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biochem > biochem lecture 11 pt1 > Flashcards

biochem lecture 11 pt1 Flashcards

1
Q

what are the two biosynthesis pathways for nucleotides

A

de novo synthesis, salvage pathway

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2
Q

what are we focusing on

A

biosynthesis of the nucleotides, building blocks for DNA/RNA (not actual DNA synthesis)

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3
Q

what is de novo synthesis

A

compounds synthesized from scratch/minimal components

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4
Q

what are building blocks for de novo synthesis of nucleotides

A

metabolic precursors; parts of AAs, ribose-5-phosphate (byproduct of pentose phosphate pathway),

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5
Q

what is ribose-5-phosphate important for

A

providing the structure that will become either the deoxyribose or ribose sugar in DNA and RNA

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6
Q

what are salvage pathways

A

synthesis of nucleotides from scavenged components

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7
Q

what are scavenged components

A

recycled free bases, nucleosides (present from breakdown of nucleic acids)

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8
Q

what are 2 types of nitrogen containing bases

A

purines and pyrimidines

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9
Q

describe purines structure

A

bicyclic

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10
Q

describe pyrimidine structure

A

single ring

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11
Q

what are the purines

A

adenine, guanine

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12
Q

what are the pyrimidines

A

uracil, thymine, cytosine

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13
Q

for purine de novo biosynthesis, what are the sources of parts of purine bicyclic ring structure

A

aspartic acid, formate, glycine, amine N of glutamine, Co2

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14
Q

what is important precursor for purine de novo synthesis

A

5-phosphoribosyl 1-pyrophosphate (PRPP)

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15
Q

what does de-novo synthesis of purine begin and end with

A

begins with PRPP, ends w/ inosinate (IMP) formation

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16
Q

what is another important intermediate

A

inosinate (IMP) or inosinate monophosphate

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17
Q

why is IMP formation important

A

from IMP synthesis, we have a bifurcation

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18
Q

what is the purine bicyclic ring structure built off of in de novo synthesis

A

PRPP; serves as precursor for sugar

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19
Q

what is IMP an important common intermediate for

A

synthesis of both AMP and GMP

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20
Q

what do we have in each of these split, bifurcated pathways

A

an E source (GTP or ATP), and an amino group source (NH3)

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21
Q

what do we have as the E source for AMP synthesis

A

GTP

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22
Q

what do we have as the amino group for AMP synthesis

A

aspartate

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23
Q

describe what’s in AMP synthesis

A

GTP as E source, aspartate provides amino group that’s part of adenylate structure for AMP

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24
Q

what is E source for GMP synthesis

A

ATP

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25
Q

what is amino group source for GMP synthesis

A

glutamine

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26
Q

describe what’s in GMP synthesis

A

ATP as an E source, glutamine as an amino source

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27
Q

what are both AMP and GMP

A

parent compounds

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28
Q

what happens to AMP and GMP

A

go through a set of phosphorylated rxns that will result in triphosphorylated forms

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29
Q

describe regulation of adenine and guanine nucleotide synthesis in bacteria

A

3 major feedback inhibition mechanisms/points of control

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30
Q

what are the 3 points of control in adenine/guanine nucleotide biosynthesis

A

PRPP syntethase, glutamine-PRPP amidotransferase, and adenylosuccinate synthesis

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31
Q

what do the 3 points of control represent

A

the 3 major feedback inhibition points

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32
Q

how do we balance the pool of different nucleotides in terms of ensuring you have appropriate levels of all 4/5 diff nucleotides

A

coordinated feedback inhibition

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33
Q

what does pyrimidine de novo synthesis involve

A

aspartate, PRPP, carbamoyl phosphate

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34
Q

what is the first enzyme in pyrimidine de novo synthesis pathway

A

aspartate transcarbamoylase or ATCase

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35
Q

how does purine pathway work

A

start off w/ PRPP, construct nitrogen containing base off the ribose moiety of that structure

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36
Q

how does pyrimidine pathway work

A

construct monocyclic ring first, middle of the pathway we attach PRPP or what eventually becomes ribose sugar

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37
Q

is there a difference between the purine and pyrimidine biosynthesis pathways

A

yup

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38
Q

what are the basic precursors for pyrimidine biosynthesis pathway

A

aspartate, PRPP, carbamoyl phosphate

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39
Q

basically how does pyrimidine biosynthesis work

A

we have the 6 member pyrimidine ring made first, that’s gonna be attached to ribose-5-phosphate

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40
Q

what carbamoyl phosphate

A

intermediate used in first step of pyrimidine de novo pathway

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41
Q

what is important for synthesis of carbamoyl phosphate

A

bacterial carbamoyl phosphate synthetase

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42
Q

what does bacterial carbamoyl phosphate synthetase use in synthesis of carbamoyl phosphate

A

glutamine and ADP

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43
Q

describe bacterial carbamoyl phosphate synthetase

A

multi-subunit enzyme complex

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44
Q

what does bacterial carbamoyl phosphate synthetase use

A

substrate channeling

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45
Q

what is substrate channeling

A

helps retain/channel/keep intermediates that are part of synthesis step close to the enzyme, so that we don’t lose those intermediates to diffusion

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46
Q

what happens if we lose intermediates to diffusion

A

can lessen efficiency of enzyme

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47
Q

when is substrate channeling particularly important

A

if intermediates are short-lived; if they decay or are unstable, we can lose those intermediates before they’re utilized in this enzyme

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48
Q

how many active sites in bacterial carbamoyl phosphate synthetase

A

3 separate active sites

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49
Q

is ATCase same as the carbamoyl phosphate synthetase

A

no; that makes carbamoyl phosphate, so it’s made by the time we get to first step in pyrimidine pathway

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50
Q

what is the first enzyme in the pyrimidine de novo synthesis pathway

A

ATCase (aspartate transcarbamoylase)

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51
Q

what kind of enzyme is ATCase

A

allosterically regulated enzyme

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52
Q

how do we know ATCase is allosterically regulated

A

because of the sigmoidal shaped curve

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53
Q

what is an important regulator of ATCase

A

CTP (cytosine triphosphate)

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54
Q

what does ATP do

A

reverses effects of CTP; serves as an antagonist, restores the same level of activity

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55
Q

what is a rightward shift indicative of

A

something inhibiting the enzyme (takes more of substrate to reach the same V)

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56
Q

what is CTP

A

feedback inhibitor of ATCase

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57
Q

what else is CTP

A

end product of one of the pyrimidines that are synthesized, so it serves as a feedback inhibitor

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58
Q

describe feedback inhibitory mechanisms in synthesis pathways

A

with synthesis pathways we’re utilizing energy that’s precious to the cell. when we have enough of end product, there are feedback inhibitory mechanisms that dampen/slow down/inhibit that process

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59
Q

what does ATP do

A

antagonistic effect on CTP; restores normal activity of ATCase

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60
Q

what happens if there’s an imbalance of pyrimidine vs. purine pool and there’s more ATP

A

ATP is purine, pyrimidines need to be balanced w/ the purine concentration in the cell, so more pyrimidines

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61
Q

what does the first enzyme in the pathway of pyrimidine de novo synthesis do

A

serves as point of regulation

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62
Q

what does CTP at the bottom do

A

serves as allosteric inhibitor (negative allosteric regulation of aspartate transcarbamylase)

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63
Q

what are 2 general types of nucleotide biosynthesis

A

ribonucleotides (RNA precursors), deoxyribonucleotides (DNA precursors)

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64
Q

what do ribonucelotides serve as

A

precursors of deoxyribonucleotides

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65
Q

what is made first in the de novo pathway

A

ribonucleotides

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66
Q

what enzyme carries out the series of redox reactions to go from ribose to deoxyribose

A

ribonucleotide reductase complex

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67
Q

what is deoxyribose to ribose

A

reduced form of ribose sugar

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68
Q

what does ribonucleotide reductase act on

A

ribonucleotide diphosphates (diphosphorylated forms of ribonucleotides)

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69
Q

what is ribonucleotide diphosphate being converted to

A

deoxyribonucleotide diphosphate

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70
Q

what does this mechanism culminate in

A

synthesis of dNDP or deoxy form of nucleotide diphosphate

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71
Q

basically what are we goin gfrom

A

OH group at the C2 carbon to H at that carbon

72
Q

what serves as source of electrons

A

NADPH

73
Q

what two pathways are important

A

one for transfer of electrons to NDP substrate, but also a resetting of the ribonucleotide reductase

74
Q

what does ribonucleotide reductase have

A

two sulfhydryl groups, which correspond to specific cysteine residues within active site of enzyme

75
Q

what is needed for enzyme to function

A

needs to be reset into the reduced form

76
Q

what happens in the last redox step

A

convert NDP to dNDP, the thiol/sulfhydryl (SH) groups get oxidized and form a disulfide bridge (S-S)

77
Q

describe path electrons take

A

NADPH to FAD, FAD to thioredoxin, ultimately electrons get transferred to ribonucleotide reductase

78
Q

how does all this get set into motion

A

we’re re-reducing these sulfurs that are part of the system

79
Q

how do we re-reduce the sulfurs

A

NADPH (serves as feeder source of electrons), sequential redox, GSH (glutathione), so we have glutathione reductase. from glutathione reductase electrons are transferred to another protein glutaredoxin. from glutaredoxin we transfer electrons to ribonucleotide reductase to regenerate the reduce form of reductase (SH groups instead of S-S bridge)

80
Q

what is this ribonucleotide reductase complex similar to

A

pyruvate dehydrogenase complex (idea of having to reset the system thru redox)

81
Q

what do we need to do in order to allow for multiple rounds of reduction of NDP to dNDP

A

we have to regenerate these reduced thiol (SH) groups for each cycle

82
Q

what do we end up doing to the sugar

A

replace 2’ OH group w/ 2’ H

83
Q

do we deplete all of the ribose (turn it all into deoxyribose?0

A

no, we use some of that to make building blocks for RNA. but others will be used for generating deoxyribose form of sugar (DNA synthesis)

84
Q

what kind of regulation does ribonucleotide reductase have

A

a complex kind of allosteric regulation

85
Q

how many levels of control in ribonucleotide reductase

A

2 levels of control

86
Q

what are the two levels of control in ribonucleotide reductase

A

primary regulation site, substrate specificity site

87
Q

what does primary regulation site serve as

A

basic on-off switch for enzyme

88
Q

how many regulatory subunits are there

A

2; R1 and R1

89
Q

how many catalytic subunits are there

A

1; R2

90
Q

what does active site have

A

thiols/cysteines with SH groups, where substrates bind

91
Q

what is the point of having a combined primary regulatory site (on-off switch) and substrate specificity site

A

to provide balanced concentration of all the diff types of nucleotides or deoxynucleotides

92
Q

what do we want in terms of the diff nucleotides

A

don’t want to be able to carry out the reduction of just one type of ribonucleotide diphosphate; we want all the diff ones (A, T, Cs, Gs) to be reduced so that we have a balanced pool of those diff building blocks

93
Q

what happens when we have an abundance of one type of nucleotide

A

effectively stimulates production of other types of nucleotides

94
Q

what is the general idea behind this regulation

A

to have balanced pool of all the diff nucleotides

95
Q

what is ribonucleotide reductase regulated by

A

dNTPs

96
Q

why does dNTP serve as a feedback inhibitor of ribonucleotide reductase

A

this enzyme converts ribonucleotide diphosphates into deoxyribonucleotide diphosphates, when we have subsequent phosphorylation of those di-phosphorylated forms to generate triphosphorylated forms, when there’s enough of the deoxy form of ATP, it will serve as a feedback inhibitor of enzyme

97
Q

what serves as an activator for ribonucleotide reductase

A

having more of the ribonucleotide (ribo ATP form)

98
Q

what effects do ATP vs dATP have on enzyme activity

A

opposing

99
Q

what is the rule regarding substrate specificity

A

the nucleotide that serves as an allosteric regulator of substrate specificity is gonna favor reduction of other or alternate types of nucleotide diphosphates

100
Q

what do dATP or ATP favor

A

reduction of UDP and CDP

101
Q

what do dTTP or dGTP favor

A

reduction of GDP and ADP

102
Q

what happens after we convert the ribo NDP to deoxy ribo NDP form by reductase

A

we need to go through additional phosphorylation

103
Q

what generates the tri-phosphorylated forms

A

a series of kinases

104
Q

what converts dCDP into dCTP

A

nucleoside diphosphate kinase

105
Q

what happens to dUDP

A

converted to dUTP by the same enzyme

106
Q

describe CTP and UTP

A

same thing, except CTP has an amino group constituent off the ring structure

107
Q

what has to happen to go from dCTP to dUTP

A

deamination reaction, by enzyme deaminase

108
Q

what does deamination reaction do

A

converts cytosine base into uracil base

109
Q

what does dUTPase do

A

converts dUTP into dUMP

110
Q

what is dUMP

A

important precursor for eventual synthesis of dTMP

111
Q

what are the triphosphorylated forms of these nucleotides

A

what is used as eventual precursors for DNA and RNA synthesis

112
Q

what are major products generated in degradation of purines and pyrimidines

A

uric acid and urea

113
Q

what is an end product for degradation of GMP and AMP

A

uric acid

114
Q

what do primates/mammals excrete

A

excess nitrogen

115
Q

is nitrogen useful from an energetic standpoint

A

not really

116
Q

what do primates generate from degradation of purines and pyrimidines

A

uric acid

117
Q

but what do primates excrete the bulk of their nitrogen as

A

urea in urea cycle (as opposed to uric acid in purine degradation)

118
Q

what are the two sources of excreted nitrogen

A

one from purines and pyrimidines, other from proteins and AAs that are degraded & used that pass thru urea cycle

119
Q

do we excrete urea or uric acid

A

some uric acid, but majority of excreted nitrogen is in form of urea

120
Q

who excretes uric acid

A

primates, birds, reptiles, insects

121
Q

who excretes allantoin

A

most mammals

122
Q

who excretes allantoate

A

bony fishes

123
Q

who excretes urea

A

amphibians, cartilaginous fishes

124
Q

who excretes ammonia

A

marine invertebrates

125
Q

what is most abundant form of excreted nitrogen in primates, and where does that come from

A

urea; comes from degradation of proteins and AAs

126
Q

important intermediate in catabolism of pyrimidines

A

methylmalonyl semialdehyde

127
Q

what is methylmalonyl semi aldehyde degraded to

A

succinyl CoA (TCA cycle intermediate)

128
Q

what is succinyl CoA

A

TCA cycle intermediate

129
Q

what happens to carbon skeleton derived from catabolism of pyrimidines

A

can be shunted into TCA cycle

130
Q

what are salvage pathways

A

pathways that scavenge or utilize free purine pyrimidine bases

131
Q

how are these free bases released

A

thru degradation of nucleotides

132
Q

do all nucleotides go through degradative pathways

A

not all, some can be salvaged and reused

133
Q

how are free purine and pyrimidine bases released

A

via metabolic degradation of NTs

134
Q

what are free purines used

A

salvaged and reused to make NTs

135
Q

what is a major pathway for purines

A

adenine + PRPP –> generates AMP and PPi (pyrophosphate)

136
Q

where else are there similar pathways

A

for pyrimidines in bacteria and mammals

137
Q

what is a genetic disorder associated w/ defects in the salvage pathway enzyme

A

Lesch-Nyhan syndrome

138
Q

Lesch-Nyhan syndrome is a result in defect in what enzyme

A

hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

139
Q

what enzyme is HGPRT

A

salvage patwhay enzyme

140
Q

what is Lesch-Nyhan syndrome

A

almost exclusive to male children; profound mental retardation, self-mutilating behavior

141
Q

what is seen in Lesch-Nyhan synddrom

A

elevated levels of de novo purine synthesis, so increase in uric acid

142
Q

what other conditions are there

A

gout

143
Q

how does gout arise

A

excess production of uric acid

144
Q

what is gout

A

painful disease, affects joints and other tissues

145
Q

why is gout created

A

b/c there are certain competitive inhibitors

146
Q

what are competitive inhibitors

A

compounds/analogs, structurally similar to naturally occurring precursor/intermediate/end product

147
Q

what are the competitive inhibitors in gout

A

enzyme xanthine oxidase, oxypurinol is its competitive inhibitor

148
Q

what is allopurinol

A

inhibitor of one of the enzymes that leads to production of excess uric acid

149
Q

what is allopurinol an inhibitor of

A

xanthine oxidase

150
Q

what is oxypurinol

A

byproduct of action of xanthine oxidase on allopurinol drug; serves as competitive inhibitor of xanthine oxidase

151
Q

what does oxypurinol do

A

inhibits XO

152
Q

where else do we see structural analogs

A

in drugs, chemo

153
Q

what is a common target of these chemotherapeutics

A

to target enzymes part of nucleotide biosynthesis pathway

154
Q

why does it make sense that chemo targets these enzymes

A

tumor cells are v active, high rates of replication. one way to slow rate of proliferation is to block their ability to synthesize nucleotides, DNA and RNA, and precursors

155
Q

what are some drugs designed for

A

to target diff points of nucleotide metabolism

155
Q

what is one way to slow replication of tumor cells

A

block their ability to synthesize nucleotides, synthesize DNA/RNA, synthesis of precursors

156
Q

what are two target points for nucleotide metabolism

A

enzyme thymidylate synthase, other enzyme is dihydrofolate reductase (DHFR)

157
Q

what is one drug that targets these points

A

FdUMP

158
Q

what is FdUMP

A

fluorine analog of the normal substrate for thymidylate synthase (dUMP)

159
Q

what does thymidylate synthase do

A

converts dUMP to dTMP

160
Q

what can happen to dTMP

A

become phosphorylated to generate dTTP, which is then used in DNA synthesis

161
Q

what is another enzyme that is targeted by drugs

A

dihydrofolate reductase

162
Q

what is dihydrofolate reductase

A

reductase; uses NADPH as an electron source, reduces folic acid

163
Q

what is folic acid

A

an important precursor for certain nucleotides

164
Q

what drugs target dihydrofolate reductase

A

methotrexate, aminopterin, trimethoprim

165
Q

what are these drugs used for

A

to treat various types of cancers

166
Q

what is FdUMP used for

A

to treat diff cancers

167
Q

what does FdUMP serve as

A

suicide inhibitors

168
Q

what are regular inhibitors

A

interact w/ enzyme via non-covalent interaction, binds and inhibits it. reversibly binding inhibitors; binding is reversible and can dissociate again

169
Q

what are suicide inhibitors

A

utilized in the catalytic activity of the enzyme. rather than inhibitor being converted into product, it becomes covalently attached to the enzyme within its active site, forms this dead-end complex.

170
Q

why is this dead-end covalent complex achieved

A

because there is a chemically reactive fluorine

171
Q

what happens in normal conversion of dUMP to dTMP

A

normal 3 step process, produces dTMP at the end

172
Q

what is FdUMP similar to

A

dUMP natural substrate for thymidylate synthase

173
Q

what does FDUMP go thru

A

regular steps of catalysis, but reactive fluorine results in formation of this covalent dead-end complex

174
Q

what happens after covalent dead-end complex

A

enzyme can no longer catalyze any reactions, because drug is covalently attached to the active site of the enzyme, so the enzyme is basically dead

175
Q

why are they called suicide inhibitors

A

get used in the biochemical rxn catalyzed by the enzyme, that effectively results in an inactivated enzyme

biochem (15 decks)

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