Enzyme Inhibition Flashcards
enzyme inhibition
ligand binds and diminishes catalysis
aspirin vs ibuprofen
ibuprofen 1/2 life is 24 hours, so it dissociates from COX and platelets can clot again; aspirin has a 1/2 life of 10 days and platelets have a life of 7-10 days, so process is essentially irreversible
penicillin
Penicillin irreversibly inhibits the enzyme transpeptidase by reacting with a serine residue in the transpeptidase. This reaction is irreversible and so the growth of the bacterial cell wall is inhibited.
penicillin resistance
beta lactamase hydrolyzes penicillin
so new penicillins are poorer substrates OR beta lactamase can be irreversibly inhibited by augmentin (clavulinic acid)
Serpins
serine protease inhibitors
irreversible suicide inhibitors; use conformational change to inhibit proteases;
protease flips on itself and gets stuck
clinically important serpins
anti-thrombin
alpha1-antitrypsin
fibrinolysis, tissue remodeling, tumor metastasis, inflammation, apoptosis
anti-thrombin
serpin
inhibits coagulation in blood clotting cascade;
regulated by heparin like molecules
alpha1- antitrypsin
trypsin (in digestive system-hydrolyzes protein)
inhibits neutrophil elastase in lungs (protective)
inactivated by cigarette smoke
low levels predispose towards emphysema and cirrhosis
mercury
irreversibly binds to sulfhydryl groups of cysteine and irreversibly inhibits many enzymes
lead
lead mimics calcium, a co-factors, and binds and inhibits calmodulin and protein kinase C
treatment for heavy metal poisoning
chelation using EDTA
irreversible inhibition as a pathology
diabetes- nonspecific glycation destroys activity of enzymes and proteins
types of reversible inhibitors
competitive, non-competitive, uncompetitive
lineweaver- burke plot
recasting data from michaelis menten plot in a line- easier to visualize effects of inhibitors
competitive inhibitio
compete with substrate for the same form of enzyme, often at same site;
affects the binding step;
Vmax does not change and Km does not change- midpoint changes
alcohol dehydrogenase
converts alcohol to aldehyde
substrates are ethanol, methanol, and ethylene glycol all which competitively inhibit the reactions of the other two
metabolic products of ethanol lead to
hangover
metabolic porudcts of methanol and ethylene glycol
death
can use ethanol as a competitive inhibitor
non-competitive inhibition
substrate can still bind to enzyme, but enzyme can’t do anything with it because inhibitor is bound somewhere else;
lowers enzyme concentration and lowers Vmax
noncompetitive inhibition of heme oxidase (HO)
normally a stress response enzyme which is present in several tumors; inhibitors resemble anti-fungal agents; does ketoconazole inhibit HO?
uncompetitive inhibition
inhibitor binds only to enzyme-substrate complex
changes Km and Vmax
acytylcholinesterase
hydrolase located in nerve synpases which hydrolyzes acetylcholine
presynaptic neuron release acetylcholine and post synaptic cell binds acetylcholine with receptors (muscarinic and nicotinic)
myasthenia gravis
neuromuscular disease;
too few receptors on post synaptic cell and acetylcholinesterase hydrolyzes acetylcholine too quickly; if one blocks acetylcholinesterase, it will allow more time for acetylcholine signal;
use carbamate as drug
carbamate
neostigmine; reversible acetylcholinesterase inhibitor
half life of 20 minutes;
can easily overdose and have too much acetylcholine in the synapse
carbamate poisoning/overdose
nerve signal is overstimulated and then paralyzed;
compete muscarinic receptors with atropine so that the acetylcholine can’t bind and the atropine complex can’t send signal (mandrake plant)
acetylcholinesterase irreversible inhibition
by nerve gas (Sarin) and pesticides; same reaction as overdose of carbamates however 1/2 life is MUCH LONGER; take pralidoxime (2-Pam) which is a stronger neucleophile so that the reaction is reversed