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UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
UDP-alpha-D-glucose + Cdc42
UDP + D-glucosyl-Cdc42
UDP-alpha-D-glucose + Cdc42Hs
UDP + D-glucosyl-Cdc42Hs
-
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
UDP-alpha-D-glucose + K-Ras
UDP + D-glucosyl-K-Ras
good substrate
-
-
?
UDP-alpha-D-glucose + murine Rho GTPase
UDP + D-glucosyl-[murine Rho GTPase]
-
-
-
?
UDP-alpha-D-glucose + N-Ras
UDP + D-glucosyl-N-Ras
good substrate
-
-
?
UDP-alpha-D-glucose + Rac GTPase
UDP + D-glucosyl-[Rac GTPase]
UDP-alpha-D-glucose + Rac1
UDP + D-glucosyl-Rac1
UDP-alpha-D-glucose + Rac1 GTPase
UDP + D-glucosyl-[Rac1 GTPase]
UDP-alpha-D-glucose + Ral GTPase
UDP + D-glucosyl-[Ral GTPase]
UDP-alpha-D-glucose + RalC
UDP + D-glucosyl-RalC
good substrate
-
-
?
UDP-alpha-D-glucose + Rap GTPase
UDP + D-glucosyl-[Rap GTPase]
UDP-alpha-D-glucose + Rap2A
UDP + D-glucosyl-Rap2A
UDP-alpha-D-glucose + Ras GTPase
UDP + D-glucosyl-[Ras GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
UDP-alpha-D-glucose + RhoB
UDP + D-glucosyl-Rhob
-
-
-
?
UDP-alpha-D-glucose + RhoC
UDP + D-glucosyl-RhoC
-
-
-
?
UDP-alpha-D-glucose + RhoG
UDP + D-glucosyl-RhoG
-
-
-
?
UDP-alpha-D-glucose + TC10
UDP + D-glucosyl-TC10
good substrate
-
-
?
UDP-alpha-D-glucose + TCL signaling G protein
UDP + D-glucosyl-TCL signaling G protein
good substrate
-
-
?
UDP-N-acetyl-alpha-D-glucosamine + H-Ras
UDP + N-acetyl-alpha-D-glucosamine-H-Ras
UDP-N-acetyl-alpha-D-glucosamine + RhoA
UDP + N-acetyl-D-glucosamine-RhoA
additional information
?
-
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + Cdc42
UDP + D-glucosyl-Cdc42
-
-
-
?
UDP-alpha-D-glucose + Cdc42
UDP + D-glucosyl-Cdc42
-
-
-
?
UDP-alpha-D-glucose + Cdc42
UDP + D-glucosyl-Cdc42
-
-
-
?
UDP-alpha-D-glucose + Cdc42
UDP + D-glucosyl-Cdc42
-
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
-
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
good substrate
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
Ras is the exclusive substrate of the Ras subfamily of GTPases. Ras is a better substrate in the GTDP-bound form than in the GTP-bound form
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
Ras is the exclusive substrate of the Ras subfamily of GTPases. Ras is a better substrate in the GTDP-bound form than in the GTP-bound form
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
-
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
good substrate
-
-
?
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
activity of toxin A in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
?
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
activity of toxin A in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
?
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
activity of toxin TcsL in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
?
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
activity of toxin TcsL in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
?
UDP-alpha-D-glucose + Rac GTPase
UDP + D-glucosyl-[Rac GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rac GTPase
UDP + D-glucosyl-[Rac GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rac1
UDP + D-glucosyl-Rac1
-
-
-
?
UDP-alpha-D-glucose + Rac1
UDP + D-glucosyl-Rac1
-
-
-
?
UDP-alpha-D-glucose + Rac1
UDP + D-glucosyl-Rac1
-
-
-
?
UDP-alpha-D-glucose + Rac1
UDP + D-glucosyl-Rac1
very good substrate
-
-
?
UDP-alpha-D-glucose + Rac1
UDP + D-glucosyl-Rac1
Rac is the exclusive substrate of the Rho subfamily of GTPases. Rac is a better substrate in the GTDP-bound form than in the GTP-bound form
-
-
?
UDP-alpha-D-glucose + Rac1
UDP + D-glucosyl-Rac1
Rac is the exclusive substrate of the Rho subfamily of GTPases. Rac is a better substrate in the GTDP-bound form than in the GTP-bound form
-
-
?
UDP-alpha-D-glucose + Rac1
UDP + D-glucosyl-Rac1
very good substrate
-
-
?
UDP-alpha-D-glucose + Rac1 GTPase
UDP + D-glucosyl-[Rac1 GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rac1 GTPase
UDP + D-glucosyl-[Rac1 GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Ral GTPase
UDP + D-glucosyl-[Ral GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Ral GTPase
UDP + D-glucosyl-[Ral GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rap GTPase
UDP + D-glucosyl-[Rap GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rap GTPase
UDP + D-glucosyl-[Rap GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rap2A
UDP + D-glucosyl-Rap2A
modification occurs in vitro and in cells
-
-
?
UDP-alpha-D-glucose + Rap2A
UDP + D-glucosyl-Rap2A
modification occurs in vitro and in cells
-
-
?
UDP-alpha-D-glucose + Rap2A
UDP + D-glucosyl-Rap2A
good substrate
-
-
?
UDP-alpha-D-glucose + Rap2A
UDP + D-glucosyl-Rap2A
good substrate
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
toxin B catalyses the incorporation of up to one mole of glucose per mole of RhoA at the amino acid threonine at position 37. UDP-glucose selectively serves as cosubstrate for the monoglucosylation reaction
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
no substrate for wild-type. Mutation S385/A387Q reverses the donor specificity of alpha-toxin from UDP-N-acetylglucosamine to UDP-glucose
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
no substrate for wild-type. Mutation S385/A387Q reverses the donor specificity of alpha-toxin from UDP-N-acetylglucosamine to UDP-glucose
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
-
?
UDP-N-acetyl-alpha-D-glucosamine + H-Ras
UDP + N-acetyl-alpha-D-glucosamine-H-Ras
no substrate for wild-type, but substrate for mutant I383S/Q385A
-
-
?
UDP-N-acetyl-alpha-D-glucosamine + H-Ras
UDP + N-acetyl-alpha-D-glucosamine-H-Ras
no substrate for wild-type, but substrate for mutant I383S/Q385A
-
-
?
UDP-N-acetyl-alpha-D-glucosamine + RhoA
UDP + N-acetyl-D-glucosamine-RhoA
wild-type shows negligible activity, mutant I383S/Q385A has catalytic activity on UDP-N-acetyl-D-glucosamine
-
-
?
UDP-N-acetyl-alpha-D-glucosamine + RhoA
UDP + N-acetyl-D-glucosamine-RhoA
wild-type shows negligible activity, mutant I383S/Q385A has catalytic activity on UDP-N-acetyl-D-glucosamine
-
-
?
additional information
?
-
enzyme glucosylates and inactivates small GTPases of the Rho or Ras families, culminating in cytotoxicity
-
-
?
additional information
?
-
in the absence of target proteins toxin A acts as hydrolase cleaving UDP-D-glucose to UDP and D-glucose
-
-
?
additional information
?
-
UDP-alpha-D-glucose selectively serves as cosubstrate for toxin A-catalyzed modification. The acceptor amino acid of glucosylation is Thr37. Mutation of Thr37 to Ala completely abolishes glucosylation. No substrates: H-Ras, Rab5, and Arf1
-
-
?
additional information
?
-
Clostridioides difficile toxin B is not active on human Ras-GTPase in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
-
additional information
?
-
Clostridioides difficile toxin B is not active on human Ras-GTPase in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
-
additional information
?
-
-
Clostridioides difficile toxin B is not active on human Ras-GTPase in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
-
additional information
?
-
Clostridioides difficile toxin B is not active on human Ras-GTPase in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
-
additional information
?
-
Clostridioides difficile toxin B is not active on human Ras-GTPase in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
-
additional information
?
-
a circular electron transfer reaction is suggested tha does not directly involve any residues from the toxin. The transfer starts with the split of the glycosidic bond leading to the most stable transient state. The split increases the pK of the phosphoryl oxygen atom, facilitating deprotonation of the accepor, and provides space for the nucleophilic attack
-
-
?
additional information
?
-
a circular electron transfer reaction is suggested tha does not directly involve any residues from the toxin. The transfer starts with the split of the glycosidic bond leading to the most stable transient state. The split increases the pK of the phosphoryl oxygen atom, facilitating deprotonation of the accepor, and provides space for the nucleophilic attack
-
-
?
additional information
?
-
lethal toxin from Clostridium sordellii is a glucosyltransferase, which uses UDP-glucose as cosubstrate to modify low molecular mass GTPases. Lethal toxin selectively modifies Rac and Ras. In Rac, acceptor amino acid is residue threonine 35. No substrates: Rho, Cdc42, Rab, Arf
-
-
?
additional information
?
-
full-length hemorrhagic toxin TcsH exclusively glucosylates Rho-GTPases. The recombinant transferase domain glucosylates preferably Rho-GTPases but also Ras-GTPases to some extent. Vero cells treated with full length TcsH also show glucosylation of Ras, albeit to a lower extent than of Rho-GTPases
-
-
?
additional information
?
-
full-length hemorrhagic toxin TcsH exclusively glucosylates Rho-GTPases. The recombinant transferase domain glucosylates preferably Rho-GTPases but also Ras-GTPases to some extent. Vero cells treated with full length TcsH also show glucosylation of Ras, albeit to a lower extent than of Rho-GTPases
-
-
?
additional information
?
-
-
full-length hemorrhagic toxin TcsH exclusively glucosylates Rho-GTPases. The recombinant transferase domain glucosylates preferably Rho-GTPases but also Ras-GTPases to some extent. Vero cells treated with full length TcsH also show glucosylation of Ras, albeit to a lower extent than of Rho-GTPases
-
-
?
additional information
?
-
lethal toxin from Clostridium sordellii is a glucosyltransferase, which uses UDP-glucose as cosubstrate to modify low molecular mass GTPases. Lethal toxin selectively modifies Rac and Ras. In Rac, acceptor amino acid is residue threonine 35. No substrates: Rho, Cdc42, Rab, Arf
-
-
?
additional information
?
-
full-length hemorrhagic toxin TcsH exclusively glucosylates Rho-GTPases. The recombinant transferase domain glucosylates preferably Rho-GTPases but also Ras-GTPases to some extent. Vero cells treated with full length TcsH also show glucosylation of Ras, albeit to a lower extent than of Rho-GTPases
-
-
?
additional information
?
-
full-length hemorrhagic toxin TcsH exclusively glucosylates Rho-GTPases. The recombinant transferase domain glucosylates preferably Rho-GTPases but also Ras-GTPases to some extent. Vero cells treated with full length TcsH also show glucosylation of Ras, albeit to a lower extent than of Rho-GTPases
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
UDP-alpha-D-glucose + murine Rho GTPase
UDP + D-glucosyl-[murine Rho GTPase]
-
-
-
?
UDP-alpha-D-glucose + Rac GTPase
UDP + D-glucosyl-[Rac GTPase]
UDP-alpha-D-glucose + Rac1 GTPase
UDP + D-glucosyl-[Rac1 GTPase]
UDP-alpha-D-glucose + Ral GTPase
UDP + D-glucosyl-[Ral GTPase]
UDP-alpha-D-glucose + Rap GTPase
UDP + D-glucosyl-[Rap GTPase]
UDP-alpha-D-glucose + Rap2A
UDP + D-glucosyl-Rap2A
UDP-alpha-D-glucose + Ras GTPase
UDP + D-glucosyl-[Ras GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
additional information
?
-
enzyme glucosylates and inactivates small GTPases of the Rho or Ras families, culminating in cytotoxicity
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + a small GTPase
UDP + D-glucosyl-[a small GTPase]
-
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
-
-
-
?
UDP-alpha-D-glucose + H-Ras
UDP + D-glucosyl-H-Ras
-
-
-
?
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
activity of toxin A in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
?
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
activity of toxin A in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
?
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
activity of toxin TcsL in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
?
UDP-alpha-D-glucose + human Ras-GTPase
UDP + D-glucosyl-[human Ras-GTPase]
activity of toxin TcsL in human epithelial colorectal adenocarcinoma Caco-2 cells
-
-
?
UDP-alpha-D-glucose + Rac GTPase
UDP + D-glucosyl-[Rac GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rac GTPase
UDP + D-glucosyl-[Rac GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rac1 GTPase
UDP + D-glucosyl-[Rac1 GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rac1 GTPase
UDP + D-glucosyl-[Rac1 GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Ral GTPase
UDP + D-glucosyl-[Ral GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Ral GTPase
UDP + D-glucosyl-[Ral GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rap GTPase
UDP + D-glucosyl-[Rap GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rap GTPase
UDP + D-glucosyl-[Rap GTPase]
murine host substrate
-
-
?
UDP-alpha-D-glucose + Rap2A
UDP + D-glucosyl-Rap2A
modification occurs in vitro and in cells
-
-
?
UDP-alpha-D-glucose + Rap2A
UDP + D-glucosyl-Rap2A
modification occurs in vitro and in cells
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
-
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
no substrate for wild-type. Mutation S385/A387Q reverses the donor specificity of alpha-toxin from UDP-N-acetylglucosamine to UDP-glucose
-
-
?
UDP-alpha-D-glucose + RhoA
UDP + D-glucosyl-RhoA
no substrate for wild-type. Mutation S385/A387Q reverses the donor specificity of alpha-toxin from UDP-N-acetylglucosamine to UDP-glucose
-
-
?
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additional information
the toxin requires InsP6-dependent autocleavage for activation
malfunction
the deletion mutant TcdBD1756-1780 shows similar glucosyltransferase and cysteine protease activity, cellular binding, and pore formation to wild-type TcdB, but it fails to induce the glucosylation of Rho GTPase Rac1 of host cells. Moreover, TcdBD1756-1780 is rapidly degraded in the endosome of target cells, and therefore its intact glucosyltransferase domain is unable to translocate efficiently into host cytosol. The decrease in the alpha helical structure in the composition of TcdBD1756-1780 may be due to the deletion of AA 1756-1780. Domain structures of wild-type and mutant enzymes, overview. The deletion of region 1756-1780 might lead to locking of the TcdB in endosomes, resulting in a failure to deliver GTD
malfunction
the difference in cellular Rac1 and Ras glucosylation when the autoprocessing activity is ablated (mutation C698A) suggests that there is a localization difference for Rac1 and Ras. Mutations in the GTD membrane localization domain inhibit TcsL cytotoxicity
malfunction
-
the difference in cellular Rac1 and Ras glucosylation when the autoprocessing activity is ablated (mutation C698A) suggests that there is a localization difference for Rac1 and Ras. Mutations in the GTD membrane localization domain inhibit TcsL cytotoxicity
-
metabolism
cytotoxin A possesses an inherent cysteine protease activity, which is responsible for auto-cleavage of glucosylating toxins
metabolism
cytotoxin B possesses an inherent cysteine protease activity, which is responsible for auto-cleavage of glucosylating toxins
physiological function
glucosylation of Ras by lethal toxin results in inhibition of the epidermal growth factor-stimulated p42/p44 MAP-kinase signal pathway
physiological function
-
in cell culture toxin A inhibits Clostridium botulinum ADP-ribosyltransferase C3-catalyzed ADP-ribosylation of the low molecular mass GTP-binding Rho proteins. Toxin A-induced decrease in ADP-ribosylation is observed also in cell lysates and with recombinant RhoA protein
physiological function
-
microinjection of RhoA previously glucosylated by toxin B into monolayer cells causes disaggregation of actin filaments, indicating a dominant-negative activity of glucosylated RhoA
physiological function
-
phosphorylated mitogen-activated protein kinase MK-2 is activated by toxins TcdA and TcdB and regulates the expression of proinflammatory cytokines. Activation of p38-MK2 in infected animals and humans suggests that this pathway is a key driver of intestinal inflammation in patients with Clostridium difficile infection
physiological function
-
stimulation of murine intestinal epithelial cells with toxin A results in the upregulation of chemokine CX3CL1. Expression of CX3CL1 is dependent on nuclear factor kappaB and I?appaB kinase activation. A pathway, including p38 mitogen-activated protein kinase, IkappaB kinase , and nuclear factor kappaB activation, is required for CX3CL1 induction in intestinal epithelial cells exposed to toxin A and may regulate the development of intestinal inflammation induced by infection with toxigenic Peptoclostridium difficile
physiological function
-
strain 8864 which does not produce toxin A produces a modified toxin B. After treatment of fibroblasts with toxin B from strain 10463, which produces both toxin A and toxin B, cells become rounded and highly arborised, giving the characteristic actinomorphic appearance. With the toxin B from strain 8864, no arborisation of cells occurrs but there is rounding and significant detachment
physiological function
-
toxin A interacts with ERK1 and ERK2 in human colonocyte cell lines NCM460 and HT29 by direct binding thereby inhibiting their kinase activites
physiological function
-
toxin A significantly decreases activating phosphorylations of erythropoietin receptor EpoR and its downstream signaling molecules Janus kinase JAK-2 and signal transducer and activator of transcription STAT5. Inhibition of JAK2 by toxin A in colonocytes causes inactivation of EpoR, thereby enhancing the inhibition of focal contact formation and loss of tight junctions known to be associated with the enzymatic activity of toxin A
physiological function
-
toxin A, toxin B or crude toxin preparations have no effect on membrane integrity of either intestinal cells or McCoy cells as judged by nucleotide leakage. Toxins A and B, on their own ortogether in crude preparations, have no effect on the rate of protein synthesis in isolated intestinal cells in vitro. Both toxins inhibit protein synthesis in McCoy cells, and inhibition of protein synthesis could be a causative factor in the development of cytopathic effects
physiological function
-
toxin A-positive, toxin B-positive strains representing 12 variant toxinotypes all express considerably lower levels of toxin A and are less cytotoxic in vitro than non-variant strain VPI 10463. Truncated forms of toxin occur in toxinotype VI and VII strains and these toxins are differentiated from each other and from toxin A of the non-variant strain. Toxin A-positive, toxin B-positive strains of toxinotypes IX, XIV and XV are able to exhibit an alternative Clostridium sordellii-like cytopathic effect on Vero cells, characterized by marked cell clumping. The abnormal cytotoxicity observed for these strains is due to an altered toxin B
physiological function
-
toxin B elicits an arachidonic acid release in a cell mutant resistant to the toxin B effect on the microfilaments. This effect effect is neither a cause nor a consequence of toxin-induced microfilament disorganization
physiological function
-
toxin B stimulates secretion from isolated pancreatic acini. Doses of toxin B from 10-30 ng/ml increases enzyme secretion by 15-20%, doses between 30 ng and 60 ng/ml show a regression of this effect, whereafter the rate of secretion of amylase, trypsinogen, and chymotrypsinogen increases with increasing concentrations of the toxin. Toxin B concentration of 800 ng/ml enhances amylase, trypsinogen and chymotrypsinogen secretion by 119%, 185% and 195%, respectively, when compared with the basal level
physiological function
full-length hemorrhagic toxin TcsH exclusively glucosylates Rho-GTPases. The recombinant transferase domain glucosylates preferably Rho-GTPases but also Ras-GTPases to some extent. Vero cells treated with full length TcsH also show glucosylation of Ras, albeit to a lower extent than of Rho-GTPases. In addition, enzyme induces a rapid dephosphorylation of pY118-paxillin and of pS144/141-PAK1/2 prior to actin filament depolymerization
physiological function
isoform TcsL enters target cells via receptor-mediated endocytosis and delivers the N-terminal catalytic domain (TcsL-cat) into the cytosol. TcsL-cat binds to brain phosphatidylserine-containing membranes and to phosphatidic acid and, to a lesser extent, to other anionic lipids, but not to neutral lipids, sphingolipids or sterol. The lipid unsaturation status influences TcsL-cat binding to phospholipids, phosphatidylserines with unsaturated acyl chains and phosphatidic acids with saturated acyl chains being the preferred binding substrates. The phospholipid binding site is localized at the N-terminal four helical bundle structure (1-93 domain). Recombinant TcsL-1-93 binds to a broad range of substrates, whereas TcsL-cat, which is the active domain physiologically delivered into the cytosol, selectively binds to phosphatidylserine and phosphatidic acid
physiological function
sub-lethal concentrations of Clostridium difficile TcdA are able to alter cell polarity by causing redistribution of plasma membrane components between distinct surface domains
physiological function
the phosphatidylserine binding site is localized on the tip of the N-terminal four-helix bundle which is rich in positively-charged amino acids. Residues Y14, V15, F17, and R18 on loop 1, between helices 1 and 2, in coordination with R68 from loop 3, between helices 3 and 4, form a pocket which accommodates L-serine. The functional phosphatidylserine-binding site is required for N-terminal glucosylating domain TcsL-cat binding to the plasma membrane and subsequent cytotoxicity. TcsL-cat binding to phosphatidylserine facilitates a high enzymatic activity towards membrane-anchored Ras by about three orders of magnitude as compared to Ras in solution
physiological function
Clostridioides difficile toxin A (TcdA) and Toxin B (TcdB) trigger inflammasome activation with caspase-1 activation in cultured cells, which in turn induce the release of IL-6, IFN-g, and IL-8. Release of these proinflammatory responses is positively regulated by Ras-GTPases, which leads to the hypothesis that Ras glucosylation by glucosylating toxins results in (at least) reduced proinflammatory responses. Quantitative evaluation of the GTPase substrate profiles glucosylated in human colonic (Caco-2) cells treated with either TcdA, TcdB, or the related Clostridium sordellii lethal toxin (TcsL), performed by using multiple reaction monitoring (MRM) mass spectrometry. TcdA (not TcdB) glucosylates Ras subtype GTPases correlating with the fact that TcdB (not TcdA) is primarily responsible for inflammatory responses in Clostridioides difficile infection (CDI)
physiological function
maturation of the host cell endosome causes a conformational change in the pore-forming domain of TcsL, causing it to form a pore in the endosomal membrane. The autoprocessing domain is activated by host inositol hexakisphosphate and cleaves the glucosyltransferase domain (GTD), presumably to permit access to substrates residing at the plasma membrane. The GTD glucosylates small GTPases, predominately Rac, Ras, Ral, and Rap. The glucosylation leads to cytoskeletal rearrangement and rounding of the cells and also causes the induction of apoptosis. Lethal-toxin TcsL shows cytotoxicity in murine pulmonary microvascular endothelial cells (mPMVECs) as model cells, incubation at 33°C or 37°C. Cell viability is determined by CellTiter-Glo luciferase 24 h after intoxication. TcsL autoprocessing and glucosyltransferase activities are important for cytotoxicity, TcsL cytotoxicity is dependent upon GTD localization to the cell membrane. The membrane localization domain (MLD) interaction with the membrane is important for the glucosylation of both Rac1 and Ras
physiological function
quantitative evaluation of the GTPase substrate profiles glucosylated in human colonic (Caco-2) cells treated with either TcdA, TcdB, or the related Clostridium sordellii lethal toxin (TcsL), performed by using multiple reaction monitoring (MRM) mass spectrometry
physiological function
quantitative evaluation of the GTPase substrate profiles glucosylated in human colonic (Caco-2) cells treated with either TcdA, TcdB, or the related Clostridium sordellii lethal toxin (TcsL), performed by using multiple reaction monitoring (MRM) mass spectrometry. TcdA (not TcdB) glucosylates Ras subtype GTPases correlating with the fact that TcdB (not TcdA) is primarily responsible for inflammatory responses in Clostridioides difficile
physiological function
two exotoxins, toxin A (TcdA) and toxin B (TcdB), are the major virulence factors involved in Clostridium difficile infection (CDI), and both belong to the family of clostridial glucosylating toxins. The toxins are multi-domain proteins containing at least four functional domains. The N-terminus of the toxin harbors the glucosyltransferase domain (GTD) that inactivates host Rho GTPases by glucosylation and a cysteine protease domain (CPD) responsible for autoprocessing. The C-terminus, consisting of combined repetitive oligopeptides (CROP), is predicted to be a receptor binding domain (RBD). The receptor for TcdB has been identified recently, but additional receptors may exist. A large region between the CPD and RBD is thought to be the translocation domain (TD) which is important for delivery of N-terminal enzymatic domains into the host cytosol via pore formation. The segment of 97 amino acids (AA 1756-1852, designated D97) within the translocation domain of TcdB is essential for the in vitro and in vivo toxicity of TcdB. smaller fragment, amino acids 1756-1780, located in the N-terminus of the D97 fragment, is essential for translocation of the effector glucosyltransferase domain into the host cytosol. A sequence of 25AA within D97 is predicted to form an alpha helical structure and is the critical part of D97
physiological function
-
quantitative evaluation of the GTPase substrate profiles glucosylated in human colonic (Caco-2) cells treated with either TcdA, TcdB, or the related Clostridium sordellii lethal toxin (TcsL), performed by using multiple reaction monitoring (MRM) mass spectrometry
-
physiological function
-
glucosylation of Ras by lethal toxin results in inhibition of the epidermal growth factor-stimulated p42/p44 MAP-kinase signal pathway
-
physiological function
-
toxin A significantly decreases activating phosphorylations of erythropoietin receptor EpoR and its downstream signaling molecules Janus kinase JAK-2 and signal transducer and activator of transcription STAT5. Inhibition of JAK2 by toxin A in colonocytes causes inactivation of EpoR, thereby enhancing the inhibition of focal contact formation and loss of tight junctions known to be associated with the enzymatic activity of toxin A
-
physiological function
-
toxin A interacts with ERK1 and ERK2 in human colonocyte cell lines NCM460 and HT29 by direct binding thereby inhibiting their kinase activites
-
physiological function
-
Clostridioides difficile toxin A (TcdA) and Toxin B (TcdB) trigger inflammasome activation with caspase-1 activation in cultured cells, which in turn induce the release of IL-6, IFN-g, and IL-8. Release of these proinflammatory responses is positively regulated by Ras-GTPases, which leads to the hypothesis that Ras glucosylation by glucosylating toxins results in (at least) reduced proinflammatory responses. Quantitative evaluation of the GTPase substrate profiles glucosylated in human colonic (Caco-2) cells treated with either TcdA, TcdB, or the related Clostridium sordellii lethal toxin (TcsL), performed by using multiple reaction monitoring (MRM) mass spectrometry. TcdA (not TcdB) glucosylates Ras subtype GTPases correlating with the fact that TcdB (not TcdA) is primarily responsible for inflammatory responses in Clostridioides difficile infection (CDI)
-
physiological function
-
quantitative evaluation of the GTPase substrate profiles glucosylated in human colonic (Caco-2) cells treated with either TcdA, TcdB, or the related Clostridium sordellii lethal toxin (TcsL), performed by using multiple reaction monitoring (MRM) mass spectrometry. TcdA (not TcdB) glucosylates Ras subtype GTPases correlating with the fact that TcdB (not TcdA) is primarily responsible for inflammatory responses in Clostridioides difficile
-
physiological function
-
strain 8864 which does not produce toxin A produces a modified toxin B. After treatment of fibroblasts with toxin B from strain 10463, which produces both toxin A and toxin B, cells become rounded and highly arborised, giving the characteristic actinomorphic appearance. With the toxin B from strain 8864, no arborisation of cells occurrs but there is rounding and significant detachment
-
physiological function
-
full-length hemorrhagic toxin TcsH exclusively glucosylates Rho-GTPases. The recombinant transferase domain glucosylates preferably Rho-GTPases but also Ras-GTPases to some extent. Vero cells treated with full length TcsH also show glucosylation of Ras, albeit to a lower extent than of Rho-GTPases. In addition, enzyme induces a rapid dephosphorylation of pY118-paxillin and of pS144/141-PAK1/2 prior to actin filament depolymerization
-
physiological function
-
maturation of the host cell endosome causes a conformational change in the pore-forming domain of TcsL, causing it to form a pore in the endosomal membrane. The autoprocessing domain is activated by host inositol hexakisphosphate and cleaves the glucosyltransferase domain (GTD), presumably to permit access to substrates residing at the plasma membrane. The GTD glucosylates small GTPases, predominately Rac, Ras, Ral, and Rap. The glucosylation leads to cytoskeletal rearrangement and rounding of the cells and also causes the induction of apoptosis. Lethal-toxin TcsL shows cytotoxicity in murine pulmonary microvascular endothelial cells (mPMVECs) as model cells, incubation at 33°C or 37°C. Cell viability is determined by CellTiter-Glo luciferase 24 h after intoxication. TcsL autoprocessing and glucosyltransferase activities are important for cytotoxicity, TcsL cytotoxicity is dependent upon GTD localization to the cell membrane. The membrane localization domain (MLD) interaction with the membrane is important for the glucosylation of both Rac1 and Ras
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C698A
mutant is able to glucosylate Rac protein but does not display cytotoxicity. Mutant does not show autocatalytical activity
D587N
mutant is able to glucosylate Rac protein but does not display cytotoxicity. Mutant does not show autocatalytical activity
H653A
mutant is able to glucosylate Rac protein but does not display cytotoxicity. Mutant does not show autocatalytical activity
I383S
mutation in toxin B, 67% of wild-type catalytic efficiency with substrate UDP-alpha-D-glucose
I383S/Q385A
mutation in toxin B, 23% of wild-type catalytic efficiency with substrate UDP-alpha-D-glucose. Mutation largely increases the acceptance of UDP-Nacetylglucosamine as a sugar donor for modification of RhoA
Q385A
mutation in toxin B, 58% of wild-type catalytic efficiency with substrate UDP-alpha-D-glucose
I383S
-
mutation in toxin B, 67% of wild-type catalytic efficiency with substrate UDP-alpha-D-glucose
-
I383S/Q385A
-
mutation in toxin B, 23% of wild-type catalytic efficiency with substrate UDP-alpha-D-glucose. Mutation largely increases the acceptance of UDP-Nacetylglucosamine as a sugar donor for modification of RhoA
-
Q385A
-
mutation in toxin B, 58% of wild-type catalytic efficiency with substrate UDP-alpha-D-glucose
-
C698A
site-directed mutagenesis of the autoprocessing domain, mutant TcsL C698A is able to quickly glucosylate Rac1, similar to wild-type TcsL, but is attenuated in its ability to glucosylate Ras GTPases. The introduction of the autoprocessing mutation does not impact the glucosylation of Rac1 or H-Ras in an in vitro assay
F17K
mutation strongly decreases binding to brain phosphatidylserine
F17N/R18A
site-directed mutagenesis in the GTD membrane localization domain, on the surface of the membrane localization domain (MLD), the mutant shows a defect in membrane association in a liposome binding assay
F17N/R18A/C698A
site-directed mutagenesis in the GTD membrane localization domain, on the surface of the membrane localization domain (MLD), the mutant shows a defect in membrane association in a liposome binding assay. The triple mutant is also inhibited in both Rac1 and Ras glucosylation
I383S/Q385A
mutation allow modification of Ras in the presence of UDP-N-acetyl-glucosamine and reduces the acceptance of UDP-glucose as a donor for glycosylation
K11I
mutation moderately decreases binding to brain phosphatidylserine
K16I
mutation moderately decreases binding to brain phosphatidylserine
Q10A
mutation does not significantly decrease binding to brain phosphatidylserine
Q20A
mutation moderately decreases binding to brain phosphatidylserine
R18P
mutation strongly decreases binding to brain phosphatidylserine
R68A
mutation strongly decreases binding to brain phosphatidylserine
S38A
mutation does not significantly decrease binding to brain phosphatidylserine
V15S
mutation strongly decreases binding to brain phosphatidylserine
Y14A
mutation strongly decreases binding to brain phosphatidylserine
Y78A
mutation does not significantly decrease binding to brain phosphatidylserine
I383S/Q385A
-
mutation allow modification of Ras in the presence of UDP-N-acetyl-glucosamine and reduces the acceptance of UDP-glucose as a donor for glycosylation
-
C698A
-
site-directed mutagenesis of the autoprocessing domain, mutant TcsL C698A is able to quickly glucosylate Rac1, similar to wild-type TcsL, but is attenuated in its ability to glucosylate Ras GTPases. The introduction of the autoprocessing mutation does not impact the glucosylation of Rac1 or H-Ras in an in vitro assay
-
F17N/R18A
-
site-directed mutagenesis in the GTD membrane localization domain, on the surface of the membrane localization domain (MLD), the mutant shows a defect in membrane association in a liposome binding assay
-
F17N/R18A/C698A
-
site-directed mutagenesis in the GTD membrane localization domain, on the surface of the membrane localization domain (MLD), the mutant shows a defect in membrane association in a liposome binding assay. The triple mutant is also inhibited in both Rac1 and Ras glucosylation
-
S385/A387Q
mutation reverses the donor specificity of alpha-toxin from UDP-N-acetylglucosamine to UDP-glucose
S385/A387Q
-
mutation reverses the donor specificity of alpha-toxin from UDP-N-acetylglucosamine to UDP-glucose
-
additional information
-
a nontoxigenic peptide corresponding to amino acids 2394 to 2706 of toxin A acts a a mucosal adjuvant. The adjuvant effect following oral, but not intranasal, immunization is dose dependent. Splenocytes of immunized mice challenged in vitro with keyhole limpet hemocyanin indicate the induction of a mixed Th1/Th2-type immune response, with prevalence of the Th1 branch
additional information
construction of truncation mutants. The enzymatic domain for binding UDP-glucose, for catalytically transferring glucose to Rho A and for recognizing the interaction interface of Rho A resides in the first N-terminal 659 amino acids of toxin A
additional information
expression of a fragment of toxin B, covering residues 1955. Wild-type fragment of toxin B is always recovered as a cleaved product with fragments of 63 and 47 kDa, whereas the mutants with changes C698A or H653A are expressed in full length
additional information
expression of a fragment of toxin B, covering residues 1955. Wild-type fragment of toxin B is always recovered as a cleaved product with fragments of 63 and 47 kDa, whereas the mutants with changes C698A or H653A are expressed in full length
additional information
-
modification of toxin A with diethyl dicarbonate leads to concentration dependent labelling of histidine residues and abolishes both its cytotoxic activity and the ability of the toxin to bind Zn-Sepharose gel. Histidine modification has no effect on the glucosyl transferase enzyme activity of toxin A. However, modification abolishes the binding of toxin to bovine thyroglobulin in an ELISA and reduces ligand binding activity in a rabbit erythrocyte haemagglutination assay. The data suggest that the histidine residues may be crucial to the receptor-binding activity of toxin A
additional information
the Dxd motif, i.e. residues D286-D288, is required at least for activation of the UDP-glucose hydrolysis activity by Mn2+
additional information
-
the Dxd motif, i.e. residues D286-D288, is required at least for activation of the UDP-glucose hydrolysis activity by Mn2+
additional information
25AA (1756-1780) are deleted to construct the deletion mutant TcdBD1756-1780. The deletion mutant TcdBD1827-1851, with deletion of a different 25AA, 1827-1851, located in the C-terminus of D97, serves as the control. The deletion mutants are expressed with His6-tags at the C-terminal in a Bacillus megaterium expression system. Wild-type and mutant toxins are introduced into mouse CT26 host cells. Both TcdBD1756-1780 and TcdBfl successfully induce autocleavage, releasing a 63kD fragment containing GTD, in the presence of InsP6. TcdBD1756-1780 undergoes autocleavage after incubation with a series of concentrations of InsP6 for several hours. The TcdBD1756-1780 mutant efficiently induces Rac1 glucosylation using CT26 cell lysate as the substrate, but fails to glucosylate Rac1 in intact CT26 cells. Thus, the deletion of amino acids 1756-1780 does not change the structure and function of the cysteine protease and glucosytransferase domains, but may result in an inability to deliver GTD into the host cytosol. The deletion of region 1756-1780 might lead to locking of the TcdB in endosomes, resulting in a failure to deliver GTD
additional information
-
a nontoxigenic peptide corresponding to amino acids 2394 to 2706 of toxin A acts a a mucosal adjuvant. The adjuvant effect following oral, but not intranasal, immunization is dose dependent. Splenocytes of immunized mice challenged in vitro with keyhole limpet hemocyanin indicate the induction of a mixed Th1/Th2-type immune response, with prevalence of the Th1 branch
-
additional information
-
modification of toxin A with diethyl dicarbonate leads to concentration dependent labelling of histidine residues and abolishes both its cytotoxic activity and the ability of the toxin to bind Zn-Sepharose gel. Histidine modification has no effect on the glucosyl transferase enzyme activity of toxin A. However, modification abolishes the binding of toxin to bovine thyroglobulin in an ELISA and reduces ligand binding activity in a rabbit erythrocyte haemagglutination assay. The data suggest that the histidine residues may be crucial to the receptor-binding activity of toxin A
-
additional information
the Dxd motif, i.e. residues D286-D288, is required at least for activation of the UDP-glucose hydrolysis activity by Mn2+
additional information
-
the Dxd motif, i.e. residues D286-D288, is required at least for activation of the UDP-glucose hydrolysis activity by Mn2+
additional information
when glucosyltransferase-deficient TcsL mutant, TcsL DxD, is used to intoxicate cells, the loss of the glucosyltransferase activity renders the mutant unable to glucosylate both Rac1 and Ras
additional information
-
when glucosyltransferase-deficient TcsL mutant, TcsL DxD, is used to intoxicate cells, the loss of the glucosyltransferase activity renders the mutant unable to glucosylate both Rac1 and Ras
additional information
-
when glucosyltransferase-deficient TcsL mutant, TcsL DxD, is used to intoxicate cells, the loss of the glucosyltransferase activity renders the mutant unable to glucosylate both Rac1 and Ras
-
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Paeniclostridium sordellii (M9ZTT7), Paeniclostridium sordellii (V5T923), Paeniclostridium sordellii, Paeniclostridium sordellii vpi9048 (M9ZTT7), Paeniclostridium sordellii vpi9048 (V5T923)
brenda
Varela Chavez, C.; Hoos, S.; Haustant, G.M.; Chenal, A.; England, P.; Blondel, A.; Pauillac, S.; Lacy, D.B.; Popoff, M.R.
The catalytic domains of Clostridium sordellii lethal toxin and related large clostridial glucosylating toxins specifically recognize the negatively charged phospholipids phosphatidylserine and phosphatidic acid
Cell. Microbiol.
17
1477-1493
2015
Paeniclostridium sordellii (V5T923), Paeniclostridium sordellii
brenda
Baliban, S.M.; Michael, A.; Shammassian, B.; Mudakha, S.; Khan, A.S.; Cocklin, S.; Zentner, I.; Latimer, B.P.; Bouillaut, L.; Hunter, M.; Marx, P.; Sardesai, N.Y.; Welles, S.L.; Jacobson, J.M.; Weiner, D.B.; Kutzler, M.A.
An optimized, synthetic DNA vaccine encoding the toxin A and toxin B receptor binding domains of Clostridium difficile induces protective antibody responses in vivo
Infect. Immun.
82
4080-4091
2014
Clostridioides difficile (P16154), Clostridioides difficile (P18177)
brenda
Kasendra, M.; Barrile, R.; Leuzzi, R.; Soriani, M.
Clostridium difficile toxins facilitate bacterial colonization by modulating the fence and gate function of colonic epithelium
J. Infect. Dis.
209
1095-1104
2014
Clostridioides difficile (P16154)
brenda
Varela Chavez, C.; Haustant, G.M.; Baron, B.; England, P.; Chenal, A.; Pauillac, S.; Blondel, A.; Popoff, M.R.
The tip of the four N-terminal alpha-helices of Clostridium sordellii lethal toxin contains the interaction site with membrane phosphatidylserine facilitating small GTPases glucosylation
Toxins
8
90
2016
Paeniclostridium sordellii (V5T923), Paeniclostridium sordellii
brenda
Thiele, T.L.; Stuber, T.P.; Hauer, P.J.
Detection of Clostridium sordellii strains expressing hemorrhagic toxin (TcsH) and implications for diagnostics and regulation of veterinary vaccines
Vaccine
31
5082-5087
2013
Paeniclostridium sordellii (M9ZTT7), Paeniclostridium sordellii (V5T923), Paeniclostridium sordellii, Paeniclostridium sordellii VPI 9048 (M9ZTT7), Paeniclostridium sordellii VPI 9048 (V5T923)
brenda
Genth, H.; Schelle, I.; Just, I.
Metal ion activation of Clostridium sordellii lethal toxin and Clostridium difficile toxin B
Toxins
8
109
2016
Clostridioides difficile (P18177), Clostridioides difficile, Paeniclostridium sordellii (V5T923), Paeniclostridium sordellii
brenda
Genth, H.; Junemann, J.; Laemmerhirt, C.M.; Luecke, A.C.; Schelle, I.; Just, I.; Gerhard, R.; Pich, A.
Difference in mono-O-glucosylation of Ras subtype GTPases between toxin A and toxin B from Clostridioides difficile strain 10463 and lethal toxin from Clostridium sordellii strain 6018
Front. Microbiol.
9
3078
2018
Clostridioides difficile (P16154), Clostridioides difficile (P18177), Clostridioides difficile, Paeniclostridium sordellii (Q46342), Paeniclostridium sordellii, Paeniclostridium sordellii 6018 (Q46342), Clostridioides difficile 10463 (P16154), Clostridioides difficile 10463 (P18177)
brenda
Craven, R.; Lacy, D.
Clostridium sordellii lethal-toxin autoprocessing and membrane localization activities drive GTPase glucosylation profiles in endothelial cells
mSphere
1
e00012-15
2016
Paeniclostridium sordellii (Q46342), Paeniclostridium sordellii, Paeniclostridium sordellii JGS6382 (Q46342)
brenda
Chen, S.; Wang, H.; Gu, H.; Sun, C.; Li, S.; Feng, H.; Wang, J.
Identification of an essential region for translocation of Clostridium difficile toxin B
Toxins
8
241
2016
Clostridioides difficile (P18177)
brenda