Enzyme inhibitors

Question 1

What are the 3 key roles of enzyme inhibitors?

Answer 1

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

Question 2

What does enzyme inhibition lead to

Answer 2

increase in conc of substrate or decrease in conc of product or metabolite

Question 3

What are the classes for enzyme inhibitors?

Answer 3

competitive reversible, transition state, non-competitive reversible, suicide inhibitors, substrate analogues, product mimics, non-competitive irreversible

Question 4

How are the put into these classes

Answer 4

based on modes of interaction with enzyme and by considering emulation of certain step of enzymatic reaction

Question 5

How do you differentiate between reversible and irreversible

Answer 5

based on affinity for enzyme

Question 6

Role of irreversible (non-competitive inhibitors)

Answer 6

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

Question 7

Examples of irreversible non-competitive inhibitors

Answer 7

nerve gases, Penicillins, disulfuram, PPI, orlistat & cephalosporins

Question 8

How do reversible inhibitors bind to enzyme?

Answer 8

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

Question 9

Examples of drugs and classes that are reversible inhibitors

Answer 9

sulfonamides, statins, diuretics, protease inhibitors, kinase inhibitors, antidepressants, ACE inhibitors, Methotrexate

Question 10

What are competitive inhibitors?

Answer 10

a compound which closely resembles the chemical structure and molecular geometry of substrate. It competes with substrate for access to AS

Question 11

What does the amount of inhibition depend on?

Answer 11

inhibitor conc, substrate conc and relative affinities for the AA

Question 12

Describe the process of enzyme catalysis

Answer 12

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

Question 13

What are substrate analogues?

Answer 13

compounds that emulate the structure of unbound or bound substrate at its ground state, they are reversible competitive inhibitors

Question 14

What are product mimics?

Answer 14

compounds that emulate the structure of product, bound or unbound, they are reversible non-competitive inhibitors

Question 15

What are transition state analogues?

Answer 15

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

Question 16

What are the 3 groups of irreversible inhibitors?

Answer 16

group specific reagents, affinity labels and suicide inhibitors

Question 17

Amino acids possessing nucleophilic groups

Answer 17

serine, cysteine and histidine

Question 18

What do group specific reagents do?

Answer 18

React with specific AA side chains

Question 19

What are affinity labels?

Answer 19

Reactive substrate analogues which are structurally similar to the substrate and capable of binding covalently to the AS. More specific than group specific reagents

Question 20

What do suicide inhibitors do?

Answer 20

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

Question 21

Give 3 pharmaceutical drawbacks of irreversible inhibitors

Answer 21

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

Question 22

Explain the pharmaceutical drawbacks of suicide inactivators

Answer 22

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

Question 23

What are the 2 main classes of mechanism based inhibitors

Answer 23

suicide (irreversible) and transition state (reversible)

Question 24

Examples of suicide inhibitors

Answer 24

5-fluorouracil, tienillic acid, Penicillins, clavulanic acid

Question 25

Examples of transition state inhibitors

Answer 25

Statins, ACE inhibitors, protease inhibitors , Aliskeren

Question 26

Why should a transition state be bound more strongly to an enzyme than a substrate or product?

Answer 26

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

Question 27

Describe the mechanism of action of Penicillin

Answer 27

inhibits cell wall synthesis by inhibiting Transpeptidase , becomes covalently linked to the active site leading to irreversible inhibition

Question 28

Describe the key factors of bacterial resistance to Penicillins

Answer 28

enzymes that inactivate Penicillins do so by opening b-lactam rings