| ProGT ID | ProGT3 (Toxin A) |
| Organism Information |
| Organism Name | Clostridium difficile VPI 10463 |
| Clinical Implication | Pathogenic |
| Domain | Bacteria |
| Classification | Phylum : Firmicutes
Class : Clostridia
Orders : Eubacteriales
Family : Peptostreptococcaceae
Genus : Clostridium
Species : difficle
Strain : VPI 10463 |
| Taxonomic ID (NCBI) | 1496 |
| Genome Information |
| Gene Information |
| Gene Name | toxA |
| NCBI Reference Sequence | X51797 |
| Protein information |
| Protein Name | Toxin A |
| 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. |
| 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 | UDP-Glc |
| Donor Specificity | Nucleotide activated sugars |
| Glycan Information |
| Glycan transferred | Monosaccharide (Glc) |
| 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 | 1995 |
| Reference | Just, I., Wilm, M., Selzer, J., Rex, G., von Eichel-Streiber, C., Mann, M. and Aktories, K., 1995. The Enterotoxin from Clostridium difficile (ToxA) Monoglucosylates the Rho Proteins?. Journal of Biological Chemistry, 270(23), pp.13932-13936.
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| Corresponding Author | Institute of Pharmacology and Toxicology, University of the Saarland, Homburg / Saar, Germany.
|
| Reference | Genth, H., Aktories, K. and Just, I., 1999. Monoglucosylation of RhoA at threonine 37 blocks cytosol-membrane cycling. Journal of biological chemistry, 274(41), pp.29050-29056.
|
| Corresponding Author | Institute of Pharmacology and Toxicology, University of Freiburg, Hermann-Herder-Strasse 5, D-79104 Freiburg, Germany.
|
| Reference | Reinert, D.J., Jank, T., Aktories, K. and Schulz, G.E., 2005. Structural basis for the function of Clostridium difficile toxin B. Journal of molecular biology, 351(5), pp.973-981.
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| Corresponding Author | 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. and Aktories, K., 2005. Change of the donor substrate specificity of Clostridium difficile toxin B by site-directed mutagenesis. Journal of Biological Chemistry, 280(45), pp.37833-37838.
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| Corresponding Author | 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. and Gerhard, R., 2006. Cellular stability of Rho-GTPases glucosylated by Clostridium difficile toxin B. FEBS letters, 580(14), pp.3565-3569.
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| Corresponding Author | Department of Toxicology, Hannover Medical School, Germany
|
| Reference | Orth, P., Xiao, L., Hernandez, L.D., Reichert, P., Sheth, P.R., Beaumont, M., Yang, X., Murgolo, N., Ermakov, G., DiNunzio, E. and Racine, F., 2014. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. Journal of biological chemistry, 289(26), pp.18008-18021.
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| Corresponding Author | From Merck & Co., Inc., Kenilworth, New Jersey
|
| Reference | Papatheodorou, P., Zamboglou, C., Genisyuerek, S., Guttenberg, G. and Aktories, K., 2010. Clostridial glucosylating toxins enter cells via clathrin-mediated endocytosis. PloS one, 5(5), p.e10673.
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| Corresponding Author | Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
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| Reference | Kuehne, S.A., Cartman, S.T., Heap, J.T., Kelly, M.L., Cockayne, A. and Minton, N.P., 2010. The role of toxin A and toxin B in Clostridium difficile infection. Nature, 467(7316), pp.711-713.
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| Corresponding Author | 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. and Ng, K.K., 2014. Structural basis for antibody recognition in the receptor-binding domains of toxins A and B from Clostridium difficile. Journal of Biological Chemistry, 289(4), pp.2331-2343.
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| Corresponding Author | Department of Biological Sciences and Alberta Glycomics Centre, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
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| Reference | Genth, H., Pauillac, S., Schelle, I., Bouvet, P., Bouchier, C., Varela?Chavez, C., Just, I. and 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), pp.1706-1721.
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| Corresponding Author | Institute of Toxicology, Medical School Hannover, Hannover, Germany.
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