Choi JY

References (13)

Title : Pretreatment of rhesus monkeys with transdermal patches containing physostigmine and procyclidine: implications of the delivery system for the potential application against VX nerve agent intoxication in humans - Nam_2023_Arch.Toxicol__
Author(s) : Nam JH , Kim MS , Song YJ , Kim CH , Kim WS , Yu CH , Joe HE , Hur GH , Seo MR , Kim Y , Park KE , Choi JY , Chung SJ , Shin YK
Ref : Archives of Toxicology , : , 2023
Abstract : Physostigmine (Phs) is a reversible inhibitor of acetylcholinesterase (AChE) that penetrates the blood-brain barrier (BBB) and could be used to protect the central nervous system (CNS) against the effects of nerve agents. For prophylactic effectiveness, long, steady, and adequate inhibition of AChE activity by Phs is needed to broadly protect against the CNS effects of nerve agents. Here, we evaluated the efficacy of transdermal patches containing Phs and procyclidine (PC) as prophylactic agents. Patches (25 cm(2)) containing 4.4smg Phs and 17.8smg PC had a protective ratio of approximately 78.6-fold in rhesus monkeys challenged with VX nerve agent and given an antidote. Physiologically based pharmacokinetic model in conjunction with an indirect pharmacodynamic (PBPK/PD) was developed for Phs and scaled to rhesus monkeys. The model was able to reproduce the concentration profile and inhibitory effect on AChE of Phs in monkeys, as evidenced by correlation coefficients of 0.994 and 0.992 for 25 cm(2) and 49 cm(2) patches, respectively (i.e., kinetic data), and 0.989 and 0.968 for 25 cm(2) and 49 cm(2) patches, respectively (i.e., dynamic data). By extending the monkey PBPK/ PD model to humans, the effective human dose was predicted to be five applications of a 25 cm(2) patch (i.e., 22smg Phs), and two applications of a 49scm(2) patch (i.e., 17.4smg Phs). Therefore, given that patch application of Phs in rhesus monkeys has a prolonged effect (namely, AChE inhibition of 19.6% for the 25 cm(2) patch and 23.0% for the 49 cm(2) patch) for up to 216sh, patch formulation of Phs may provide similar protection against nerve agent intoxication in humans.
ESTHER : Nam_2023_Arch.Toxicol__
PubMedSearch : Nam_2023_Arch.Toxicol__
PubMedID: 36633609

Title : Babesia BdFE1 Esterase is Required for the Anti-parasitic Activity of the ACE Inhibitor Fosinopril - Vydyam_2023_J.Biol.Chem__105313
Author(s) : Vydyam P , Choi JY , Gihaz S , Chand M , Gewirtz M , Thekkiniath J , Lonardi S , Gennaro JC , Ben Mamoun C
Ref : Journal of Biological Chemistry , :105313 , 2023
Abstract : Effective and safe therapies for the treatment of diseases caused by intraerythrocytic parasites are impeded by the rapid emergence of drug resistance and the lack of novel drug targets. One such disease is human babesiosis, which is a rapidly emerging tick-borne illness caused by Babesia parasites. In this study, we identified fosinopril, a phosphonate-containing, FDA-approved Angiotensin Converting Enzyme (ACE) inhibitor commonly used as a prodrug for hypertension and heart failure, as a potent inhibitor of B. duncani parasite development within human erythrocytes. Cell biological and mass spectrometry analyses revealed that the conversion of fosinopril to its active diacid molecule, fosinoprilat, is essential for its antiparasitic activity. We show that this conversion is mediated by a parasite-encoded esterase, BdFE1, which is highly conserved among apicomplexan parasites. Parasites carrying the L238H mutation in the active site of BdFE1 failed to convert the prodrug to its active moiety and became resistant to the drug. Our data set the stage for the development of this class of drugs for therapy of vector-borne parasitic diseases.
ESTHER : Vydyam_2023_J.Biol.Chem__105313
PubMedSearch : Vydyam_2023_J.Biol.Chem__105313
PubMedID: 37797695
Gene_locus related to this paper: 9apic-BdFE1

Title : Neuroprotective Effects of Davallia mariesii Roots and Its Active Constituents on Scopolamine-Induced Memory Impairment in In Vivo and In Vitro Studies - Lee_2023_Pharmaceuticals.(Basel)_16_
Author(s) : Lee CH , Ko MS , Kim YS , Ham JE , Choi JY , Hwang KW , Park SY
Ref : Pharmaceuticals (Basel) , 16 : , 2023
Abstract : Beta-amyloid (Abeta) proteins, major contributors to Alzheimer's disease (AD), are overproduced and accumulate as oligomers and fibrils. These protein accumulations lead to significant changes in neuronal structure and function, ultimately resulting in the neuronal cell death observed in AD. Consequently, substances that can inhibit Abeta production and/or accumulation are of great interest for AD prevention and treatment. In the course of an ongoing search for natural products, the roots of Davallia mariesii T. Moore ex Baker were selected as a promising candidate with anti-amyloidogenic effects. The ethanol extract of D. mariesii roots, along with its active constituents, not only markedly reduced Abeta production by decreasing beta-secretase expression in APP-CHO cells (Chinese hamster ovary cells which stably express amyloid precursor proteins), but also exhibited the ability to diminish Abeta aggregation while enhancing the disaggregation of Abeta aggregates, as determined through the Thioflavin T (Th T) assay. Furthermore, in an in vivo study, the extract of D. mariesii roots showed potential (a tendency) for mitigating scopolamine-induced memory impairment, as evidenced by results from the Morris water maze test and the passive avoidance test, which correlated with reduced Abeta deposition. Additionally, the levels of acetylcholine were significantly elevated, and acetylcholinesterase levels significantly decreased in the brains of mice (whole brains). The treatment with the extract of D. mariesii roots also led to upregulated brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding protein (p-CREB) in the hippocampal region. These findings suggest that the extract of D. mariesii roots, along with its active constituents, may offer neuroprotective effects against AD. Consequently, there is potential for the development of the extract of D. mariesii roots and its active constituents as effective therapeutic or preventative agents for AD.
ESTHER : Lee_2023_Pharmaceuticals.(Basel)_16_
PubMedSearch : Lee_2023_Pharmaceuticals.(Basel)_16_
PubMedID: 38004471

Title : Observational Study of Clinical and Functional Progression Based on Initial Brain MRI Characteristics in Patients with Alzheimer's Disease - Choi_2018_J.Alzheimers.Dis_66_1721
Author(s) : Choi H , Yang Y , Han HJ , Jeong JH , Park MY , Kim YB , Jo KD , Choi JY , Kang KH , Kang H , Kwon DY , Yoo BG , Lee HJ , Shin BS , Jeon SM , Kwon OD , Kim JS , Lee SJ , Kim Y , Park TH , Kim YJ , Yang HJ , Park HY , Shin HE , Lee JS , Jung YH , Lee AY , Shin DI , Shin KJ , Park KH
Ref : J Alzheimers Dis , 66 :1721 , 2018
Abstract : BACKGROUND: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer's disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. OBJECTIVE: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. METHODS: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. RESULTS: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. CONCLUSION: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients' functional status.
ESTHER : Choi_2018_J.Alzheimers.Dis_66_1721
PubMedSearch : Choi_2018_J.Alzheimers.Dis_66_1721
PubMedID: 30452413

Title : Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus - Lawrenson_2016_Nat.Commun_7_12675
Author(s) : Lawrenson K , Kar S , McCue K , Kuchenbaeker K , Michailidou K , Tyrer J , Beesley J , Ramus SJ , Li Q , Delgado MK , Lee JM , Aittomaki K , Andrulis IL , Anton-Culver H , Arndt V , Arun BK , Arver B , Bandera EV , Barile M , Barkardottir RB , Barrowdale D , Beckmann MW , Benitez J , Berchuck A , Bisogna M , Bjorge L , Blomqvist C , Blot W , Bogdanova N , Bojesen A , Bojesen SE , Bolla MK , Bonanni B , Borresen-Dale AL , Brauch H , Brennan P , Brenner H , Bruinsma F , Brunet J , Buhari SA , Burwinkel B , Butzow R , Buys SS , Cai Q , Caldes T , Campbell I , Canniotto R , Chang-Claude J , Chiquette J , Choi JY , Claes KB , Cook LS , Cox A , Cramer DW , Cross SS , Cybulski C , Czene K , Daly MB , Damiola F , Dansonka-Mieszkowska A , Darabi H , Dennis J , Devilee P , Diez O , Doherty JA , Domchek SM , Dorfling CM , Dork T , Dumont M , Ehrencrona H , Ejlertsen B , Ellis S , Engel C , Lee E , Evans DG , Fasching PA , Feliubadalo L , Figueroa J , Flesch-Janys D , Fletcher O , Flyger H , Foretova L , Fostira F , Foulkes WD , Fridley BL , Friedman E , Frost D , Gambino G , Ganz PA , Garber J , Garcia-Closas M , Gentry-Maharaj A , Ghoussaini M , Giles GG , Glasspool R , Godwin AK , Goldberg MS , Goldgar DE , Gonzalez-Neira A , Goode EL , Goodman MT , Greene MH , Gronwald J , Guenel P , Haiman CA , Hall P , Hallberg E , Hamann U , Hansen TV , Harrington PA , Hartman M , Hassan N , Healey S , Heitz F , Herzog J , Hogdall E , Hogdall CK , Hogervorst FB , Hollestelle A , Hopper JL , Hulick PJ , Huzarski T , Imyanitov EN , Isaacs C , Ito H , Jakubowska A , Janavicius R , Jensen A , John EM , Johnson N , Kabisch M , Kang D , Kapuscinski M , Karlan BY , Khan S , Kiemeney LA , Kjaer SK , Knight JA , Konstantopoulou I , Kosma VM , Kristensen V , Kupryjanczyk J , Kwong A , de la Hoya M , Laitman Y , Lambrechts D , Le N , De Leeneer K , Lester J , Levine DA , Li J , Lindblom A , Long J , Lophatananon A , Loud JT , Lu K , Lubinski J , Mannermaa A , Manoukian S , Le Marchand L , Margolin S , Marme F , Massuger LF , Matsuo K , Mazoyer S , McGuffog L , McLean C , McNeish I , Meindl A , Menon U , Mensenkamp AR , Milne RL , Montagna M , Moysich KB , Muir K , Mulligan AM , Nathanson KL , Ness RB , Neuhausen SL , Nevanlinna H , Nord S , Nussbaum RL , Odunsi K , Offit K , Olah E , Olopade OI , Olson JE , Olswold C , O'Malley D , Orlow I , Orr N , Osorio A , Park SK , Pearce CL , Pejovic T , Peterlongo P , Pfeiler G , Phelan CM , Poole EM , Pylkas K , Radice P , Rantala J , Rashid MU , Rennert G , Rhenius V , Rhiem K , Risch HA , Rodriguez G , Rossing MA , Rudolph A , Salvesen HB , Sangrajrang S , Sawyer EJ , Schildkraut JM , Schmidt MK , Schmutzler RK , Sellers TA , Seynaeve C , Shah M , Shen CY , Shu XO , Sieh W , Singer CF , Sinilnikova OM , Slager S , Song H , Soucy P , Southey MC , Stenmark-Askmalm M , Stoppa-Lyonnet D , Sutter C , Swerdlow A , Tchatchou S , Teixeira MR , Teo SH , Terry KL , Terry MB , Thomassen M , Tibiletti MG , Tihomirova L , Tognazzo S , Toland AE , Tomlinson I , Torres D , Truong T , Tseng CC , Tung N , Tworoger SS , Vachon C , van den Ouweland AM , van Doorn HC , van Rensburg EJ , Van't Veer LJ , Vanderstichele A , Vergote I , Vijai J , Wang Q , Wang-Gohrke S , Weitzel JN , Wentzensen N , Whittemore AS , Wildiers H , Winqvist R , Wu AH , Yannoukakos D , Yoon SY , Yu JC , Zheng W , Zheng Y , Khanna KK , Simard J , Monteiro AN , French JD , Couch FJ , Freedman ML , Easton DF , Dunning AM , Pharoah PD , Edwards SL , Chenevix-Trench G , Antoniou AC , Gayther SA
Ref : Nat Commun , 7 :12675 , 2016
Abstract : A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 x 10(-20)), ER-negative BC (P=1.1 x 10(-13)), BRCA1-associated BC (P=7.7 x 10(-16)) and triple negative BC (P-diff=2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 x 10(-3)) and ABHD8 (P<2 x 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
ESTHER : Lawrenson_2016_Nat.Commun_7_12675
PubMedSearch : Lawrenson_2016_Nat.Commun_7_12675
PubMedID: 27601076

Title : Biochemical and toxicological properties of two acetylcholinesterases from the common bed bug, Cimex lectularius - Hwang_2014_Pestic.Biochem.Physiol_110_20
Author(s) : Hwang CE , Kim YH , Kwon DH , Seong KM , Choi JY , Je YH , Lee SH
Ref : Pestic Biochem Physiol , 110 :20 , 2014
Abstract : We examined the molecular and enzymatic properties of two acetylcholinesterases (AChEs; ClAChE1 and ClAChE2) from the common bed bug, Cimex lectularius. Native polyacrylamide gel electrophoresis followed by activity staining and Western blotting revealed that ClAChE1 is the main catalytic enzyme and is abundantly expressed in various tissues. Both ClAChEs existed in dimeric form connected by a disulfide bridge and were attached to the membrane via a glycophosphatidylinositol anchor. To determine their kinetic and inhibitory properties, both ClAChE1 and ClAChE2 were in vitro expressed in Sf9 cells using a baculovirus expression system. ClAChE1 showed higher catalytic efficiency toward acetylcholine, supporting the hypothesis that ClAChE1 plays a major role in postsynaptic transmission. An inhibition assay revealed that ClAChE1 is generally more sensitive to organophosphates and carbamates examined although ClAChE2 was >4000-fold more sensitive to malaoxon than ClAChE1. The relatively higher correlation between the in vitro ClAChE1 inhibition and the in vivo toxicity suggested that ClAChE1 is the more relevant toxicological target for organophosphates and carbamates. Although the physiological function of ClAChE2 remains to be elucidated, ClAChE2 also appears to have neuronal functions, as judged by its tissue distribution and molecular and kinetic properties. Our findings help expand our knowledge on insect AChEs and their toxicological properties.
ESTHER : Hwang_2014_Pestic.Biochem.Physiol_110_20
PubMedSearch : Hwang_2014_Pestic.Biochem.Physiol_110_20
PubMedID: 24759047
Gene_locus related to this paper: cimle-ACHE1 , cimle-ACHE2

Title : The overexpression of acetylcholinesterase compensates for the reduced catalytic activity caused by resistance-conferring mutations in Tetranychus urticae - Kwon_2012_Insect.Biochem.Mol.Biol_42_212
Author(s) : Kwon DH , Choi JY , Je YH , Lee SH
Ref : Insect Biochemistry & Molecular Biology , 42 :212 , 2012
Abstract : The mutations (G228S, A391T and F439W) and duplication of the acetylcholinesterase (AChE) gene (Tuace) are involved in monocrotophos resistance in the two-spotted spider mites, Tetranychus urticae (Kwon et al., 2010a, b). The overexpression of T. urticae AChE (TuAChE) as a result of Tuace duplication was confirmed in several field-collected populations by Western blotting using an AChE-specific antibody. To investigate the effects of each mutation on the insensitivity and fitness cost of AChE, eight variants of TuAChE were expressed in vitro using the baculovirus expression system. Kinetic analysis revealed that the G228S and F439W mutations confer approximately 26-fold and 99-fold increases in the insensitivity to monocrotophos, respectively, whereas the insensitivity increased over 1165-fold in the AChE with double mutations. Nevertheless, the presence of these mutations reduced the catalytic efficiency of AChE significantly. In particular, the TuAChE having both mutations together exhibited a 17.8 approximately 27.1-fold reduced catalytic efficiency, suggesting an apparent fitness cost in the monocrotophos-resistant mites. The A391T mutation did not change the kinetic properties of either the substrate or inhibitor when present alone but mitigated the negative impacts of the F439 mutation. To simulate the catalytic activity of the overexpressed TuAChE in two T. urticae strains (approximately 6 copies for AD strain vs. 2 copies for PyriF strain), appropriate TuAChE variants were combined to make up the desired AChE copies and mutation frequencies, and their enzyme kinetics were determined. The reconstituted 6-copy and 2-copy TuAChEs exhibited catalytic efficiency levels comparable to those of a single-copy wildtype TuAChE, suggesting that, if mutations are present, multiple copies of AChE are required to restore a normal level of catalytic activity in the monocrotophos-resistant mites. In summary, the present study provides clear evidence that Tuace duplication resulted in the proportional overexpression of AChE, which was necessary to compensate for the reduced catalytic activity of AChE caused by mutations.
ESTHER : Kwon_2012_Insect.Biochem.Mol.Biol_42_212
PubMedSearch : Kwon_2012_Insect.Biochem.Mol.Biol_42_212
PubMedID: 22198354
Gene_locus related to this paper: tetur-ACHE

Title : Acetylthiocholine (ATC)--cleaving cholinesterase (ChE) activity as a potential biomarker of pesticide exposure in the Manila clam, Ruditapes philippinarum, of Korea - Choi_2011_Mar.Environ.Res_71_162
Author(s) : Choi JY , Yu J , Yang DB , Ra K , Kim KT , Hong GH , Shin KH
Ref : Mar Environ Research , 71 :162 , 2011
Abstract : The acetylthiocholine (ATC) - cleaving cholinesterase (ChE) activity in Manila clam, which is widely distributed throughout the coastal environment of Korea, was assayed as a potentially useful biomarker of organophosphorous pesticides (OPs). A clear dose-response relationship was determined between inhibited ChE in adductor muscle of clams and four OPs (methidathion, chlorpyrifos, diazinon, IBP) which are heavily used OPs in Korea. The measured EC(50)-24 h values of methidathion, chlorpyrifos, diazinon, and IBP for Ruditapes philippinarum were 7.16 mug l(-1), 0.34 mg l(-1), 3.01 mg l(-1), and 3.41 mg l(-1), respectively. In field studies, ChE activity in Manila clams collected from 23 stations in the mid-western coastal region demonstrated spatial variation with statistical differences. These results suggest that ChE activity in R. philippinarum is a potential biomarker for assessing organophosphorous pesticide contamination in coastal environments.
ESTHER : Choi_2011_Mar.Environ.Res_71_162
PubMedSearch : Choi_2011_Mar.Environ.Res_71_162
PubMedID: 21262527

Title : Three acetylcholinesterases of the pinewood nematode, Bursaphelenchus xylophilus: insights into distinct physiological functions - Kang_2011_Mol.Biochem.Parasitol_175_154
Author(s) : Kang JS , Lee DW , Choi JY , Je YH , Koh YH , Lee SH
Ref : Molecular & Biochemical Parasitology , 175 :154 , 2011
Abstract : Acetylcholinesterase (AChE) plays a key role in postsynaptic transmission in most animals. Nematodes encode multiple AChEs, implying its functional diversity. To explore physiological functions of multiple AChEs, three distinct AChEs (BxACE-1, BxACE-2, and BxACE-3) were identified and characterized from the pinewood nematode. Sequencing comparison with Torpedo AChE and Caenorhabditis elegans ACEs identified choline-binding site, catalytic triad functional site, three internal disulfide bonds and aromatic residues for the catalytic gorge. Transcriptional profiling by quantitative real-time PCR revealed that BxACE-3 is more actively transcribed than BxACE-1 (2-3 times) and BxACE-2 (9-18 times) in both propagative and dispersal stages. The three BxACEs were functionally expressed using baculovirus system. Kinetic analysis of in vitro-expressed BxACEs revealed that the substrate specificity was highest in BxACE-1 whereas the catalytic efficiency was highest in BxACE-2. In inhibition assay, BxACE-3 showed the lowest inhibition rate. Taken together, it appears that both BxACE-1 and BxACE-2 play common but non-overlapping roles in synaptic transmission, whereas BxACE-3 may have non-neuronal functions. The current findings should provide valuable insights into the evolutionary process and various physiological roles of AChE.
ESTHER : Kang_2011_Mol.Biochem.Parasitol_175_154
PubMedSearch : Kang_2011_Mol.Biochem.Parasitol_175_154
PubMedID: 21074580
Gene_locus related to this paper: burxy-ACHE1 , burxy-ACHE2 , burxy-ACHE3

Title : Binding of 2-[18F]fluoro-CP-118,954 to mouse acetylcholinesterase: microPET and ex vivo Cerenkov luminescence imaging studies - Kim_2011_Nucl.Med.Biol_38_541
Author(s) : Kim DH , Choe YS , Choi JY , Lee KH , Kim BT
Ref : Nucl Med Biol , 38 :541 , 2011
Abstract : Acetylcholinesterase (AChE) has been an important cholinergic factor for the diagnosis of Alzheimer's disease (AD), because of reduced AChE activity in the postmortem brains of AD patients. We previously developed 5,7-dihydro-3-(2-(1-(2-[(18)F]fluorobenzyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3,2,f )-1,2-benzisoxazol-6-one (2-[(18)F]fluoro-CP-118,954) for in vivo studies of AChE in mice. In the present study, we automated the synthesis of 2-[(18)F]fluoro-CP-118,954 for the routine use and evaluated the radioligand by microPET and ex vivo Cerenkov luminescence imaging of mouse AChE. 4-[(18)F]Fluoro-donepezil, another AChE inhibitor, was used for comparison. Automated syntheses of 2-[(18)F]fluoro-CP-118,954 and 4-[(18)F]fluoro-donepezil resulted in high radiochemical yields (25-33% and 30-40%) and high specific activity (27.1-35.4 and 29.7-37.3 GBq/mumol). Brain microPET images of two ICR mice injected with 2-[(18)F]fluoro-CP-118,954 demonstrated high uptake in the striatum (ROI analysis: 5.1 %ID/g for the first 30 min and 4.1 %ID/g for another 30 min), and a blocking study with injection of CP-118,954 into one of the mice at 30 min after radioligand injection led to complete blocking of radioligand uptake in the striatum (ROI analysis: 1.9 %ID/g), whereas (18)F-labeled donepezil did not show specific uptake in the striatum. In another set of experiments, the brain tissues (striatum, parietal cortex, frontal cortex and cerebellum) were excised after brain microPET/CT imaging of mouse injected with 2-[(18)F]fluoro-CP-118,954, and a high striatal uptake was also detected in ex vivo optical and microPET images (ROI analysis: 1.4 %ID/g) and in gamma-counting data (2.1 %ID/g at 50 min post-injection) of the brain tissues. Taken together, these results demonstrated that 2-[(18)F]fluoro-CP-118,954 specifically binds to AChE in mouse brains.
ESTHER : Kim_2011_Nucl.Med.Biol_38_541
PubMedSearch : Kim_2011_Nucl.Med.Biol_38_541
PubMedID: 21531291

Title : Functional analysis and molecular characterization of two acetylcholinesterases from the German cockroach, Blattella germanica - Kim_2010_Insect.Mol.Biol_19_765
Author(s) : Kim YH , Choi JY , Je YH , Koh YH , Lee SH
Ref : Insect Molecular Biology , 19 :765 , 2010
Abstract : Two acetylcholinesterases (AChEs; BgAChE1 and BgAChE2) from Blattella germanica were functionally expressed using the baculovirus system. Kinetic analysis demonstrated that BgAChE2 had higher catalytic efficiency but lower substrate specificity than BgAChE1. With the exceptions of paraoxon and propoxur, BgAChE1 was generally less sensitive to inhibitors than BgAChE2. Western blot analysis using anti-BgAChE antibodies revealed that BgAChE1 was far more abundant in all examined tissues compared to BgAChE2, which is only present in the central nervous system. Both BgAChEs existed in dimeric form, covalently connected via a disulphide bridge under native conditions. Most fractions of BgAChE1 had a glycophosphatidylinositol (GPI) anchor, but a small fraction comprised a collagen-like tail. BgAChE2 appeared to have a collagen-GPI-fused tail. Based on the kinetic and molecular properties, tissue distribution and abundance, BgAChE1 was confirmed to play a major role in postsynaptic transmission.
ESTHER : Kim_2010_Insect.Mol.Biol_19_765
PubMedSearch : Kim_2010_Insect.Mol.Biol_19_765
PubMedID: 20738424
Gene_locus related to this paper: blage-ACHE1 , blage-ACHE2

Title : Mutations of acetylcholinesterase1 contribute to prothiofos-resistance in Plutella xylostella (L.) - Lee_2007_Biochem.Biophys.Res.Commun_353_591
Author(s) : Lee DW , Choi JY , Kim WT , Je YH , Song JT , Chung BK , Boo KS , Koh YH
Ref : Biochemical & Biophysical Research Communications , 353 :591 , 2007
Abstract : Insensitive acetylcholinesterase (AChE) is involved in the resistance of organophosphorous and carbamate insecticides. We cloned a novel full-length AChE cDNA encoding ace1 gene from adult heads of the diamondback moth (DBM, Plutella xylostella). The ace1 gene encoding 679 amino acids has conserved motifs including catalytic triad, choline-binding site and acyl pocket. Northern blot analysis revealed that the ace1 gene was expressed much higher than the ace2 in all examined body parts. The biochemical properties of expressed AChEs showed substrate specificity for acetylthiocholine iodide and inhibitor specificity for BW284C51 and eserine. Three mutations of AChE1 (D229G, A298S, and G324A) were identified in the prothiofos-resistant strain, two of which (A298S and G324A) were expected to be involved in the prothiofos-resistance through three-dimensional modeling. In vitro functional expression of AChEs in Sf9 cells revealed that only resistant AChE1 is less inhibited with paraoxon, suggesting that resistant AChE1 is responsible for prothiofos-resistance.
ESTHER : Lee_2007_Biochem.Biophys.Res.Commun_353_591
PubMedSearch : Lee_2007_Biochem.Biophys.Res.Commun_353_591
PubMedID: 17196934
Gene_locus related to this paper: pluxy-ACHE , pluxy-ACHE1

Title : Synthesis and evaluation of radioiodine-labelled CP-118,954 for the in-vivo imaging of acetylcholinesterase - Lee_2007_Nucl.Med.Commun_28_561
Author(s) : Lee I , Choe YS , Ryu EK , Choi BW , Choi JY , Choi Y , Lee KH , Kim BT
Ref : Nucl Med Commun , 28 :561 , 2007
Abstract : OBJECTIVES: Alzheimer's disease (AD) is characterized by reduced acetylcholinesterase (AChE) activity in the post-mortem tissues of AD patients. Therefore, AChE has been an attractive target for the diagnosis of AD. In the present study, 5,7-dihydro-3-[2-(1-(phenylmethyl)-4-piperidinyl)ethyl]-6H-pyrrolo[3,2-f]-1,2-ben zisoxazol-6-one (CP-118,954), a potent AChE inhibitor, was labelled with radioiodine and evaluated as an AChE imaging agent for SPECT. METHODS: Radioiodine-labelled CP-118,954 was prepared from CP-144,885 and [(125)I]iodobenzyl bromide, and anti-AChE activities of iodine-substituted CP-118,954 were measured. Metabolism studies were carried out in samples of blood and whole brain of mice injected with 2-[(123)I]iodo-CP-118,954 ((123)I-1). Tissue distribution studies were also performed in mice injected with I-1, and samples of blood, thyroid, stomach, and brain tissue (cerebellum, striatum and cortex) were removed, weighed and counted. RESULTS: Of the ligands, 2-iodo-CP-118,954 exhibited higher binding affinity for AChE (IC50=24 nM) than the other positional isomers. 2-[(125)I]Iodo-CP-118,954 was found to have a lipophilicity (log P=2.1) favouring brain permeability and metabolic stability in mouse brain, but a marginal target (striatum) to non-target (cerebellum) uptake ratio (1.1) in mouse brain. CONCLUSION: This result demonstrates that 2-[(125)I]iodo-CP-118,954 may be unsuitable for AChE imaging. These findings suggest that radioligands suitable for AChE imaging should have not only a specific structure but also a sub-nanomolar to low nanomolar IC50.
ESTHER : Lee_2007_Nucl.Med.Commun_28_561
PubMedSearch : Lee_2007_Nucl.Med.Commun_28_561
PubMedID: 17538398