRYYFDTDTAIAFNGYKTIDGKHFYFDSDCVVKIGVFSTSNGFEYFA PANTYNNNIEGQAIVYQSKFLTLNGKKYYFDNNSKAVTGLQTIDSKKYYFNTNTAEAATG WQTIDGKKYYFNTNTAEAATGWQTIDGKKYYFNTNTAIASTGYTIINGKHFYFNTDGIMQ IGVFKGPNGFEYFAPANTDANNIEGQAILYQNEFLTLNGKKYYFGSDSKAVTGWRIINNK KYYFNPNNAIAAIHLCTINNDKYYFSYDGILQNGYITIERNNFYFDANNESKMVTGVFKG PNGFEYFAPANTHNNNIEGQAIVYQNKFLTLNGKKYYFDNDSKAVTGWQTIDGKKYYFNL NTAEAATGWQTIDGKKYYFNLNTAEAATGWQTIDGKKYYFNTNTFIASTGYTSINGKHFY FNTDGIMQIGVFKGPNGFEYFAPANTDANNIEGQAILYQNKFLTLNGKKYYFGSDSKAVT GLRTIDGKKYYFNTNTAVAVTGWQTINGKKYYFNTNTSIASTGYTIISGKHFYFNTDGIM QIGVFKGPDGFEYFAPANTDANNIEGQAIRYQNRFLYLHDNIYYFGNNSKAATGWVTIDG NRYYFEPNTAMGANGYKTIDNKNFYFRNGLPQIGVFKGSNGFEYFAPANTDANNIEGQAI RYQNRFLHLLGKIYYFGNNSKAVTGWQTINGKVYYFMPDTAMAAAGGLFEIDGVIYFFGV DGVKAPGIYG |
| EMBL CDS | CAA36094.1. |
| Sequence length | 2710 AA |
| Subcellular Location | Host cell plasma membrane |
| Function in Native Organism | 1) It is a secretory glycosyltransferase which glycosylates the Rho family proteins of the host cell. |
| Potential Application | 1) Structural information on TcdA-carbohydrate interactions provides a rational basis for improving the effectiveness of promising new therapeutic approaches. 2) targeting the TcdA and TcdB the intestine caused by C. dif?cile infections. 3) Residues involved in binding with trisaccharides are conserved in all seven putative binding sites in TcdA, this information can be exploited for the rational design of novel therapeutics. |
| Additional Information | 1) TcdA is glycosyltransferase utilizes carbohydrate-binding receptor to enter the intestinal epithelial cells and disrupts normal signaling pathways necessary for maintaining the cell?s cytoskeleton that ultimately causes in?ammation and diarrhea. |
| PDB ID | 2F6E 2G7C 2QJ6 3HO6 4DMV 4DMW 4R04 5UMI 5UQK 5UQL. |
| Glycosyltransferase Information | |
| Glycosylation Type | O- (Thr) linked |
| CAZY Family | GT44 |
| EC Number (BRENDA) | 2.4.1.B62.13625. |
| Mechanism of Glycan Transfer | Sequential |
| Donor Type | Nucleotide activated sugars |
| Donor Specificity | UDP-Glc |
| Glycan Information | |
| Glycan transferred | Monosaccharide (Glc)Â |
| Method of Glycan Indentification | LC-ESI-MS and MS/MS |
| Experimental_strategies | In vivo and In vitro |
| Acceptor Subtrate Information | |
| Acceptor Substrate name | RhoA |
| Acceptor Substrate name | Rac1 |
| Acceptor Substrate name | Cdc42 |
| Acceptor Substrate name | RhoB |
| Litrature | |
| Year Of Validation | 1995Â |
| Reference | Just, I., Wilm, M., Selzer, J., Rex, G., von Eichel-Streiber, C., Mann, M., & Aktories, K. (1995). The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. Journal of Biological Chemistry, 270(23), 13932-13936. |
| Authors | Just, I., Wilm, M., Selzer, J., Rex, G., von Eichel-Streiber, C., Mann, M., & Aktories, K. |
| Research groups | Institute of Pharmacology and Toxicology, University of the Saarland, Homburg / Saar, Germany. |
| Corresponding Author | Aktories, K. |
| Contacts | Institute of Pharmacology and Toxicology, University of the Saarland, Homburg / Saar, Germany. |
| Reference | Genth, H., Aktories, K., & Just, I. (1999). Monoglucosylation of RhoA at threonine 37 blocks cytosol-membrane cycling. Journal of biological chemistry, 274(41), 29050-29056. |
| Authors | Genth, H., Aktories, K., & Just, I. |
| Research groups | Institute of Pharmacology and Toxicology, University of Freiburg, Hermann-Herder-Strasse 5, D-79104 Freiburg, Germany. |
| Corresponding Author | Just, I. |
| Contacts | Institute of Pharmacology and Toxicology, University of Freiburg, Hermann-Herder-Strasse 5, D-79104 Freiburg, Germany. |
| Reference | Reinert, D. J., Jank, T., Aktories, K., & Schulz, G. E. (2005). Structural basis for the function of Clostridium difficile toxin B. Journal of molecular biology, 351(5), 973-981. |
| Authors | Reinert, D. J., Jank, T., Aktories, K., & Schulz, G. E. |
| Research groups | Institute of Organic Chemistry and Biochemistry, Albert-Ludwigs-University, Albertstr. 21, 79104 Freiburg im Breisgau, Germany |
| Corresponding Author | Schulz, G. E. |
| Contacts | Institute of Organic Chemistry and Biochemistry, Albert-Ludwigs-University, Albertstr. 21, 79104 Freiburg im Breisgau, Germany |
| Reference | Jank, T., Reinert, D. J., Giesemann, T., Schulz, G. E., & Aktories, K. (2005). Change of the donor substrate specificity of Clostridium difficile toxin B by site-directed mutagenesis. Journal of Biological Chemistry, 280(45), 37833-37838. |
| Authors | Jank, T., Reinert, D. J., Giesemann, T., Schulz, G. E., & Aktories, K. |
| Research groups | Institute of Organic Chemistry and Biochemistry, Albert-Ludwigs-University, Albertstr. 21, 79104 Freiburg im Breisgau, Germany |
| Corresponding Author | Aktories, K. |
| Contacts | Institute of Organic Chemistry and Biochemistry, Albert-Ludwigs-University, Albertstr. 21, 79104 Freiburg im Breisgau, Germany |
| Reference | Genth, H., Huelsenbeck, J., Hartmann, B., Hofmann, F., Just, I., & Gerhard, R. (2006). Cellular stability of Rho?GTPases glucosylated by Clostridium difficile toxin B. FEBS letters, 580(14), 3565-3569. |
| Authors | Genth, H., Huelsenbeck, J., Hartmann, B., Hofmann, F., Just, I., & Gerhard, R. |
| Research groups | Department of Toxicology, Hannover Medical School, Germany |
| Corresponding Author | Gerhard, R. |
| Contacts | Department of Toxicology, Hannover Medical School, Germany |
| Reference | Orth, P., Xiao, L., Hernandez, L.D., Reichert, P., Sheth, P., Beaumont, M., Yang, X., Murgolo, N., Ermakov, G.,& Racine, F. (2014). Mechanism of action and epitopes of the Clostridium difficile toxin B neutralizing antibody bezlotoxumab revealed by x-ray crystallography. Journal of biological chemistry, jbc-M114. |
| Authors | Orth, P., Xiao, L., Hernandez, L.D., Reichert, P., Sheth, P., Beaumont, M., Yang, X., Murgolo, N., Ermakov, G.,& Racine, F. |
| Research groups | 1 Merck & Co., Inc., Kenilworth, New Jersey
2 Merck & Co., Inc., Palo Alto, California
3 Merck & Co., Inc., West Point, Pennsylvania
|
| Corresponding Author | Racine, F. |
| Contacts | From Merck & Co., Inc., Kenilworth, New Jersey |
| Reference | Papatheodorou, P., Zamboglou, C., Genisyuerek, S., Guttenberg, G., & Aktories, K. (2010). Clostridial glucosylating toxins enter cells via clathrin-mediated endocytosis. PloS one, 5(5), e10673. |
| Authors | Papatheodorou, P., Zamboglou, C., Genisyuerek, S., Guttenberg, G., & Aktories, K. |
| Research groups | Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University Freiburg, Freiburg, Germany. |
| Corresponding Author | Aktories K |
| Contacts | Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University Freiburg, Freiburg, Germany. |
| Reference | Kuehne, S. A., Cartman, S. T., Heap, J. T., Kelly, M. L., Cockayne, A., & Minton, N. P. (2010). The role of toxin A and toxin B in Clostridium difficile infection. Nature, 467(7316), 711 |
| Authors | Kuehne, S. A., Cartman, S. T., Heap, J. T., Kelly, M. L., Cockayne, A., & Minton, N. P. |
| Research groups | Clostridia Research Group, Centre for Biomolecular Sciences, School of Molecular Medical Sciences, Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, University of Nottingham, Nottingham NG7 2RD, UK |
| Corresponding Author | Minton, N. P. |
| Contacts | Clostridia Research Group, Centre for Biomolecular Sciences, School of Molecular Medical Sciences, Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, University of Nottingham, Nottingham NG7 2RD, UK |
| Reference | Murase, T., Eugenio, L., Schorr, M., Hussack, G., Tanha, J., Kitova, E.N., Klassen, J.S. & Ng, K. K. (2013). Structural basis for antibody recognition in the receptor-binding domains of toxins A and B from Clostridium difficile. Journal of Biological Chemistry, jbc-M113. |
| Authors | Murase, T., Eugenio, L., Schorr, M., Hussack, G., Tanha, J., Kitova, E.N., Klassen, J.S. & Ng, K. K |
| Research groups | Department of Biological Sciences and Alberta Glycomics Centre, University of Calgary, Calgary, Alberta T2N 1N4, Canada. |
| Corresponding Author | Ng, K. K |
| Contacts | Department of Biological Sciences and Alberta Glycomics Centre, University of Calgary, Calgary, Alberta T2N 1N4, Canada. |
| Reference | Genth, H., Pauillac, S., Schelle, I., Bouvet, P., Bouchier, C., Varela?Chavez, C., Just, I. & Popoff, M. R. (2014). Haemorrhagic toxin and lethal toxin from C lostridium sordellii strain vpi9048: molecular characterization and comparative analysis of substrate specificity of the large clostridial glucosylating toxins. Cellular microbiology, 16(11), 1706-1721. |
| Authors | Genth, H., Pauillac, S., Schelle, I., Bouvet, P., Bouchier, C., Varela?Chavez, C., Just, I. & Popoff, M. R. |
| Research groups | Institute of Toxicology, Medical School Hannover, Hannover, Germany. |
| Corresponding Author | c |
| Contacts | Institute of Toxicology, Medical School Hannover, Hannover, Germany. |