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Biochemistry I > Chapter 7: Irreversible Inhibitors > Flashcards

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
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2
Q

Irreversible inhibitor effects

A
  • May permanently damage functional groups, rendering them inactive
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3
Q

Kinetic effect of irreversible inhibitors

A
  • Reduce the concentration of active enzymes

- Minimize the levels of the ES complex

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4
Q

Heavy metals

A
  • Produce toxic effects that irreversibly react with specific groups on target enzymes
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5
Q

P-chloromercuribenzoate

A
  • Irreversibly inhibits the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase
  • Binds to sulfhydryl groups at the enzyme’s active site
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6
Q

Glyceraldehyde 3-phosphate dehydrogenase

A
  • P-chloromercuribenzoate binds to sulfhydryl groups at its active site and
  • Irreversible
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7
Q

Chelation

A
  • Removes toxic agents (heavy metals)

- Organ damage can be irreversible and this process will not be effective

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8
Q

Organophosphates

A
  • Irreversibly inhibit the acetylcholinesterase enzyme

- Causes accumulation of acetylcholine in the nerve endings and the muscarinic signs of poisoning

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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
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10
Q

Accumulation of acetylcholine in the brain/spinal cord

A
  • Results in characteristic central nervous system damage that is ultimately fatal
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11
Q

Aspirin (acetylsalicylic acid)

A
  • Non steroidal anti inflammatory drug

- Irreversibly inhibits the synthesis of prostaglandins and thromboaxanes

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12
Q

Eicosanoids (NSAIDs)

A
  • Local hormones that perform a diverse array of physiological functions in the body
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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

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14
Q

COX I and COX II

A
  • The most widely known isoenzymes of cyclooxygenase
  • Aspirin inhibits both isoenzymes
  • Inhibition reduces prostaglandin synthesis
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15
Q

Side effects of aspirin use

A
  • Gastrointestinal bleeding

- Primarily results from inhibition of the COX I housekeeping enzyme

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16
Q

Penicililn

A
  • Unstable compound

- Consists of a beta-lactam ring structure and a variable R-group attached by a peptide bond

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17
Q

Penicillin inhibition

A
  • Irreversibly inhibits the final step in the synthesis of the rigid bacterial cell wall
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18
Q

Rigid bacterial cell wall (synthesis inhibited by penicillin)

A
  • Cross-linking of the cell wall macromolecule peptidoglycan

- Catalyzed by glycopeptide transpeptidase

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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
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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
Q

Anticancer agents

A
  • Irreversible inhibition
  • Suicide inhibition
  • Target the enzymes of cell replication
26
Q

6-mercaptopurine

A
  • An analog of hypoxanthine, adenine, and guanine

- Works similar to suicide inhibition

27
Q

Cytosine arabinside (ara-C)

A
  • Nucleotide pro-drug that is phosphorylated to the active agent disrupting DNA replication
28
Q

Cyanide

A
  • 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
Q

Effects of cyanide

A
  • Aerobic energy production is diminished
  • Forces cells to respire anaerobically, making poisoning fatal in high doses
  • CNS and heart most vulnerable
30
Q

Lopinavir (Keletra)

A
  • First generation HIV protease inhibitor

- Binds covalently to the carboxyl groups of aspartate residues at the active site of HIV protease I

31
Q

Tipranavir (Aptivus)

A
  • Second generation HIV protease inhibitor
  • Target lysl and tyrosyl residues
  • Fewer off-target side effects
32
Q

Combining first and second-generation HIV protease inhibtors (combination therapy)

A
  • Reverse transcriptase inhibitors
  • Generally more effective than monotherapy
  • Reduces the amount of HIV in the blood to an undetectable level
33
Q

AZT

A
  • An analog of thymidine
  • Marketed under brand name Retrovir
  • Combination treatment drug
34
Q

Serpins

A
  • Class of natural irreversible inhibitors
  • Irreversible serine protease inhibitors
  • Synthesized by the hepatocyte
35
Q

Serpin ES complex formation

A
  • Possess a common central core of 350 amino acids

- Inactivate any excess serine protease in the circulation

36
Q

Hepatic receptor-mediated mechanism

A
  • Removes serpin ES complex from circulation

- Important regulatory mechanism in various biochemical processes

37
Q

alpha1-protease inhibitor (Alpha 1 globulin)

A
  • Belongs to superfamily of serine protease inhibitors

- Responsible for inhibiting the leukocyte elastase that degrades elastin and other proteins

38
Q

Circulating level of alpha1-protease inhibitor

A
  • High in the blood (> 25um) and becomes further elevated with injury to counter the associated increase in elastase activity
39
Q

Alpha1-protease inhibitor deficiency

A
  • May result in uncontrolled elastase activity that can destroy normal lung tissue (emphysema)
40
Q

Emphysema

A
  • Produced as a result of alpha1-protease inhibitor deficiency
41
Q

Thrombin

A
  • Serine protease in the clotting cascade (IXa, Xa, XIa, and XIIa)
42
Q

Antithrombin

A
  • Irreversibly inhibits serine proteases in the clotting cascade
  • Produced in the liver
  • Resembles alpha1-protease inhibitor
43
Q

Antithrombin efficiency

A
  • Inhibits thrombin with much greater efficiency than elastase
44
Q

Antithrombin in clotting

A
  • Opposes blood clotting

- Deficiency leads to reoccurring venous thromboembolism

45
Q

Heparin

A
  • Glycosaminoglycan
  • Sulfating increases degree of thrombin in vitro inhibition by 1000 times
  • Used as a therapeutic anticoagulant
46
Q

Irreversible inhibitors summary

A
  • Bind to the enzyme molecule with high affinity to reduce enzyme activity
47
Q

Kinetic studies unable to be performed due to

A
  • The covalent nature of the enzyme-inhibitor interaction
48
Q

Medically relevant irreversible inhibitors of enzyme action

A
  • Heavy metals
  • Organophosphates
  • Aspirin
  • Penicillin
  • Fluorouracil
  • Lopinavir
  • Tipranavir
49
Q

Natural serpins, alpha1-protease inhibitor, and antithrombin

A
  • Function as irreversible enzyme inhibitors in vivo

Biochemistry I (34 decks)

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