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Pharmaceutical Sciences > PharmSci IV Exam 3 > Flashcards

PharmSci IV Exam 3 Flashcards

1
Q

In the Michaelis-Menten Enzyme kinetics model, describe the reaction velocity at different concentrations of substrate. (2 components)

A
  1. At low [S], velocity is proportional to [S].

2. At high [S], reaction is independent of [S] and plateaus.

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2
Q

Why is it useful to define the Michaelis-Menten constant, Km? (2 components)

A
  1. [ES] is a transient species, that cannot be measured, dependent on reaction rates of association and dissociation. Km contains these reaction rates
  2. With steady-state assumption, [ES] = [E][S]/Km.
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3
Q

What is the simplified Michaelis-Menten equation?

A

V = Vmax * ([S]/[S] + Km])

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4
Q

How does the simplified Michael-Menten equation fit the observations of enzyme reaction velocity at different concentrations of substrate? (2 components)

A
  1. When Km&raquo_space; [S], equation simplifies to V = (Vmax/Km)[S], e.g. it is proportional to [S].
  2. When [S]&raquo_space; Km, equation simplifies to V = Vmax, e.g. reaction plateaus.
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5
Q

State the Lineweaver-Burke Equation for Enzyme kinetics.

A

1/V = (1/Vmax) + (Km/Vmax)*(1/[S])

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6
Q

State the values of the slope, y-intercept and x-intercept of the Lineweaver-Burke Equation. (3 components)

A
  1. Slope = (Km/Vmax)
  2. Y-intercept = (1/Vmax)
  3. X-intercept = -1/Km.
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7
Q

How is Lineweaver-Burke plot used experimentally? (3 steps)

A
  1. Measure V for different [S]
  2. Plot 1/V vs. 1/[S]
  3. Use slope, y-intercept and x-intercept to calculate Km and Vmax in order to characterize the enzyme.
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8
Q

What is the physical significance of Km? (2 components)

A
  1. Using Lineweaver-Burke equation, when [S] = Km, V = Vmax/2. Thus Km is the [S] at which velocity is half of maximum.
  2. Therefore, an enzyme with a small Km reaches maximum catalytic activity at a low [S]. This makes it more efficient. Thus Km is a means to compare the [S] required for efficient catalysis… often this means it is a measure of affinity for substrate. (Remember: Small Km = High Affinity)
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9
Q

Define Kcat

A

Kcat = Vmax / [total enzyme]

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10
Q

What is the physical significance of Kcat?

A

It is the number of substrate molecules that undergo catalytic production per unit time (seconds). It is the “turnover number.”

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11
Q

What is the purpose of Kcat/Km?

A
  1. A measure of catalytic efficiency.

2. This number is high when there is a large turnover (large Kcat) or high affinity (small Km).

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12
Q

Define Enzyme Unit (U)

A

An enzyme unit is that which catalyzes that conversion of one mMol of substrate per minute.

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13
Q

Describe and define specific enzymatic activity (2 components)

A
  1. Specific activity relates the Enzyme Unit (a measure of activity) to the total Amount of Enzyme.
  2. Define as Enzyme Unit / mg protein.
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14
Q

What are seven (7) factors affecting enzyme activity in vivo?

A
  1. Genetic
  2. Age
  3. Sex
  4. Nutrition and Disease
  5. Enzyme activation/inhibition
  6. Enzyme induction
  7. Species differences
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15
Q

Define an isoenzyme

A

Different amino acid sequence (different genes), same chemical reaction (substrate).

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16
Q

Define an isoform

A

Same gene, but different ultimate protein structure (through RNA splicing mechanisms)

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17
Q

Describe enterohepatic cycling? (4 components)

A

A circuit from:

  1. Liver
  2. Bile
  3. Small Intestine… reabsorption
  4. Liver
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18
Q

What is the net effect of enterohepatic cycling?

A
  1. Drugs and other substances (e.g. bile) may stay within the enterohepatic cycle for a long time
  2. Unexpected changes in plasma concentration may be seen as a result of cycling
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19
Q

What are three (3) classes of enzymes involved with biotransformation?

A
  1. Xenobiotic-transforming enzymes
  2. Endobiotic transforming enzymes
  3. Microflora enzymes
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20
Q

What tissues express enzymatic proteins?

A

Virtually all tissues.

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21
Q

Where does most xenobiotic metabolism occur?

A

Endoplasmic reticulum of liver.

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22
Q

What are four (4) common organelles that contain enzymatic proteins?

A
  1. Microsomes (endoplasmic reticulum)
  2. Cytosol
  3. Plasma membrane
  4. Inner mitochondrial membrane
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23
Q

What are five (5) major factors affecting drug metabolism?

A
  1. Genetics
  2. Physiologic factors (e.g. age, gender, microflora)
  3. Pharmacodynamic (e.g. dose, frequency, route)
  4. Environmental factors (e.g. pesticides)
  5. Transporter proteins
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24
Q

What are five (5) models for studying metabolism/enzymes?

A
  1. Whole animal
  2. Organ/Cell
  3. Cell fractions (subcellular)
  4. Purified enzymes
  5. X-ray crystallography
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25
Q

What is first-pass metabolism?

A

Metabolism that occurs from by small intestine and liver before entering systemic circulation.

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26
Q

What is the mechanism of monooxygenase?

A
  1. Two atoms of oxygen are reduced to -OH and -H2O (from O2)

2. -OH is added to the substrate.

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27
Q

What are the enzymes and cofactors for hydroxylation?

A

CYP, NADPH, H+, O2

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28
Q

What are the products for aromatic hydroxylation? (2 components)

A
  1. arene oxide

2. phenol

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29
Q

What are the products for aliphatic hydroxylation? (2 components)

A
  1. If alkane, then alcohol.

2. If alkene, then epoxide.

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30
Q

What are the enzymes and cofactors for dealkylation?

A

CYP, NADPH, H+, O2

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31
Q

What are the products of N-dealkylation?

A

An amine + (aldehyde or ketone.)

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32
Q

What is the intermediate for N-dealkylation?

A

Hemiaminal… put an -OH on the C of N-C.

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33
Q

What are the products of O-Dealkylation?

A

(An alcohol or phenol) + (aldehyde or ketone.)

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34
Q

What is the intermediate for O-Dealkylation?

A

Hemiacetal… put an -OH on the C of O-C.

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35
Q

What are the enzymes and cofactors for N-oxidation?

A

(CYP or FMO), NADPH, H+, O2

  1. CYP prefers amides and primary amines
  2. FMO prefers secondary and tertiary amines
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36
Q

What is the product of N-oxidation?

A

NH converted to N-OH

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37
Q

What are the enzymes and cofactors for S-oxidation?

A

(Primarily FMO, or CYP), NADPH, H+, O2

38
Q

What are the products of S-oxidation?

A

Add =O to sulfur; can also have O=S=O

39
Q

What are the products of Beta-oxidation of carboxylic acids?

A

Cleave at the Beta carbon and form two carboxylic acids.

40
Q

What are the enzymes and cofactors for purine and pyrimidine oxidation?

A

Xanthine oxidase

41
Q

What is the product of purine and pyrimidine oxidation?

A

Add -OH between N of each ring; one on each ring.

42
Q

What are the enzymes and cofactors for oxidative desulfuration?

A

CYP, NADPH, H+, O2

43
Q

What are the products for oxidative desulfuration?

A

Replace =S with =O

44
Q

What are the enzymes and cofactors for dehalogenation?

A

CYP, NADPH, H+, O2

45
Q

What are the products of dehalogenation?

A

Replace HX with =O; e.g. CHCl3 becomes COCl2 (phosgene)

46
Q

What are the enzymes and cofactors for deamination?

A

Monoamine oxidase, O2

47
Q

What are the products of deamination?

A

A primary amine becomes an (aldehyde or ketone) + NH3 + H2O2

48
Q

What are the enzymes and cofactors for alcohol oxidation?

A

Alcohol dehydrogenase (ADH), NAD+

49
Q

What are the products of alcohol oxidation?

A

Alcohol becomes (aldehyde or ketone)

50
Q

What are the enzymes and cofactors for aldehyde oxidation?

A

Aldehyde dehydrogenase, NAD+

51
Q

What are the products of aldehyde oxidation?

A

Aldehyde becomes carboxylic acid.

52
Q

What are the enzymes and cofactors for dihydrodiol oxidation?

A

Dihydrodiol dehydrogenase, NADP+

53
Q

What are the products for dihydrodiol oxidation?

A

A quinone

54
Q

What are the enzymes and cofactors for aldehyde/ketone reduction?

A

carbonyl reductase, NADPH

55
Q

What are the products of aldehyde/ketone reduction?

A

(Aldehyde or ketone) becomes an alcohol

56
Q

What are the enzymes and cofactors for azo reduction?

A

gut CYP or microflora enzymes

57
Q

What are the products of azo reduction?

A

R-N=N-R’ becomes R-NH2 and R’-NH2

58
Q

What are the enzymes and cofactors for nitro reduction?

A

gut CYP or microflora enzymes

59
Q

What are the products of nitro reduction?

A

R-NO2 becomes R-NH2

60
Q

What are the enzymes and cofactors for quinone reduction?

A

Quinone reductase

61
Q

Why is quinone dangerous in the body?

A
  1. One-electron reductino of quinone yields semiquinone radical.
  2. Semiquinone radical reacts with O2 to form superoxide radical which damages DNA.
62
Q

What are the enzymes and cofactors for epoxide hydrolysis?

A

Epoxide hydrolase, H2O

63
Q

What are the products of epoxide hydrolysis?

A

An epoxide becomes a diol.

64
Q

What are the enzymes and cofactors for ester hydrolysis?

A

Esterases, H2O

65
Q

What are the products of ester hydrolysis?

A

An ester becomes an acid + alcohol.

66
Q

What are the products of amide hydrolysis?

A

An amide becomes an acid + amine.

67
Q

What is transesterification?

A

Esterase enzymes can catalyze the transfer of alkyl groups between an ester and an alcohol.

68
Q

What are the enzymes and cofactors involved with glucoronidation?

A

UGT, UDPGA

69
Q

What are the acceptors for glucoronidation? (4 components)

A

Nucleophiles

  1. R-OH
  2. R-NH2
  3. Acids
  4. R-SH
70
Q

Describe the activity of glucoronidation in terms of affinity and capacity

A

Low affinity, high capacity.

71
Q

What are the enzymes and cofactors involved with sulfation?

A

Sulfotransferase (SULT), PAPS

72
Q

What are the acceptors of sulfation?

A

R-OH

73
Q

Describe the activity of sulfation in terms of affinity and capacity

A

High affinity, low capacity

74
Q

What are the enzymes and cofactors involved with acetylation?

A

N-Acetyl Transferase (NAT), acetyl CoA

75
Q

What are the acceptors of acetylation?

A

Primary amines, -NH2 becomes -NH-CCH3=O

76
Q

What are the enzymes and cofactors involved with glycine conjugation?

A

CoA, Glycine

77
Q

What are the acceptors for glycine conjugation?

A

Carboxylate (carboxylic acid) accepts glycine and forms amide.

78
Q

What are the enzymes and cofactors involved with glutathione conjugation?

A

Glutathione-S-Transferase (GST), Glutathione (GSH)

79
Q

What is the amino acid structure of Glutathione?

A

Gamma-Glu-Cys-Gly

80
Q

What are the acceptors for glutathione conjugation? (4 components)

A

Electrophiles

  1. Halides
  2. Epoxides
  3. Unsatured carbonyls
  4. Quinones
81
Q

What enzyme is involved with the conjugation of glutathione to peroxide?

A

Glutathione peroxidase

82
Q

What occurs after glutathione is conjugated to a substrate? (2 components)

A
  1. Undergoes processing to form a mercapturic acid

2. Excreted

83
Q

What enzymes and cofactors are involved with methylation?

A

Methyl transferase, SAM

84
Q

What chemical structures are dangerous in the body? (4 components)

A
  1. Quinones
  2. Aldehydes/carbonyls/ketones
  3. Epoxides
  4. Unsaturated carbonyls
85
Q

What is hyperplasia?

A

Uncontrolled cell growth

86
Q

What is anaplasia?

A

Lack of differentiation [resembles embryonic cells]

87
Q

What is metastasis?

A

Movement of tumor from primary to secondary site [characterizes malignant tumor]

88
Q

What are three ways carcinogens can cause cancer?

A
  1. Damage to oncogenes, resulting in uncontrolled cell proliferation
  2. Damage to tumor suppressor genes
  3. Loss of function of DNA repair genes/proteins
89
Q

What oxidation reactions involve FMO enzyme?

A

N-oxidation of substitute amines, S-oxidation

90
Q

Describe the difference between FMO and CYP intermediates

A
  1. CYP has a heme with activated oxygen intermediate

2. FMO has a flavin hydroperoxide intermediate

Pharmaceutical Sciences (9 decks)

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