Association between human paraoxonase 2 protein and efficacy of acetylcholinesterase inhibiting drugs used against Alzheimer's disease

Autor: Fauzia Parween, K. P. Singh, Rinkoo D. Gupta, Md. Summon Hossain
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Hydrolases
Artificial Gene Amplification and Extension
Pharmacology
Alzheimer's Disease
Biochemistry
Polymerase Chain Reaction
Esterase
chemistry.chemical_compound
Medical Conditions
Medicine and Health Sciences
Donepezil
education.field_of_study
Crystallography
Multidisciplinary
biology
Physics
Hydrolysis
Esterases
Chemical Reactions
Software Engineering
Neurodegenerative Diseases
Condensed Matter Physics
Acetylcholinesterase
Enzymes
Chemistry
Neurology
Physical Sciences
Crystal Structure
Engineering and Technology
Medicine
Gene Cloning
Research Article
Protein Binding
Pyridostigmine Bromide
Computer and Information Sciences
Science
Population
Research and Analysis Methods
Computer Software
Alzheimer Disease
Donepezil Hydrochloride
Mental Health and Psychiatry
Solid State Physics
Humans
Molecular Biology Techniques
education
Molecular Biology
Enzyme Kinetics
Aryldialkylphosphatase
Biology and Life Sciences
Proteins
Enzyme assay
chemistry
Mutation
Enzymology
biology.protein
Cholinergic
Dementia
Cholinesterase Inhibitors
Gene polymorphism
Cloning
Zdroj: PLoS ONE, Vol 16, Iss 10, p e0258879 (2021)
PLoS ONE, Vol 16, Iss 10 (2021)
PLoS ONE
ISSN: 1932-6203
Popis: Serum Paraoxonase 2 (PON2) level is a potential biomarker owing to its association with a number of pathophysiological conditions such as atherosclerosis and cardiovascular disease. Since cholinergic deficiency is closely linked with Alzheimer’s disease (AD) progression, acetylcholinesterase inhibitors (AChEIs) are the treatment of choice for patients with AD. However, there is a heterogenous response to these drugs and mostly the subjects do not respond to the treatment. Gene polymorphism, the simultaneous occurrence of two or more discontinuous alleles in a population, could be one of the important factors for this. Hence, we hypothesized that PON2 and its polymorphic forms may be hydrolyzing the AChEIs differently, and thus, different patients respond differently. To investigate this, two AChEIs, donepezil hydrochloride (DHC) and pyridostigmine bromide (PB), were selected. Human PON2 wildtype gene and four mutants, two catalytic sites, and two polymorphic sites were cloned, recombinantly expressed, and purified for in vitro analysis. Enzyme activity and AChE activity were measured to quantitate the amount of DHC and PB hydrolyzed by the wildtype and the mutant proteins. Herein, PON2 esterase activity and AChE inhibitor efficiency were found to be inversely related. A significant difference in enzyme activity of the catalytic site mutants was observed as compared to the wildtype, and subsequent AChE activity showed that esterase activity of PON2 is responsible for the hydrolysis of DHC and PB. Interestingly, PON2 polymorphic site mutants showed increased esterase activity; therefore, this could be the reason for the ineffectiveness of the drugs. Thus, our data suggested that the esterase activity of PON2 was mainly responsible for the hydrolysis of AChEI, DHC, and PB, and that might be responsible for the variation in individual response to AChEI therapy.
Databáze: OpenAIRE
Externí odkaz: