Roberts S

References (4)

Title : Inhibition of human cholinesterases by drugs used to treat Alzheimer disease - Darvesh_2003_Alzheimer.Dis.Assoc.Disord_17_117
Author(s) : Darvesh S , Walsh R , Kumar R , Caines A , Roberts S , Magee D , Rockwood K , Martin E
Ref : Alzheimer Disease & Associated Disorders , 17 :117 , 2003
Abstract : Current approaches to the treatment of cognitive and behavioral symptoms of Alzheimer disease emphasize the use of cholinesterase inhibitors. The kinetic effects of the cholinesterase inhibitors donepezil, galantamine, metrifonate, physostigmine, rivastigmine, and tetrahydroaminoacridine were examined with respect to their action on the esterase and aryl acylamidase activities of human acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE). Each of these drugs inhibited both AChE and BuChE, but to different degrees. Inhibition of BuChE by these compounds was approximately the same, or better, when acetylthiocholine, the analog of the neurotransmitter acetylcholine, was used as the substrate, instead of butyrylthiocholine. In addition, for these drugs, the inhibition of aryl acylamidase activity paralleled that observed for inhibition of esterase activity of AChE and BuChE. Given that drugs that are currently in use for the treatment of Alzheimer disease inhibit both AChE and BuChE, the development of drugs targeted toward the exclusive inhibition of one or the other cholinesterase may be important for understanding the relative importance of inhibition of BuChE and AChE in the treatment of this disease.
ESTHER : Darvesh_2003_Alzheimer.Dis.Assoc.Disord_17_117
PubMedSearch : Darvesh_2003_Alzheimer.Dis.Assoc.Disord_17_117
PubMedID: 12794390

Title : Multifunctional Xylooligosaccharide\/Cephalosporin C Deacetylase Revealed by the Hexameric Structure of the Bacillus subtilis Enzyme at 1.9A Resolution - Vincent_2003_J.Mol.Biol_330_593
Author(s) : Vincent F , Charnock SJ , Verschueren KH , Turkenburg JP , Scott DJ , Offen WA , Roberts S , Pell G , Gilbert HJ , Davies GJ , Brannigan JA
Ref : Journal of Molecular Biology , 330 :593 , 2003
Abstract : Esterases and deacetylases active on carbohydrate ligands have been classified into 14 families based upon amino acid sequence similarities. Enzymes from carbohydrate esterase family seven (CE-7) are unusual in that they display activity towards both acetylated xylooligosaccharides and the antibiotic, cephalosporin C. The 1.9A structure of the multifunctional CE-7 esterase (hereinafter CAH) from Bacillus subtilis 168 reveals a classical alpha/beta hydrolase fold encased within a 32 hexamer. This is the first example of a hexameric alpha/beta hydrolase and is further evidence of the versatility of this particular fold, which is used in a wide variety of biological contexts. A narrow entrance tunnel leads to the centre of the molecule, where the six active-centre catalytic triads point towards the tunnel interior and thus are sequestered away from cytoplasmic contents. By analogy to self-compartmentalising proteases, the tunnel entrance may function to hinder access of large substrates to the poly-specific active centre. This would explain the observation that the enzyme is active on a variety of small, acetylated molecules. The structure of an active site mutant in complex with the reaction product, acetate, reveals details of the putative oxyanion binding site, and suggests that substrates bind predominantly through non-specific contacts with protein hydrophobic residues. Protein residues involved in catalysis are tethered by interactions with protein excursions from the canonical alpha/beta hydrolase fold. These excursions also mediate quaternary structure maintenance, so it would appear that catalytic competence is only achieved on protein multimerisation. We suggest that the acetyl xylan esterase (EC and cephalosporin C deacetylase (EC enzymes of the CE-7 family represent a single class of proteins with a multifunctional deacetylase activity against a range of small substrates.
ESTHER : Vincent_2003_J.Mol.Biol_330_593
PubMedSearch : Vincent_2003_J.Mol.Biol_330_593
PubMedID: 12842474
Gene_locus related to this paper: bacsu-CAH

Title : Butyrylcholinesterase-Mediated enhancement of the enzymatic activity of trypsin - Darvesh_2001_Cell.Mol.Neurobiol_21_285
Author(s) : Darvesh S , Kumar R , Roberts S , Walsh R , Martin E
Ref : Cellular Molecular Neurobiology , 21 :285 , 2001
Abstract : 1. Acetylcholinesterase (AChE, EC and butyrylcholinesterase (BuChE, EC are enzymes that catalyze the hydrolysis of esters of choline. 2. Both AChE and BuChE have been shown to copurify with peptidases. 3. BuChE has also been shown to copurify with other proteins such as transferrin, with which it forms a stable complex. In addition, BuChE is found in association with beta-amyloid protein in Alzheimer brain tissues. 4. Since BuChE copurifies with peptidases, we hypothesized that BuChE interacts with these enzymes and that this association had an influence on their catalytic activities. One of the peptidases that copurifies with cholinesterases has specificity similar to trypsin, hence, this enzyme was used as a model to test this hypothesis. 5. Purified BuChE causes a concentration-dependent enhancement of the catalytic activity of trypsin while trypsin does not influence the catalytic activity of BuChE. 6. We suggest that, in addition to its esterase activity, BuChE may assume a regulatory role by interacting with other proteins.
ESTHER : Darvesh_2001_Cell.Mol.Neurobiol_21_285
PubMedSearch : Darvesh_2001_Cell.Mol.Neurobiol_21_285
PubMedID: 11569538

Title : Heterogeneity of adverse hepatic reactions to tetrahydroaminoacridine - Ames_1990_Aust.N.Z.J.Med_20_193
Author(s) : Ames DJ , Bhathal PS , Davies BM , Fraser JR , Gibson PR , Roberts S
Ref : Aust N Z J Med , 20 :193 , 1990
Abstract : Of 14 patients taking tetrahydroaminoacridine (THA) for the trial treatment of Alzheimer's disease, five developed mildly abnormal liver function tests. Four asymptomatic patients with persistently abnormal serum transaminase levels underwent liver biopsy, in order to determine the nature of the hepatic lesions. One subject had granulomatous hepatitis while three showed focal, predominantly centrilobular, liver cell necrosis and mild fatty change. One of the latter showed both tissue and peripheral blood eosinophilia. The liver function tests of the fifth patient, who was symptomatic, became normal after reduction of the dose of THA so he did not undergo biopsy. These findings suggest that the pathogenic mechanisms for THA-induced liver injury are heterogeneous ranging from hypersensitivity reactions to direct injury, and including combinations of the two. Patients receiving THA for treatment of Alzheimer's disease need regular monitoring of liver function.
ESTHER : Ames_1990_Aust.N.Z.J.Med_20_193
PubMedSearch : Ames_1990_Aust.N.Z.J.Med_20_193
PubMedID: 2344330