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Pharmacology 200 > 3 - epigenetic drugs > Flashcards

3 - epigenetic drugs Flashcards

1
Q

what is epigenetics

A

modification of gene expression rather than the DNA code itself

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2
Q

what are 2 criteria for something to be epigenetic

A

1-change in gene function without mutation

2-heritable

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3
Q

what happens when you change chromatin structure

A

it alters accessibility to transcription factors

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4
Q

what is euchromatin

A

open, accessible, genes on, acetylated histone

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5
Q

what is heterochromatin

A

close, inaccessible, genes off, deacetylated histone

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6
Q

is euchromatin or heterochromatin acetylated

A

euchromatin

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7
Q

is euchromatin or heterochromatin deacetylated

A

heterochromatin

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8
Q

what are two types of histone modification

A

methylation and acetylation

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9
Q

where does methylation and acetylation occur and why

A

on positive residue (lysine, arginine) to neutralize negative charge of DNA

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10
Q

what is changed when there is epigenetic modifications

A

structure of chromatin and its accessibility is changed

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11
Q

where are 2 places that there can be epigenetic modifications

A

DNA or histones

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12
Q

what gets methylated in DNA methylation

A

cytosine

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13
Q

what happens in DNA methylation

A

Methylation of cytosine bases is associated with

transcriptionally inactive DNA, usually recruits histone modifications.

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14
Q

why is epigenetics important (3)

A

because it can turn genes on and off (things like growth, specialized cell types and X-chromosomal inactivation)

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15
Q

what causes skin cells to be so different than hair and brain cells

A

epigenetics!

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16
Q

what type of epigenetic alterations are often found with cancer genes

A

turned off tumor supressor gene or turned on oncogene

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17
Q

how does cancer spread if epigenetic changes arent hertiable

A

no, they are heritable

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18
Q

what often happens to promotors in aging

what does this mean

A

they undergo DNA hypermethylation

-less promotor activity

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19
Q

what often happens to intragenic regions in aging

what does this mean

A

they become hypomethylated

-more intragenic region activity (?)

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20
Q

what two things cause histone methylation and acetylation to change

A

age and environment

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21
Q

what is histone methylation

A

post translational modification where a methyl group is transferred to a histone protein

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22
Q

which part of the histone is methylate

A

the positive residues (lysine arginine) to neutralize charge

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23
Q

what does histone methylation do to the interactions between histones and DNA

A

weakens interactions (neutralized the positive charge)

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24
Q

which amino acid does histone methylated happen to more often

A

lysine more so than arginine

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25
Q

can histone methylation occur on all 4 histones

A

yes

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26
Q

what are the two primary methyltransferase enzyme families

A

SET1 and SUV family

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27
Q

how do histone methyltransferases work

A

they comsume S-adenosyl methionine (SAM) cofactor to move methyl groups

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28
Q

what are two main classes of histone demethylases

A

LSD type and JHD1 type

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29
Q

how do you classify LSD-type vs JHD1-type histone demethylases

A

based on the cofactor they use

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30
Q

which cofactor for LSD-type use

A

(FAD)-dependent amine oxidase

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31
Q

which cofactor for JHD1-type use

A

Fe(II) and alpha-KG-dependent hydroxylase

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32
Q

which histone methylation drug is being tested in cancer

A

LSD1 inhibitors

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33
Q

why are many histone demethylation drugs not used clinically

A

because they are often non-specific

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34
Q

what is tazemetostat

A

an inhibitor of EZH2 histone methyltranferases

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35
Q

what can tazemetostat be used for

A

hematopoetic malignancies

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36
Q

what does tazemetostat do to methylation and chromatin

A

inhibits histone methylation(methyltransferases), tighter DNA and histone interactions, heterochromatin, turn genes off

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37
Q

what do LSD1 inhibitors do to methylation

A

they inhibit histone demethylation, meaning that there will be more methylation

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38
Q

what is histone acetylation

A

PTM modification that adds acetyl group onto lysine residue of histone proteins

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39
Q

where does hsitone acetylation occur

A

onto lysine

40
Q

what does histone acetylation do to chromatin and why

A

often activates because it neutralizes the charge so it makes euchromatin

41
Q

does histone acetylation or methylation weaken the histone-DNA attraction

A

both! (but histone acetylation does most of the time not always)

42
Q

how do histone acetyltransferases work

A

they transfer acetyl-CoA’s (Cofactor) acetyl to lysine on histone

43
Q

which cofactor do histone acetyltransferases use

A

acetyl-CoA

44
Q

what are the 2 major histone acetyltransferases enzymes

A

PCAF and P300

45
Q

what do histone deacetylases produce

A

deacetylated histones and acetate

46
Q

what are the 3 major classes of histone deacetylases

A

Class 1, 2, 3

47
Q

what do class 1 and 2 histone deacetylases do

A

use Zn2+ as a cofactor to make a deacetylated histone and acetate

48
Q

what do class 3 histone deacetylases do

A

sirtuins!! they use NAD+ as their cofactor

49
Q

whata is another name for class 3 histone deacetylases

A

sirtuins

50
Q

do histone deacetylases make euchromatin or heterochromatin

A

heterochromatin (remove acetyl, tight, inaccessible)

51
Q

what are the histone acetylation drugs designed to do

A

inhibit HDAC enzymes

52
Q

how can histone acetylation drugs be used/good for cancer

A

to reactivate silenced tumor suppressor genes

53
Q

what makes sirtuins different than class 1 and 2

A

they deacetylate histones and other proteins too

54
Q

what is vorinostat

A

an inhibitor of Class 1 and 2 histone acetylases

55
Q

what can vorinostat be used for

A

T cell lymphoma

56
Q

what is DNA methylation

A

addition of methyl at the 5’ position of a cytosine

57
Q

where does most DNA methylation occur

A

in CGCGCGCGCG regions of DNA

58
Q

what does DNA methylation do to genes

A

often suppressive by blocking the promotor recognition of a TF BUT it can also activate

59
Q

how does DNA methylation change during DNA replication

A

enzymes can move and copy methylation but sometimes it doesnt happen

60
Q

does DNA methylation interfere with base pairing

A

no

61
Q

how do DNA methyltransferases work

A

by using SAM as a cofactor

62
Q

in general, what does SAM cofactor move

A

methyl groups

63
Q

what are 3 types of DNA methyltransferases

A

Dnmt1, Dnmt3a and Dnmt3b

64
Q

what does Dnmt1 do

A

copies methylation to second DNA strand if the first one has it

65
Q

what does Dnmt3a and Dnmtb do

A

can methylate wherever they want

66
Q

which Dnmt acts as maintenance (making sure methylation is preserved during replication)

A

Dnmt1

67
Q

what are 2 ways that demethylation occurs

A

dilution in DNA replication or actively from enzymes

68
Q

what are 2 enzymes that do DNA demethylation

A

activation induced cytidine deaminase enzyme (AID) and Ten Eleven Translocation enzymes (TET)

69
Q

how do most DNA methylation drugs work

A

inhibit Dnmt enzymes

70
Q

how are DNA methylation drugs good for cancer/effective

A

reactivate silenced transcription factors

71
Q

what is decitabine

A

inhibitor of Dnmts

72
Q

what does Vitamin C do

A

activate the TET DNA demethylase enzymes

73
Q

how do histone and DNA modifications work together

A

they help direct open vs closed chromatin

74
Q

which enzyme acts as a histone methyltransferase

A

SET1 and SUV1

75
Q

which enzyme required FAD as a cofactor

A

LSD1

76
Q

which enzyme required Fe(II) and alpha-JG-dependent hydroxylase as a cofactor

A

JHD1-type histone demethylases

77
Q

which enzyme required acetyl-CoA as a cofactor

A

CAF and P300 which are histone acetyltransferases

78
Q

which enzyme required Zn2+ as a cofactor

A

Class 1 and 2 histone deacetylases

79
Q

which enzyme required NAD+ as a cofactor

A

class 3 histone deacetylases - sirtuins

80
Q

what is LSD use as cofactor

A

FAD

81
Q

what is LSD-type do

A

histone demethylase

82
Q

what is JHD1 type cofactor

A

Fe and KG hydroxylase

83
Q

what does JHD1 do

A

histone demethylase

84
Q

what cofactr do SUV and SET1 need

A

SAM

85
Q

what do SUV abd SET1 do

A

histone methyltransferase

86
Q

what do PCAF and P300 use as cofactor

A

acetyl coa

87
Q

what do PCAF and P300 do

A

histone acetyltransferase

88
Q

what cofactor do class 1 and 2 use

A

zinc

89
Q

what do class 1 2 3 (sirt) do

A

histone deacetylase

90
Q

what co factor do sitruins class 3 use

A

NAD

91
Q

what does vorinostat do

A

inhibit class 1 2 deacetylases

92
Q

what does dnmt family do

A

DNA methyltransferases

93
Q

what ofactor do dnmt fammy use

A

SAM

94
Q

what does AID and TET do

A

DNA demetyhlase

95
Q

what does Vit C do

A

activates TET demthylase

96
Q

what does decitabine do

A

inhibits dnmts

97
Q

what is the goal of decitabine

A

reactive silenced tumor suppressor genes

Pharmacology 200 (29 decks)

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