Chapter 7: Irreversible Inhibitors Flashcards
1
Q
Irreversible inhibitors
A
- Interact tightly with enzymes by either covalent bonds or strong non-covalent interactions
- Reduce enzyme activity and cause permanent inactivation
2
Q
Irreversible inhibitor effects
A
- May permanently damage functional groups, rendering them inactive
3
Q
Kinetic effect of irreversible inhibitors
A
- Reduce the concentration of active enzymes
- Minimize the levels of the ES complex
4
Q
Heavy metals
A
- Produce toxic effects that irreversibly react with specific groups on target enzymes
5
Q
P-chloromercuribenzoate
A
- Irreversibly inhibits the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase
- Binds to sulfhydryl groups at the enzyme’s active site
6
Q
Glyceraldehyde 3-phosphate dehydrogenase
A
- P-chloromercuribenzoate binds to sulfhydryl groups at its active site and
- Irreversible
7
Q
Chelation
A
- Removes toxic agents (heavy metals)
- Organ damage can be irreversible and this process will not be effective
8
Q
Organophosphates
A
- Irreversibly inhibit the acetylcholinesterase enzyme
- Causes accumulation of acetylcholine in the nerve endings and the muscarinic signs of poisoning
9
Q
Muscarining signs of poisoing
A
- Emptying of the bowels and bladder
- Blurred vision
- Profuse sweating and salivation
- Stimulation of smooth muscles
- Paralysis of respiratory muscles
10
Q
Accumulation of acetylcholine in the brain/spinal cord
A
- Results in characteristic central nervous system damage that is ultimately fatal
11
Q
Aspirin (acetylsalicylic acid)
A
- Non steroidal anti inflammatory drug
- Irreversibly inhibits the synthesis of prostaglandins and thromboaxanes
12
Q
Eicosanoids (NSAIDs)
A
- Local hormones that perform a diverse array of physiological functions in the body
13
Q
Cyclooxygenase (COX) enzyme
A
- Has a serine residue (ser530) at its active site
- Binds irreversibly with aspirin (acetylates ser530) at its active site
14
Q
COX I and COX II
A
- The most widely known isoenzymes of cyclooxygenase
- Aspirin inhibits both isoenzymes
- Inhibition reduces prostaglandin synthesis
15
Q
Side effects of aspirin use
A
- Gastrointestinal bleeding
- Primarily results from inhibition of the COX I housekeeping enzyme
16
Q
Penicililn
A
- Unstable compound
- Consists of a beta-lactam ring structure and a variable R-group attached by a peptide bond
17
Q
Penicillin inhibition
A
- Irreversibly inhibits the final step in the synthesis of the rigid bacterial cell wall
18
Q
Rigid bacterial cell wall (synthesis inhibited by penicillin)
A
- Cross-linking of the cell wall macromolecule peptidoglycan
- Catalyzed by glycopeptide transpeptidase
19
Q
Penicillin structure
A
- A transition state analog that resembles the D-ala-D-ala moiety of the natural substrate of the enzyme
- Covalently binds to a serine residue at the enzymes active site
20
Q
Effects of glycopeptide transpeptidase
A
- Increased stability inhibits the enzyme
- Makes the bacteria more vulnerable
21
Q
Beta-lactamase enzyme
A
- Production by bacteria of this enzyme makes them more resistant to penicillin
22
Q
Fluorouracil (adrucil)
A
- Anticancer agent
- A thymine analog
- Converted in vivo into fluorodeoxyuracidylate
23
Q
Fluorodeoxyuracidylate
A
- First acts as a normal substrate for the enzyme thymidylate synthase
- Then performs covalent complex with the enzyme (irreversibly inhibited)
24
Q
Suicide inhibition
A
- Enzyme itself converts the inhibitor precursor to its active form
- Exhibited by anticancer agents such as fluorouracil
25
Anticancer agents
- Irreversible inhibition
- Suicide inhibition
- Target the enzymes of cell replication
26
6-mercaptopurine
- An analog of hypoxanthine, adenine, and guanine
| - Works similar to suicide inhibition
27
Cytosine arabinside (ara-C)
- Nucleotide pro-drug that is phosphorylated to the active agent disrupting DNA replication
28
Cyanide
- Binds covalently and irreversibly to the ferric iron (Fe+++) of mitochondrial cytochrome oxidase (complex IV) of the ETC
- Also binds to hemoglobin, reducing oxygen binding
29
Effects of cyanide
- Aerobic energy production is diminished
- Forces cells to respire anaerobically, making poisoning fatal in high doses
- CNS and heart most vulnerable
30
Lopinavir (Keletra)
- First generation HIV protease inhibitor
| - Binds covalently to the carboxyl groups of aspartate residues at the active site of HIV protease I
31
Tipranavir (Aptivus)
- Second generation HIV protease inhibitor
- Target lysl and tyrosyl residues
- Fewer off-target side effects
32
Combining first and second-generation HIV protease inhibtors (combination therapy)
- Reverse transcriptase inhibitors
- Generally more effective than monotherapy
- Reduces the amount of HIV in the blood to an undetectable level
33
AZT
- An analog of thymidine
- Marketed under brand name Retrovir
- Combination treatment drug
34
Serpins
- Class of natural irreversible inhibitors
- Irreversible serine protease inhibitors
- Synthesized by the hepatocyte
35
Serpin ES complex formation
- Possess a common central core of 350 amino acids
| - Inactivate any excess serine protease in the circulation
36
Hepatic receptor-mediated mechanism
- Removes serpin ES complex from circulation
| - Important regulatory mechanism in various biochemical processes
37
alpha1-protease inhibitor (Alpha 1 globulin)
- Belongs to superfamily of serine protease inhibitors
| - Responsible for inhibiting the leukocyte elastase that degrades elastin and other proteins
38
Circulating level of alpha1-protease inhibitor
- High in the blood (> 25um) and becomes further elevated with injury to counter the associated increase in elastase activity
39
Alpha1-protease inhibitor deficiency
- May result in uncontrolled elastase activity that can destroy normal lung tissue (emphysema)
40
Emphysema
- Produced as a result of alpha1-protease inhibitor deficiency
41
Thrombin
- Serine protease in the clotting cascade (IXa, Xa, XIa, and XIIa)
42
Antithrombin
- Irreversibly inhibits serine proteases in the clotting cascade
- Produced in the liver
- Resembles alpha1-protease inhibitor
43
Antithrombin efficiency
- Inhibits thrombin with much greater efficiency than elastase
44
Antithrombin in clotting
- Opposes blood clotting
| - Deficiency leads to reoccurring venous thromboembolism
45
Heparin
- Glycosaminoglycan
- Sulfating increases degree of thrombin in vitro inhibition by 1000 times
- Used as a therapeutic anticoagulant
46
Irreversible inhibitors summary
- Bind to the enzyme molecule with high affinity to reduce enzyme activity
47
Kinetic studies unable to be performed due to
- The covalent nature of the enzyme-inhibitor interaction
48
Medically relevant irreversible inhibitors of enzyme action
- Heavy metals
- Organophosphates
- Aspirin
- Penicillin
- Fluorouracil
- Lopinavir
- Tipranavir
49
Natural serpins, alpha1-protease inhibitor, and antithrombin
- Function as irreversible enzyme inhibitors in vivo
