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Pharm 410: Fundamentals of Drug Action and Metabolism > Day 5: Enzymes > Flashcards

Day 5: Enzymes Flashcards

1
Q

What is the delta G?

A

determines whether the reaction will be spontaneous or not.

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2
Q

What does it mean if the delta G is negative?

A

the reaction is spontaneous, will move forward

We do not know the speed of the reaction

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3
Q

What is the Gibbs free-energy change represented by?

A

The delta G. Which tells you if the rxn is spontaneous of not

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4
Q

What does it mean if the delta G is positive?

A

the rx will be backward

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5
Q

What does an enzyme increase?

A

The rate of a rxn without affecting its equilibrium concentration

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6
Q

What are enzymes as catalysts?

A

greatly increase the rate of chemical reactions by decreasing the activation energy.

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7
Q

What is chemical equilibrium?

A

is the state in which both reactants and products are present in concentrations which have no further tendency to change with time
Happens when forward rate is happening at the same as reverse rxn

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8
Q

What is the active site of an enzyme?

A

The region that binds the substrates (and cofactors )

generally cleft or crevices

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9
Q

What is the “lock and key” model?

A

The activities of enzymes are determined by their three-dimensional structure.
Enzymes are very specific and it was suggested by Emil Fischer in the 1890s that this was because the enzyme had a particular shape into which the preferred substrate(s) fit exactly like a specific key

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10
Q

What is the induced-fit model?

A

The enzyme changes shape (conformation change) in the binding substrate. This converts the enzyme into a new structure which aligns to accelerate the rxn.

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11
Q

What are apoenzymes?

A

Enzymes that require cofactors in order to function.

*requires not only binding by the substrate but also something else to make it happen

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12
Q

What is a holoenzyme?

A

When a cofactor and the apoenzyme (subtrate as well) are binding together and able to catalyze rxns

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13
Q

How do cofactors work?

A

providing functional groups needed for the reaction or by slightly altering the structural conformation of the enzyme to which they are bound

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14
Q

What are the three types of cofactors?

A

Metal cofactor
coenzyme
prosthetic group

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15
Q

What is a metal cofactor?

A

cofactor can be a metal ion like, iron, copper, magnesium, manganese, zinc, calcium, or cobalt. (Example: Zn++ is cofactor of carbonic anhydrase

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16
Q

What is a coenzyme?

A

: an organic cofactor that is loosely bound to the enzyme, like a substrate.
Examples: NADP(H), NAD(H), ATP

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17
Q

What is a prosthetic group?

A

an organic or inorganic cofactor that is tightly bound to the enzyme.
Examples: Heme, iron-sulfur clusters, metal ions

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18
Q

What are most of the enzyme cofactors made of?

A

are directly or precursor of vitamins and minerals and required from outside source.

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19
Q

What is an allosteric site

A

Any site on the enzyme other than the active site

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20
Q

How does temp affect enzyme activity?

A

affects enzyme catalyzed reactions greatly. Reaction rate increases as temperature goes up but if the temperature is high enough, enzymes undergo denaturation and loose their catalytic properties since enzymes are protein too
Each enzyme has its optimal range but most are 37 degrees C due to that being our body temp

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21
Q

How does pH affect enzyme activity?

A

Depending upon the R-groups, pH can cause enzyme to perform better or worse. Every enzyme has a working range of pH, outside that range, the enzyme(protein) will denature and lose its function.

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22
Q

What are the steps for an enzyme-catalyzed rxn?

A
  1. Binding of substrate (S) and enzyme (E)
    S+E = SE
  2. conversion of bound substrate to bound product.
    SE - EP
  3. formation of product
    EP - E + P
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23
Q

What are the assumptions you have to make in order to use the michaelis-menton equation?

A
  1. one substrate only
  2. [S]&raquo_space;> [E]
  3. only the initial rxn rate is considered (low [P])
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24
Q

what is the michaelis-menton equation?

A

v = vmax([s]/Km+[s])

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25
Q

What is the Km and what does it represent?

A

Michaelis-menten constant

represents the affinity, the smaller the Km or Kd, the greater the affinity

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26
Q

What is the Kd and what does it represent?

A

Dissociation constant - measures the dissociation of the ligand from ligand: receptor complex
represents the affinity, the smaller the Km or Kd, the greater the affinity

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27
Q

What is a rule of thumb when it comes to using the Km or the Kd

A

During enzyme kinetics use the Km and during drug-drug interactions use the Kd

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28
Q

What are the uses of the Km value?

A
  1. determines the affinity of an enzyme
  2. determines the substrate preferences of an enzyme (if more than one compound can act as sub for enz, sub with lowest Km is prefered)
  3. Distinguish isozymes.
  4. measurement of Km is used to check for abnormalities in an enzyme: altered Km reflects some change in the way the enzyme binds
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29
Q

What are the types of Enzyme Inhibitors?

A
  1. Reversible competitive
  2. Reversible uncompetitive
  3. Reversible mixed (Noncompetetive)
  4. Irreversible
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30
Q

What is an enzyme that is Reversible competitive?

A

It competes with the active site for the substrate

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31
Q

What is an enzyme that is reversible uncompetitive?

A

It binds to a separate site (allosteric) but ONLY AFTER the substrate is bound

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32
Q

What is an enzyme that is reversible Mixed or noncompetitive?

A

Will bind to separate site (allosteric) but both to enzyme or substrate bound enzyme
** has more binding options

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33
Q

What effects do reversible competitive inhibitors have on Km and Vmax?

A

They will increase Km but Vmax will remain the same

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34
Q

What do Reversible competitive inhibitors achieve?

A

They only compete with the substrate for binding at an active site, they lead to a decrease in the affinity to the substrate because that substrate has a harder time bonding.

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35
Q

How can you over come a reversible competitive inhibitor?

A

Simply add more substrate. These will out number the inhibitor and it will be able to bind much easier.

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36
Q

How do statins use reversible competitive inhibitors to lower cholesterol?

A

It lowers serum cholesterol by reversibly and competitively inhibiting HMG-CoA reductase, this is the enzyme that leads to the synthesis of cholesterol.
** By inhibiting the HMG-CoA enzyme it prevents the cholesterol being created

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37
Q

What is CoQ10 and its importance when it comes to statin drugs?

A

taking statins also lowers CoQ10 which can lead to muscle pains. This is why people are told to take CoQ10 in order to help their muscle pains when taking statins.

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38
Q

Why are CoQ10 levels a worry for someone who is taking a statin?

A

Because when people take a statin it is an HMG-CoA reductase inhibitor (enzyme that catalyzes rxn for mevalonate) Mevalonate leads to cholesterol and CoQ10
**So when taking a statin it not only lowers your cholesterol but also your CoQ10 levels

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39
Q

What is Uncompetitive Inhibition?

A

Only binds to the enzyme when the substrate is also bound

40
Q

What happens to the Vmax and Km in the presence of an uncompetitive inhibitor?

A

They are both lower.

41
Q

What is an example of an uncompetitive inhibitor?

A

Lithium ameliorate (makes better) manic depressive psychosis.

42
Q

What are the effects on Km and Vmax with Mixed Inhaibition (noncompetitive inhibition)?

A

Km is unaffected and Vmax is decreased

43
Q

What is the Vmax?

A

Its when the substrate completely occupy the enzyme and the rate of the rxn now depends on the enzyme.
**Basically Vmax is when the substrate completely occupy the enzyme and the rxn is happening at the highest rate possible

44
Q

What is Foscarnet?

A

Mixed Inhibitor against the activity of herpes viruses, HIV, CMV and hep C.
They inhibit viral DNA polymerases - also inhibits in kidneys causing renal dysfunction.

45
Q

What does a Competitive inhibitor do in terms of Km and Vmax?

A

Raises the Km only
(meaning Km is the substrate concentration where you have V1/2)
Higher Km means you need MORE substrate in order to achieve the rxn

46
Q

What does uncompetitive inhibition do in terms of Vmax and Km?

A

Lowers Vmax and Km

Since it Binds at both enzyme when the substrate is ALSO bound it means that the rxn will be capped for how fast it can happen.
Reduces the number of function enzymes that can carry out a rxn

47
Q

What does noncompetitive/mixed inhibition do in terms of Km and Vmax?

A

It only lowers Vmax

Vmax is lowered because you can think of the noncompetitive inhibitors to “poison” the enzyme and it can no longer do a reaction.
The Km is unchanged because it has no effect on how much substrate binds to an enzyme

48
Q

What is Irreversible Inhibition?

A

AKA “suicide substrates”
These poison the enzyme by contently modifying the active site or any other free sites of the free enzyme.
CHANGES THE ENZYME PSYCHICALLY SO IT CAN NO LONGER ACCEPT SUBSTRATE
*can be regenerated by protein synthesis

49
Q

What kind of inhibitor is Aspirin ?

A

Irreversible inhibitor

Binds to a serine residue at the active site of an enzyme which inactivates COX permanently

50
Q

What is COX responsible for in regards to aspirin?

A

Its inactivated by aspirin
COX is responsible for producing thromboxane which leads to platelet aggregation.
Since its inactived it BLOCKS platelet aggregation (Blood thinner)

51
Q

What kind of enzymes do not follow Michaelis-Menten equation?

A

Allosteric enzymes with cooperative nature

52
Q

What is the K0.5 and why is it used?

A

It indicates the same then as Km (so when you reach 50% of the Vmax) but for a allosteric enzyme

53
Q

What are the mechanisms of enzyme regulation?

A 
Product inhibition
Allosteric regulation
Covalent modification
Protein-protein regulation
Zymogen cleavage
Enzyme synthesis and degradation (role of proteases in enzyme regulation)
54
Q

What is product inhibition?

A

Simplest form of enzyme regulation
The product of an enzyme reaction is usually similar in structure to the reactant (means when product level inc it competes for the active side with reactant)

55
Q

Whats an example of Product inhibition?

A

Glycolysis
Glucose is phosporylated by hexokinase which creates glucose-6-phosphate, glucose-6-phosephate inhibits hexokinase.
This means as you increase in the amount of glucose-6-phosephate it inhibits the hexokinase which stops phosphorylation of more glucose

56
Q

What is allosteric regulation?

A

An effector molecule binds at an allosteric site and alters the 3D structure of the enzyme, this can increase binding or decrease it.

57
Q

What is allosteric regulation: feedback inhibition?

A

Happens when the product produced later on inhibits an enzyme which is upstream in the pathway. Does so thro allosteric regulation

58
Q

What is an example of Allosteric feedback inhibition?

A

Phosphofructose kinase which is a regulatory and rate limiting enzyme of glycolysis. Down stream process of glycolysis produces citric acid, this then flows upstream and allostericly binds to phosphofructo and inhibits the enzyme

59
Q

What is Covalent Regulation?

A

Phosphorylation.
Protein kinases transfer phosephate from ATP to Ser, Thr, Tyr - this causes a conformational change that can inc or dec the enzymes catalytic activity.
*effect is reversed by protein phosphatases, which remove phosephate group from the enzyme

60
Q

What is an example of covalent regulation?

A

Activity of the liver pyruvate kinase
In liver glucagon stimulates protein kinase A which phosphorylates pyruvate kinase = inactive and turns off glycolysis
Insulin will active phosphatase which dephosphorylates pyruvate kinase = turned on and leads to up-regulation of glycolysis

61
Q

What are protein-protein interactions?

A

Binding of an enzyme (protein) to another protein to form a complex this can result in activation or inhibition of the enzyme

62
Q

Whats an example of protein-protein interactions?

A

Epidermal growth factor receptor (EGFR) is over expressed in cancer. EGFR becomes active when binded to a protein EGF
Erbitux - is a drug that binds to a part of EGFR and prevents it from binding to EGF

63
Q

What is zymogen cleavage?

A

Is a larger (pro-enzyme), in its inactive form that can be activated by proteolytic cleavage

64
Q

What is enzyme synthesis and degradation?

A

The amount of an enzyme created by its gene can be increased (induced) or decreased (repressed) based on physiological demands
occurs over hours to days

65
Q

What is a protease?

A

Its an enzyme that degrades protein by hydrolysis of peptide bonds

66
Q

How many proteins in our body are proteases?

A

About 2% of them

67
Q

What are the two major types of proteases?

A

Exopeptidases

Endopeptidases

68
Q

What do exopeptidases target?

A

The terminal ends of proteins

69
Q

What do endopeptidases target?

A

Target sites within proteins

70
Q

What is Oxidoreductases class of enzyme reactions?

A

Catalyze oxidation/reduction reactions

at least one substrate gains elections becomes reduced, and another substrate loses electrons and becomes oxidized

71
Q

What is transferases class of enzyme reactions?

A

Catalyze reactions in which a functional group (amino, acetly or phosephate) is transfered from one compound to another

72
Q

What is Hydrolases class of enzyme reactions?

A

Cleave carbon-oxygen (C-O), carbon-nitrogen (C-N), or carbon-sulfur (C-S) bonds by adding water across the bond

73
Q

What is Lyases class of enzyme reactions?

A

Cleave Carbon-carbon, Carbon-oxygen (C-O), carbon-nitrogen (C-N) or carbon-sulfur (C-S) bonds without addition of water

74
Q

What is Isomerases class of enzyme reactions?

A

Catalyze rearrangements of atoms within the molecule without changing empirical formula

75
Q

What are ligases class of enzyme reactions?

A

Synthesize C-C, C-S, C-O and C-N bonds in reactions using energy derive from the breakdown of ATP or another nucleotide.
EX: DNA ligases uses ATP to ligate two nucleotides in DNA

76
Q

What are isozymes?

A

Different enzymes that catalyze the same reaction
Purpose is to allow for fine adjustment of metabolism
They have different Km and Vmax values

77
Q

How are enzymes used as markers for disease?

A

Damaged cells release isoenzymes/proteins into the blood

An elevated level indicates damage of the pertinent organ or tissue

78
Q

What can be markers for liver damage?

A

The isoenzymes/proteins AST (aspartate transaminase) and Alanine transaminase (ALT) are present in the liver. Rise in AST and ALT in blood is indicative of liver damage. ALT is more liver specific

79
Q

What are the most common enzymes used to diagnose MI?

A

CK (creatine kinase)

LDH (lactate dehydrogenase)

80
Q

What are the three isozymes of cytosolic CK?

A

Made up of two polypeptides M and B:
CK-BB
CK-MB
CK-MM

81
Q

Where do the cytosolic cks appear?

A 
CK-BB = rarely seen outside the brain 
CK-MM = predominates in skeletal muscle (usually >98%)
CK-MB = in heart muscle contains a longer proportion of CK-MB, much more than skeletal muscle or any other tissue
82
Q

What are the two plasma CK assays that are usual in diagnosing a heart attack?

A

Total CK activity = if higher than range, it could suggest heart attack but also be result of another muscle-damaging disorder
CK-MB activity = If higher than normal it indicates heart attack. CK-MB is preferred because its more specific for heart damage than for other kinds of tissue damage

83
Q

What is the elevation window for Myoglobin?

A

Appears as early as 1 h, peaks at 4-12 h, returns to normal in 24 hours

84
Q

What are the advantages and disadvantages of myoglobin for acute chest pain?

A

adv: Early AMI marker
disadv: Poor specificity

85
Q

What is the typical elevation window of CK/CK-MB marker?

A

Appears in 4-9h, peaks at 24 hours, returns to normal in 2-3 days

86
Q

What are the advantages and disadvantages of CK/CK-MB

A

Adv: routine AMI marker; detection of reperfusion
Disadv: less cardiospecific than troponins; gradually being replaced by troponin T or I

87
Q

What is the elevation window for troponins T and I?

A

Appears in 4-9h, peaks in 12-24 h, returns to baseline in 7-14 days

88
Q

What are the adv and disadv of Troponins T and I?

A

Adv: most cardiospecific marker; useful for risk stratification; detecting AMI > 48 h from onset
Disadv: less effective than CK-MB for detecting reperfusion

89
Q

What does an increase of ALP (alkaline phosphates) mean

A

congestion of bile duct or skeletal muscle damage or bone disease like osteoporosis

90
Q

What does an increase of GGT (gamma glutamyl transpeptidase) mean?

A

Indicates congestion of the bile tract and/or liver damage

91
Q

What does the finding of both AST and ALT values mean?

A

Consistent with hepatic disease (GGT is also elevated during hepatic diseases)

92
Q

What does it mean if GGT and ALP are increased?

A

Consistent with biliary obstruction disease like gall bladder stone

93
Q

What does it mean if GGT is normal and ALP is increased?

A

bone diseases

94
Q

What does streptokinnase (streptase) do?

A

Tissue plasminogen activator

enzyme that dissolves blood clots used to minimize the dmg following a heart attack

95
Q

What is Asparaginase (elspar)

A

enzyme that Starves and kills ALL (acute lymphoblastic leukemia) cells

96
Q

what is lactase (lactaid)

A

Enzyme that catalyzes conversion of dietary lactose to galactose and glucose
People who do not have this cant break down lactose and it goes to the digestive tracts and produces gas

Pharm 410: Fundamentals of Drug Action and Metabolism (8 decks)

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