AchE inhibitors Flashcards
AChE
most significant physiological mech which cholinergic is terminated - enzyme may exist in monomeric, dimeric, or multimeric forms and is attached to the extracellular surface of neurons by glycosylphophatidylinositol anchoring
AChE belongs ti the ___ family of enzymes
serine hydrolase - all use a similar triad of amino acids to carry out the esterase activity within the active site - all human AChE is coded by a single gene, alternative slicing of the pre-mRNA may lead to different splice varients
what happens if there is alternative slicing of the pre-mRNA
may lead to different splice variants - possibly leading to difference in drug binding
ACh capability is limited by
how easily it can diffuse to the active site- the enzyme has one of the highest turn over rates of any known enzyme
where is AChE located
at every cholinergic synapse and is responsible for the termmination of cholinergic transmission by hydrolyzing ach to choline and acetate
catalytic triad composed of
serine, histamine, glutamate - also cationic binding for the charged nitrogen tryptophan residue rather than anionic amino acid such as asp or glu
process by which AChE hydrolyzes Ach is
through a two-step acyl substitution reaction:
- nucleophillic attack of the choline ester by the serine hydroxyl, releasing choline.
- acetylated enzyme is then hydrolyzed to release acetate and the enzyme is returned to its original state
similarities of neostigmine and ach
quant ammonium, alcoxy
what are some differences of ach and neostigmine
ring, carbamate, looks enough like ach to get into the active site
regeneration time (hydrolysis of carbamate ester) usually longer than with the acetylated form. tell how this would effect duration of action correlated to plasma drug levels with these types of drugs
drug is active when broken down, the plasma conc may decrease as AchE handled, usually think parent to metabolite will end drug action - stigmines work when AChE acetyles carbamalating the enzyme
what do all stigmines have in common
all have one ring, carbamate ester
reversible inhibiotrs
not carbamilated, increase the plasma level which inc the effect, prevents AChE from getting to the active site endophonium, galantamine, donepezil
organophosphates
extremely toxic to mammals and humans. similar mech to carbamates the phosphorylated enzyme resistant to hydrolysis which prevents regeneration of functional enzyme
why would removal of OR2 with OH hinder the hydrolysis and slow the regeneration of enzyme-
P not electrophilic and not susceptible to nucleophilic attack - aging is leaving group going away and can’t phosphorylate
what is needed to break the serine-o-phosphoryl bond
very strong nuc much stronger than water. nuc also needs to be drawn in the active site and bind with some specificity with AChE