Enzyme inhibitors Flashcards
What are the 3 key roles of enzyme inhibitors?
to interact in a prohibitive way with an enzyme, modify the ability of an enzyme to catalyse the reaction of its natural substrates and prevent enzyme from working in normal manner
What does enzyme inhibition lead to
increase in conc of substrate or decrease in conc of product or metabolite
What are the classes for enzyme inhibitors?
competitive reversible, transition state, non-competitive reversible, suicide inhibitors, substrate analogues, product mimics, non-competitive irreversible
How are the put into these classes
based on modes of interaction with enzyme and by considering emulation of certain step of enzymatic reaction
How do you differentiate between reversible and irreversible
based on affinity for enzyme
Role of irreversible (non-competitive inhibitors)
forms covalent bond between drug and enzyme, blocks substrate from active site, can be allosteric so increasing the conc of substrate may not displace it
Examples of irreversible non-competitive inhibitors
nerve gases, Penicillins, disulfuram, PPI, orlistat & cephalosporins
How do reversible inhibitors bind to enzyme?
via intermolecular interactions, increasing substrate conc reverses inhibition, likely to be similar in structure to substrate or product, block binding of substrate and obstruct catalytic reaction. An equilibrium process
Examples of drugs and classes that are reversible inhibitors
sulfonamides, statins, diuretics, protease inhibitors, kinase inhibitors, antidepressants, ACE inhibitors, Methotrexate
What are competitive inhibitors?
a compound which closely resembles the chemical structure and molecular geometry of substrate. It competes with substrate for access to AS
What does the amount of inhibition depend on?
inhibitor conc, substrate conc and relative affinities for the AA
Describe the process of enzyme catalysis
complex ES is initially formed at the AS of the enzyme, the ES complex then breaks down either directly or through the intermediate stage, product forms, then enzyme is regenerated to give free P and E
What are substrate analogues?
compounds that emulate the structure of unbound or bound substrate at its ground state, they are reversible competitive inhibitors
What are product mimics?
compounds that emulate the structure of product, bound or unbound, they are reversible non-competitive inhibitors
What are transition state analogues?
compounds that structurally resemble the substrate, high energy transient species that cannot be isolated or synthesised portion of the unstable transition state of an enzymatic reaction
What are the 3 groups of irreversible inhibitors?
group specific reagents, affinity labels and suicide inhibitors
Amino acids possessing nucleophilic groups
serine, cysteine and histidine
What do group specific reagents do?
React with specific AA side chains
What are affinity labels?
Reactive substrate analogues which are structurally similar to the substrate and capable of binding covalently to the AS. More specific than group specific reagents
What do suicide inhibitors do?
They bind to enzyme as substrate, they can be processed by normal catalytic mechanism so will lead to a chemically reactive intermediate that will inactive enzyme through covalent modification
Give 3 pharmaceutical drawbacks of irreversible inhibitors
their inherent chemical reactivity – they are designed to be alkylating or acylating, they can be wasted destroyed or attack other cellular components with unpredictable consequences and their effective lifetimes limited by the rate of protein turnover for the target enzyme
Explain the pharmaceutical drawbacks of suicide inactivators
the inhibitor may still bind to other cell component / substrate recognition may be shared at binding level, even if other proteins don’t activate the chemical reaction / problem if target enzyme is made in the cell as an inactive pre-cursor / in some cases the SI can cause toxicity due to high reactivity
What are the 2 main classes of mechanism based inhibitors
suicide (irreversible) and transition state (reversible)
Examples of suicide inhibitors
5-fluorouracil, tienillic acid, Penicillins, clavulanic acid
Examples of transition state inhibitors
Statins, ACE inhibitors, protease inhibitors , Aliskeren
Why should a transition state be bound more strongly to an enzyme than a substrate or product?
binding interactions between enzyme and substrate are optimal during TS / speed and effectiveness of reaction depends on how much the catalyst stabilized the TS / strong interactions with S or P likely to be detrimental since it could cause slow turnover as S and P spend too much time in the active site
Describe the mechanism of action of Penicillin
inhibits cell wall synthesis by inhibiting Transpeptidase , becomes covalently linked to the active site leading to irreversible inhibition
Describe the key factors of bacterial resistance to Penicillins
enzymes that inactivate Penicillins do so by opening b-lactam rings
