Latest update: September 24, 2018


ProGT3 (Toxin A)

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ProGT ID ProGT3 (Toxin A)
Organism Information
Organism NameClostridium difficile VPI 10463
Clinical ImplicationPathogenic
DomainBacteria
PhylumFirmicutes
ClassificationFamily: Clostridiaceae
Order: Clostridiales
Class: Clostridia
Phylum: Firmicutes
Taxonomic ID (NCBI)1496
Genome Information
Gene Information
Gene NametoxA
NCBI Reference SequenceX51797
Protein information
Protein NameToxin A 
UniProtKB/ SwissProt IDP16154
NCBI Ref SeqWP_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 CDSCAA36094.1.
Sequence length2710 AA
Subcellular LocationHost cell plasma membrane
Function in Native Organism 1) It is a secretory glycosyltransferase which glycosylates the Rho family proteins of the host cell.
Potential Application1) 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 Information1) 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 TypeO- (Thr) linked 
CAZY FamilyGT44
EC Number (BRENDA)2.4.1.B62.13625.
Mechanism of Glycan TransferSequential
Donor TypeNucleotide activated sugars
Donor SpecificityUDP-Glc
Glycan Information
Glycan transferredMonosaccharide (Glc) 
Method of Glycan IndentificationLC-ESI-MS and MS/MS
Experimental_strategiesIn 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 Validation1995 
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 groupsInstitute of Pharmacology and Toxicology, University of the Saarland, Homburg / Saar, Germany.
Corresponding Author Aktories, K.
ContactsInstitute 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 groupsInstitute of Pharmacology and Toxicology, University of Freiburg, Hermann-Herder-Strasse 5, D-79104 Freiburg, Germany.
Corresponding Author Just, I.
ContactsInstitute 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 groupsInstitute of Organic Chemistry and Biochemistry, Albert-Ludwigs-University, Albertstr. 21, 79104 Freiburg im Breisgau, Germany
Corresponding Author Schulz, G. E.
ContactsInstitute 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 groupsInstitute of Organic Chemistry and Biochemistry, Albert-Ludwigs-University, Albertstr. 21, 79104 Freiburg im Breisgau, Germany
Corresponding Author Aktories, K.
ContactsInstitute 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 groupsDepartment of Toxicology, Hannover Medical School, Germany
Corresponding Author Gerhard, R.
ContactsDepartment 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 groups1 Merck & Co., Inc., Kenilworth, New Jersey 2 Merck & Co., Inc., Palo Alto, California 3 Merck & Co., Inc., West Point, Pennsylvania
Corresponding Author Racine, F.
ContactsFrom 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 groupsInstitute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Corresponding AuthorAktories K
ContactsInstitute 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 groupsClostridia 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 AuthorMinton, N. P.
ContactsClostridia 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 groupsDepartment of Biological Sciences and Alberta Glycomics Centre, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
Corresponding Author Ng, K. K
ContactsDepartment 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 groupsInstitute of Toxicology, Medical School Hannover, Hannover, Germany.
Corresponding Authorc
ContactsInstitute of Toxicology, Medical School Hannover, Hannover, Germany.