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1.
Current treatments for Alzheimer's disease involve inhibiting cholinesterases. Conversely, cholinesterase stimulation may be deleterious. Homocysteine is a known risk factor for Alzheimer's and vascular diseases and its active metabolite, homocysteine thiolactone, stimulates butyrylcholinesterase. Considering the opposing effects on butyrylcholinesterase of homocysteine thiolactone and cholinesterase inhibitors, understanding how these molecules alter this enzyme may provide new insights in the management of dementia. Butyrylcholinesterase does not strictly adhere to Michaelis-Menten parameters since, at higher substrate concentrations, enzyme activation occurs. The substrate activation equation for butyrylcholinesterase does not describe the effects of inhibitors or non-substrate activators. To address this, global data fitting was used to generate a flexible equation based on Michaelis-Menten principles. This methodology was first tested to model complexities encountered in inhibition by imidazole of beta-galactosidase, an enzyme that obeys Michaelis-Menten kinetics. The resulting equation was sufficiently flexible to permit expansion for modeling activation or inhibition of butyrylcholinesterase, while accounting for substrate activation of this enzyme. This versatile equation suggests that both the inhibitor and non-substrate activator examined here have little effect on the substrate-activated form of butyrylcholinesterase. Given that butyrylcholinesterase inhibition can antagonize stimulation of this enzyme by homocysteine thiolactone, cholinesterase inhibition may have a role in treating Alzheimer and vascular diseases related to hyperhomocysteinemia. 相似文献
2.
Current treatments for Alzheimer's disease involve inhibiting cholinesterases. Conversely, cholinesterase stimulation may be deleterious. Homocysteine is a known risk factor for Alzheimer's and vascular diseases and its active metabolite, homocysteine thiolactone, stimulates butyrylcholinesterase. Considering the opposing effects on butyrylcholinesterase of homocysteine thiolactone and cholinesterase inhibitors, understanding how these molecules alter this enzyme may provide new insights in the management of dementia. Butyrylcholinesterase does not strictly adhere to Michaelis–Menten parameters since, at higher substrate concentrations, enzyme activation occurs. The substrate activation equation for butyrylcholinesterase does not describe the effects of inhibitors or non-substrate activators. To address this, global data fitting was used to generate a flexible equation based on Michaelis–Menten principles. This methodology was first tested to model complexities encountered in inhibition by imidazole of β-galactosidase, an enzyme that obeys Michaelis–Menten kinetics. The resulting equation was sufficiently flexible to permit expansion for modeling activation or inhibition of butyrylcholinesterase, while accounting for substrate activation of this enzyme. This versatile equation suggests that both the inhibitor and non-substrate activator examined here have little effect on the substrate-activated form of butyrylcholinesterase. Given that butyrylcholinesterase inhibition can antagonize stimulation of this enzyme by homocysteine thiolactone, cholinesterase inhibition may have a role in treating Alzheimer and vascular diseases related to hyperhomocysteinemia. 相似文献
3.
1. Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) are serine hydrolase enzymes that catalyze the hydrolysis of acetylcholine.2. (–) Huperzine A is an inhibitor of AChE and is being considered for the treatment of Alzheimer's disease.3. In addition to esterase activity, AChE and BuChE have intrinsic aryl acylamidase activity.4. The function of aryl acylamidase is unknown but has been speculated to be important in Alzheimer pathology.5. Kinetic effects of (–) huperzine A and ( ±)$ huperzine A on the aryl acylamidase activity of human cholinesterases were examined.6. (–) Huperzine A inhibited the aryl acylamidase activities of both AChE and BuChE.7. (±) Huperzine A inhibited this function in AChE but stimulated BuChE aryl acylamidase suggesting that the (+) enantiomer is a powerful activator of this enzyme activity.8. The two huperzine enantiomers may prove to be useful tools to examine the function of aryl acylamidase activity, including its role in Alzheimer pathology. 相似文献
4.
Cholinesterases: New Roles in Brain Function and in Alzheimer's Disease 总被引:15,自引:0,他引:15
Giacobini E 《Neurochemical research》2003,28(3-4):515-522
The most important therapeutic effect of cholinesterase inhibitors (ChEI) on approximately 50% of Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission–experimental or pathological, such as in AD–leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on -amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to cholinesterase inhibition. A second important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain acetylcholine. 相似文献
5.
Accompanying the gradual rise in the average age of the population of most industrialized countries is a regrettable progressive rise in the number of individuals afflicted with age-related neurodegenerative disorders, epitomized by Alzheimer's disease (AD) but, additionally, including Parkinson's disease (PD) and stroke. The primary therapeutic strategy, to date, involves the use of cholinesterases inhibitors (ChEIs) to amplify residual cholinergic activity. The enzyme, acetylcholinesterase (AChE), along with other elements of the cholinergic system is depleted in the AD brain. In contrast, however, its sister enzyme, butyrylcholinesterase (BuChE), that likewise cleaves acetylcholine (ACh), is elevated and both AChE and BuChE co-localize in high amounts with the classical pathological hallmarks of AD. The mismatch between increased brain BuChE and depleted levels of both ACh and AChE, particularly late in the disease, has supported the design and development of new ChEIs with a preference for BuChE; exemplified by the novel agent, cymserine, whose binding kinetics are characterized for the first time. Specifically, as assessed by the Ellman method, cymserine demonstrated potent concentration-dependent binding with human BuChE. The IC50 was determined as 63 to 100 nM at the substrate concentration range of 25 to 800 microM BuSCh. In addition, the following new binding constants were investigated for human BuChE inhibition by cymserine: T(FPnubeta), K(nubeta), K(Bs), K(MIBA), M(IC50), D(Sc), R(f), (O)K(m), OIC100, K(sl), theta(max) and R(i). These new kinetic constants may open new avenues for the kinetic study of the inhibition of a broad array of other enzymes by a wide variety of inhibitors. In synopsis, cymserine proved to be a potent inhibitor of human BuChE in comparison to its structural analogue, phenserine. 相似文献
6.
Gracielle Alves-Amaral Marcelo Pires-Oliveira Ana Luiza Andrade-Lopes Tiago Chiavegatti Rosely Oliveira Godinho 《Chemico-biological interactions》2010,186(1):9-15
The role of acetylcholinesterase (AChE) in the termination of the cholinergic response through acetylcholine (ACh) hydrolysis and the involvement of plasma butyrylcholinesterase (BuChE), mainly of hepatic origin, in the metabolism of xenobiotics with ester bonds is well known. Besides, BuChE has a crucial role in ACh hydrolysis, especially when selective anticholinesterases inhibit AChE. Herein, we analyzed the gender-related differences and the circadian changes of rat plasma cholinesterases. Plasma and liver cholinesterase activities were evaluated in control or 2–30-day castrated adult male and female rats. Plasma and liver AChE activities did not differ between genders and were not influenced by sex hormone deprivation. BuChE plasma activity was 7 times greater in female, reflecting gender differences in liver enzyme expression. Castration increased liver and plasma BuChE activity in male, while reduced it in female, abolishing gender differences in enzyme activity. Interestingly, female AChE and BuChE plasma activities varied throughout the day, reaching values 27% and 42% lower, respectively, between 2 p.m. and 6 p.m. when compared to the morning peaks at 8 a.m. Castration attenuated daily female BuChE oscillation. On the other hand, male plasma enzymes remained constant throughout the day. In summary, our results show that liver and plasma BuChE, but not AChE, expression is influenced by sex hormones, leading to high levels of blood BuChE in females. The fluctuation of female plasma BuChE during the day should be taken into account to adjust the bioavailability and the therapeutic effects of cholinesterase inhibitors used in cholinergic-based conditions such Alzheimer's disease. 相似文献
7.
Jorge Andres Rodriguez Ana Maria Buzaleh Mariana Fossati Julio Azcurra Alcira Maria Del Carmen Batlle 《Cellular and molecular biology, including cyto-enzymology》2002,48(1):103-110
In central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyse acetylcholine. Diminished cholinesterase activity is known to alter several mental and psychomotor functions. The symptoms of cholinergic crisis and those observed during acute attacks of acute intermittent porphyria are very similar. The aim of this study was to investigate if there could be a link between the action of some porphyrinogenic drugs on brain and the alteration of the cholinergic system. To this end, AChE and BuChE activities were assayed in whole and different brain areas. Muscarinic acetylcholine receptor (mAChR) levels were also measured. Results obtained indicate that the porphyrinogenic drugs tested affect central cholinergic transmission. Quantification of mAChR gave quite different levels depending on the xenobiotic. Veronal administration inhibited 50% BuChE activity in whole brain, cortex and hippocampus; concomitantly cortex mAChR was 30% reduced. Acute and chronic isoflurane anaesthesia diminished BuChE activity by 70-90% in whole brain instead cerebellum and hippocampus mAChR levels were only altered by chronic enflurane anaesthesia. Differential inhibition of cholinesterases in the brain regions and their consequent effects may be of importance to the knowledge of the mechanisms of neurotoxicity of porphyrinogenic drugs. 相似文献
8.
I S Delamanche P Mailly C Bouchaud 《Archives d'anatomie microscopique et de morphologie expérimentale》1986,75(3):135-148
A series of organophosphorous compounds (OP) was tested using a pharmacohistochemical method applied in vitro on the rat striatum, the central structure which contains the highest levels of acetylcholine and its metabolic enzymes; the OP showed a great variety of action towards the specific cholinesterase (AChE) and non-specific cholinesterase (BuChE). Except for iso-OMPA which is specific for BuChE localized in the microvessels endothelium, all the OP doses used in the present study were more or less potent inhibitors of cholinesterases (ChE). 15 mn after LD 50 doses of OP administered by subcutaneous route, a partial inhibition of the neurophile AChE occurred, revealing some striatal neurons which displayed high residual activity, i.e. the cholinergic interneurons. During the recovery phase following the inhibition of AChE by 1.5 LD 50 doses (the animals being treated with atropine) the AChE reaction product was detected almost simultaneously in some axo-spinous synapses probably non-cholinergic. The partial inhibition and the de novo synthesis of AChE also revealed the presence of small and less reactive non-cholinergic neurons. Among all the OP tested, soman was remarkable for its patchy inhibition of AChE in the striatum. The significance of the alternation of reactive and non-reactive areas is discussed. 相似文献
9.
An in vitro evaluation of the effects of homocysteine thiolactone on key steps of angiogenesis and tumor invasion 总被引:1,自引:0,他引:1
Martínez-Poveda B Chavarría T Sánchez-Jiménez F Quesada AR Medina MA 《Biochemical and biophysical research communications》2003,311(3):649-653
Homocysteine thiolactone is a highly reactive homocysteine derivative that can react easily with proteins. Protein homocysteinylation has been suggested as a possible mechanism underlying the pathological consequences of impaired homocysteine metabolism. Homocysteine inhibits key steps of angiogenesis and tumor invasion. It can be hypothesized that homocysteine thiolactone could mimic the described anti-angiogenic and anti-invasive effects of homocysteine. Therefore, we studied the effects of homocysteine thiolactone on different key steps of angiogenesis and tumor invasion, using model endothelial and tumor cell lines. This study demonstrates that homocysteine thiolactone, in high contrast to homocysteine, is not an anti-angiogenic compound. Furthermore, our results suggest that homocysteine thiolactone could behave as a pro-angiogenic compound. 相似文献
10.
Darvesh S Kumar R Roberts S Walsh R Martin E 《Cellular and molecular neurobiology》2001,21(3):285-296
1. Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) 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 -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. 相似文献
11.
Yan JW Li YP Ye WJ Chen SB Hou JQ Tan JH Ou TM Li D Gu LQ Huang ZS 《Bioorganic & medicinal chemistry》2012,20(8):2527-2534
A series of isaindigotone derivatives and analogues were designed, synthesized and evaluated as dual inhibitors of cholinesterases (ChEs) and self-induced β-amyloid (Aβ) aggregation. The synthetic compounds had IC(50) values at micro or nano molar range for cholinesterase inhibition, and some compounds exhibited strong inhibitory activity for AChE and high selectivity for AChE over BuChE, which were much better than the isaindigotone derivatives previously reported by our group. Most of these compounds showed higher self-induced Aβ aggregation inhibitory activity than a reference compound curcumin. The structure-activity relationship studies revealed that the derivatives with higher inhibition activity on AChE also showed higher selectivity for AChE over BuChE. Compound 6c exhibiting excellent inhibition for both AChE and self-induced Aβ aggregation was further studied using CD, EM, molecular docking and kinetics. 相似文献
12.
H Jakubowski 《FASEB journal》1999,13(15):2277-2283
Homocysteine thiolactone, a cyclic thioester, is synthesized by certain aminoacyl-tRNA synthetases in editing or proofreading reactions that prevent translational incorporation of homocysteine into proteins. Although homocysteine thiolactone is expected to acylate amino groups in proteins, virtually nothing is known regarding reactivity of the thiolactone. Here it is shown that reactions of the thiolactone with protein lysine residues were robust under physiological conditions. In human serum incubated with homocysteine thiolactone, protein homocysteinylation was a major reaction that could be observed with as little as 10 nM thiolactone. Individual proteins were homocysteinylated at rates proportional to their lysine contents. Homocysteinylation led to protein damage, manifested as multimerization and precipitation of extensively modified proteins. Model enzymes, such as methionyl-tRNA synthetase and trypsin, were inactivated by homocysteinylation. Metabolic conversion of homocysteine to the thiolactone, protein homocysteinylation, and resulting protein damage may underlie involvement of Hcy in the pathology of vascular disease.-Jakubowski, H. Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels. 相似文献
13.
《Insect Biochemistry》1986,16(4):701-707
Anticholinesterase potency and toxicity for spring grain aphids of 52 organophosphorous inhibitors (OPI) of different structures were investigated. As regards sensitivity to OPI, the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of the spring grain aphid are shown to differ significantly from the “typical” cholinesterases, i.e. from human erythrocyte AChE and horse serum BuChE, which is presumably associated with differences in the structures of the active surface of these enzymes. The extremely high sensitivity of spring grain aphid AChE to cationic OPI containing the onium atom in the leaving part of the molecule indicates the fundamental importance of the anionic site in the active centre of the enzyme. By contrast, spring grain aphid BuChE has low sensitivity to OPI, typical of the cationic type, which suggests that it has no anionic site. Correlation was established between the toxicity and anticholinesterase potency of OPI which contain no cationic groups or bulky hydrophobic radicals. 相似文献
14.
Localization of mRNAs encoding acetylcholinesterase and butyrylcholinesterase in the rat spinal cord by nonradioactive in situ hybridization. 总被引:1,自引:0,他引:1
Katarina Mis Tomaz Mars Marko Jevsek Martina Brank Katarina Zajc-Kreft Zoran Grubic 《The journal of histochemistry and cytochemistry》2003,51(12):1633-1644
15.
16.
Homocysteine thiolactone is a toxic metabolite produced from homocysteine by amino-acyl t-RNA synthetase in error editing reaction. The basic cause of toxicity of homocysteine thiolactone is believed to be due to the adduct formation with lysine residues (known as protein N-homocysteinylation) leading to protein aggregation and loss of enzyme function. There was no data available until now that showed the effect of homocysteine thiolactone on the native state structural changes that led to aggregate formation. In the present study we have investigated the time dependent structural changes due to homocysteine thiolactone induced modifications on three different proteins having different physico-chemical properties (cytochrome-c, lysozyme and alpha lactalbumin). We discovered that N-homocysteinylation leads to the formation of molten globule state—an important protein folding intermediate in the protein folding pathway. We also found that the formation of the molten globule state might be responsible for the appearance of aggregate formation. The study indicates the importance of protein folding intermediate state in eliciting the homocysteine thiolactone toxicity. 相似文献
17.
Immunochemistry of mammalian cholinesterases 总被引:1,自引:0,他引:1
Advances in the study of cholinesterase biology have been facilitated by the development of polyclonal and monoclonal antibodies to acetylcholinesterase (AChE) (EC 3.1.1.7) and butyrylcholinesterase (BuChE) (EC 3.1.1.8) in several laboratories. Our work has focused on murine monoclonal antibodies to the mammalian enzymes. Two dozen antibodies are now in hand, with primary specificity for the AChE of human red blood cells, rabbit brain, and rat brain, and for the BuChE of human plasma. These antibodies exhibit a restricted but useful range of affinities for other mammalian cholinesterases of corresponding types. Several applications are described, including an analysis of BuChE phylogeny within the higher primates, an immunodisplacement assay of AChE in normal human red blood cells and cells from patients with paroxysmal nocturnal hemoglobinuria, a study of immunochemical differences between membrane-associated and soluble AChE of rabbit brain, and initial work on the immunofluorescence cytochemistry of the rat brain. 相似文献
18.
Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation 总被引:14,自引:0,他引:14
Jakubowski H 《The Journal of biological chemistry》2000,275(6):3957-3962
Homocysteine thiolactone is formed in all cell types studied thus far as a result of editing reactions of some aminoacyl-tRNA synthetases. Because inadvertent reactions of thiolactone with proteins are potentially harmful, the ability to detoxify homocysteine thiolactone is essential for biological integrity. This work shows that a single specific enzyme, present in mammalian but not in avian sera, hydrolyzes thiolactone to homocysteine. Human serum thiolactonase, a 45-kDa protein component of high density lipoprotein, requires calcium for activity and stability and is inhibited by isoleucine and penicillamine. Substrate specificity studies suggest that homocysteine thiolactone is a likely natural substrate of this enzyme. However, thiolactonase also hydrolyzes non-natural substrates, such as phenyl acetate, p-nitrophenyl acetate, and the organophospate paraoxon. N-terminal amino acid sequence of pure thiolactonase is identical with that of human paraoxonase. These and other data indicate that paraoxonase, an organophosphate-detoxifying enzyme whose natural substrate and function remained unknown up to now, is in fact homocysteine thiolactonase. By detoxifying homocysteine thiolactone, the thiolactonase/paraoxonase would protect proteins against homocysteinylation, a potential contributing factor to atherosclerosis. 相似文献
19.
B. N. Kormilitsyn S. N. Moralev A. E. Khovanskikh D. N. Dalimov 《Journal of Evolutionary Biochemistry and Physiology》2003,39(5):505-510
An antienzyme potency of 18 organophosphorus inhibitors (OPI), S-alkyl derivatives of thiophosphoric and thiophosphonic acids, to acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of the spring grain aphid and corresponding mammalian enzymes is studied. It is shown that dependence of the inhibitory potency on length of alkyl radicals differs in human and aphid AChE. Smaller differences were observed in the case of aphid and horse BuChE. The obtained data are compared to the data obtained at studying other series of OPI and cholinesterases of other animals. It is suggested that the revealed peculiarity of the inhibitory specificity of aphid AChE is due to the presence of serine instead of phenylalanine in the position 331 (the numeration according to AChE of the electric ray Torpedo californica). 相似文献
20.
Patrick Dreyfus Dina Zevin-Sonkin Shlomo Seidman Catherine Prody Rivka Zisling Haim Zakut Hermona Soreq 《Journal of neurochemistry》1988,51(6):1858-1867
To study the polymorphism of human cholinesterases (ChEs) at the levels of primary sequence and three-dimensional structure, a fragment of human butyrylcholinesterase (BuChE) cDNA was subcloned into the pEX bacterial expression vector and its polypeptide product analyzed. Immunoblot analysis revealed that the clone-produced BuChE peptides interact specifically with antibodies against human and Torpedo acetylcholinesterase (AChE). Rabbit polyclonal antibodies prepared against the purified clone-produced BuChE polypeptides interacted in immunoblots with denatured serum BuChE as well as with purified and denatured erythrocyte AChE. In contrast, native BuChE tetramers from human serum, but not AChE dimers from erythrocytes, interacted with these antibodies in solution to produce antibody-enzyme complexes that could be precipitated by second antibodies and that sedimented faster than the native enzyme in sucrose gradient centrifugation. Furthermore, both AChE and BuChE dimers from muscle extracts, but not BuChE tetramers from muscle, interacted with these antibodies. To reveal further whether the anti-cloned BuChE antibodies would interact in situ with ChEs in the neuromuscular junction, bundles of muscle fibers were microscopically dissected from the region in fetal human diaphragm that is innervated by the phrenic nerve. Muscle fibers incubated with the antibodies and with 125I-Protein A were subjected to emulsion autoradiography, followed by cytochemical ChE staining. The anti-cloned BuChE antibodies, as well as anti-Torpedo AChE antibodies, created patches of silver grains in the muscle endplate region stained for ChE, under conditions where control sera did not. These findings demonstrate that the various forms of human AChE and BuChE in blood and in neuromuscular junctions share sequence homologies, but also display structural differences between distinct molecular forms within particular tissues, as well as between similarly sedimenting molecular forms from different tissues. 相似文献