Nucleotide Metabolism Flashcards
1
Q
examples of purines
A
- adenine
- guanine
- xanthine
- hypoxanthine
- uric acid
2
Q
hypoxanthine is the base for
A
- inosine
3
Q
examples of pyrimidines
A
- cytosine
- thymine
- uracil
4
Q
nucleoside composed of
A
- base + sugar
5
Q
nucleotide composed of
A
- base + sugar + phosphate
6
Q
ribose
A
- OH at 2’ sugar
- less stable
7
Q
deoxyribose
A
-H at 2- sugar
8
Q
sources of nucleotides
A
- dietary
- de novo synthesis
- salvage pathway
9
Q
contribution of dietary
why
A
- relatively small
- most RNA and DNA in diet are degraded and excreted
10
Q
primary producer of de novo synthesis
A
- liver
11
Q
what do you end up with as the common precursor to purine nucleotides and the branch point for the synthesis of different purines
A
- IMP
12
Q
- first step of purine synthesis
synthesis of PRPP starting with
A
- ribose-5-phosphate from PPP
- with ATP
13
Q
synthesis of PRPP enzyme
A
- PRPP synthetase
14
Q
importance of PRPP
A
- pentose molecule
- synthesis and salvage of purines and pyrimidines
15
Q
what controls the rate of formation of PRPP
A
- amount of ribose-5-phosphate
16
Q
activation of synthesis of PRPP
A
- Pi
- indicates low nucleotide levels
17
Q
end product inhibition of synthesis of PRPP
A
- purine nucleotides
- ADP, GDP
18
Q
Arts syndrome caused by
A
- genetic disorder in PRPP synthase
- generally decreased PRPP synthetase
19
Q
genetics of Arts syndrome
A
- X-linked
20
Q
reduction of PRPP synthetase causes
A
- reduced purine levels
- absence of hypoxanthine from urine and uric acid in serum
21
Q
increases in PRPP synthetase causes
A
- increased levels of purines
- gout
22
Q
body system impacted to Arts syndrome
A
- severe nervous system abnormalities
23
Q
second step of purine synthesis
with help from
A
- PRPP -> 5-phosphoribosyl-1-amine
- with help of glutamine - contributes nitrogen
24
Q
importance of second step of purine synthesis
A
- committed step
- irreversible
- major regulated step
25
enzyme in second step of purine synthesis
- glutamine phosphoribosyl amidotransferase
26
inhibition of second step of purine synthesis
- AMP, GMP, IMP, XMP
| - pathway products
27
activation of second step of purine synthesis
- PRPP
28
which form of glutamine phosphoribosyl amidotransferase is the active form?
- the monomer
29
which form of glutamine phosphoribosyl amidotransferase is the inactive form?
- dimer
30
high levels of AMP, GMP, IMP on glutamine phosphoribosyl amidotransferase
- forms a less active dimer
31
high levels of PRPP on glutamine phosphoribosyl amidotransferase
- form active monomeric form
32
what levels play a major role in regulating purine synthesis
- PRPP
33
glutamine effect on kinetics of glutamine phosphoribosyl amidotransferase
- near Km
| - does not influence rate significantly
34
PRPP effect on kinetics of glutamine phosphoribosyl amidotransferase
- PRPP levels way below Km
35
importance of inhibition of glutamine phosphoribosyl amidotransferase by AMP PLUS GMP or IMP
- 2 distinct binding sites
| - regulation in additive way
36
importance of THF in purine metabolism
- carbon donor at 2 steps
37
what inhibits bacterial folic acid synthesis
- sulfa drugs
38
why don't sulfa drugs interference with human purine synthesis and DNA replication
- humans only acquire folic acid by diet
39
precursors of making THF
- folate
- dihydrofolate
- tetrahydrolate
40
enzyme that helps make THF
also required
- DHFR
| - NADPH
41
purine synthesis requires what form of THF
N10-formyl-THF
42
methotrexate often used for
MOA
- antitumor drug
| - inhibits DHFR reducing synthesis of THF
43
good effects of methotrexate
- reduces purine synthesis
- slows down DNA replication
- slows tumor growth
44
bad effects of methotrexate
- affects normally dividing cells
45
IMP precursor for
- AMP
| - GMP
46
base of IMP
- hypoxanthine
47
AMP requires what for energy
- GTP
48
other molecule AMP requires for energy
- aspartate
| - releases fumerate
49
GMP requires what for energy
- ATP
50
other molecules GMP requires for energy
- NAD+
| - glutamine
51
enzyme for formation of GMP from IMP
- GMP synthase
52
effect of high ATP on GMP/GTP synthesis
- increased
53
enzyme for formation of AMP from IMP
- adenylosuccinate synthetase
54
effect of high GTP on AMP/ATP synthesis
- increased
55
what inhibits IMP dehydrogenase
- GMP
56
what inhibits adenylosucinate synthetase
- AMP
57
purpose of mycophenolic acid
- immunosuppressant
- reduce lymphocyte proliferation
- prevent graft rejection
58
MOA of mycophenolic acid
- inhibits IMP dehydrogenase and GMP formation
59
purpose of ribavirin
- anti-viral
| - anti-tumor agent
60
MOA of ribavirin
- inhibits IMP dehydrogenase
61
enzyme that converts AMP to ADP
what else is required
- adenylate kinase
| - ATP
62
enzyme that converts GMP to GDP
what else is required
- guanylate kinase
| - ATP
63
what converts ADP, GDP, and NDPs to triphosphates
what else is required
- nucleoside diphosphate kinase
| - ATP
64
purpose of degradation of DNA and RNA
- body to reutilize nucleosides and free bases via salvage pathways
65
how do we get degraded nucleic acids
- cell death
- RNA or DNA turnover
- diet
66
nucleic aid is digested where?
by what enzyme?
- stomach
| - pepsin
67
RNAse and DNase secreted by what
- pancreas
68
what do RNAse and DNase do
- digest RNA and DNA into oligonucleotides
69
role of phosphodiesterases
- degrade oligonucleotides
| - to NMPs and dNMPs
70
role of nucleotidases or phosphatases
- remove phosphate groups
| - convert to nucleosides
71
role of nucleosidases
- degrade nucleosides
| - form free bases plus ribose and deoxyribose
72
degradation products of pyrimidine nucleotides
- all soluble
73
degradation products of purine nucleotides
- produce uric acid
| - lead to hyperuricemia
74
hyperuricemia can result in
- gout
75
degradation occurs mostly where
- liver
76
degradation of AMP to xanthine process
- AMP -> IMP -> inosine
- AMP -> adenosine -> inosine
- inosine -> hypoxanthine
- hypoxanthine -> xanthine
77
degradation of GMP to xanthine process
- GMP -> guanosine
- guanosine -> guanine
- guanine -> xanthine
78
xanthine degraded to
by what enzyme
- uric acid
| - xanthine oxidase
79
uric acid generated in
transported to
- liver
| - kidney for excretion in urine
80
MOA of allopurinol
- inhibits xanthine oxidase
| - reduces uric acid levels
81
allopurinol used to treat
- gout
82
enzyme from AMP -> IMP
- AMP deaminase
83
enzyme from IMP -> inosine
- 5'-nucleotidase
84
enzyme from AMP -> adenosine
- 5'-nucleotidase
85
enzyme from adenosine -> inosine
- adenosine deaminase
86
what condition results from blocking of adenosine deaminase
- SCID
87
what other reaction does adenosine deaminase (ADA) catalyze
- deoxyadenosine -> deoxyinosine
88
genetic deficiency of ADA results in
- accumulation of dATP
89
importance of high levels of dATP
- inhibit ribonucleotide reductase
90
importance of inhibition of ribonucleotide reductase
- reduction in DNA synthesis
91
importance of high deoxyadenosine levels
- toxic in lymphocytes
| - unable to combat infection leading to SCID
92
AMP deaminase functions in
- skeletal muscle
93
AMP deaminase deficiency symptoms
- skeletal muscle myopathy
- exercise induced fatigue and cramps
- often asymptomatic
94
AMP deaminase selective form
- AMP only
95
part of the body where savage is done
- the liver
96
salvage pathway
- building nucleotides from bases and nucleosides
97
benefit of salvage pathway
- energetically advantageous
| - less costly than de novo
98
adenine to AMP in purine to NMP salvage pathway uses which enzyme
also requires
- APRT
| - PRPP
99
hypoxanthine to IMP in purine to NMP salvage pathway uses which enzyme
- also requires
- HGPRT
PRPP
100
guanine to GMP in purine to NMP salvage pathway uses which enzyme
also requires
- HGPRT
| - PRPP
101
purine to NMP salvage pathway reactions (reversible/irreversible)
- irreversible
| - due to generation of pyrophosphate
102
inosine to which base
what also forms
- hypoxanthine
| - ribose-1-phosphate
103
inosine -> hypoxanthine by which enzyme
- purine nucleoside phosphorylase
104
guanosine to which base
what also forms
- guanine
| - ribose-1-phosphate
105
guanosine -> guanine by which enzyme
- purine nucleoside phosphorylase
106
deficiency of purine nucleoside phosphorylase leads to
- accumulation of nucleosides
-
- T-cell immunodeficiency
107
enzyme to make PRPP-> nucleotide
also requires
- APRT and HGRT
| - a base
108
hyperuricemia due to
- under excretion of uric acid
109
factors that increase PRPP synthetase lead to
- increased levels of PRPP
- increased activity of glutamine phosphoribosyl amidotransferase
- increases production of 5-phosphoribosyl 1-amine and nucleotides
110
von Gierke disease due to
- glucose-6-phosphatase deficiency
111
reduced glucose-6-phosphatase results in
- g-6-p shunted into PPP pathway
112
more G-6-P into PPP results in
- more glutamine phosphoribosyl amidotransferase activity
| - increased nucleotide synthesis
113
genetics of Lesch-Nyhan syndrome
- X-linked
| - recessive
114
cause of Lesch-Nyhan syndrome
- deficiency of HGPRT
115
symptoms of Lesch-Nyhan syndrome
- neurological and behavioral abnormalities
| - gout
116
result of Lesch-Nyhan syndrome
- cannot salvage hypoxanthine or guanine
117
what happens when you can't salvage hypoxanthine or guanine
- bases degraded to uric acid
118
Lesch-Nyhan syndrome on PRPP levels
- increases
119
Lesch-Nyhan syndrome on AMP and GMP levels
- reduced
120
Lesch-Nyhan syndrome stimulates production of
- 5-phosphoribosyl-1-amine by glutamine phosphoribosyl amidotransferase
121
importance of more PRPP levels in Lesch-Nyhan syndrome
- normally stimulates purine synthesis anyway
122
importance of less AMP and GMP levels in Lesch-Nyhan syndrome
- normally inhibits purine synthesis
| - less of them makes purine synthesis go even further
123
colchicine
- treats symptoms only
124
MOA of allopurinol and febuxostate
- inhibit xanthine oxidase
125
result of allopurinol and febuxostat
- lowers purine and uric acid levels
126
MOA of pegloticase and rasburicase
- converts uric acid to more soluble allantoin
127
MOA of probenecid and lesinurad
- promotes renal excretion of uric acid
128
allopurinol structural analog of
- hypoxanthine
129
allopurinol converts to
- oxypurinol
130
significance of oxypurinol
- irreversible inhibitor of xanthine oxidase
131
what happens when inhibition of xanthine oxidase
- accumulates xanthine and hypoxanthine
| - more soluble than uric acid
132
salvaging of hypoxanthine result
- reduces PRPP
| - reduces de novo purine synthesis
133
cancer patients with large tumors that are undergoing treatment have what
- high levels or uric acid
134
how do we reduce uric acid levels in patients undergoing cancer therapy
- allopurinol
| - rasburicase
135
pyrimidine synthesis requires which 2 amino acids
which other compound
- Gln
- Asp
- CO2
136
how do we start pyrmidine synthesis
- Glutamine + CO2 -> Carbamoyl phosphate
137
enzyme to convert - Glutamine + CO2 -> Carbamoyl phosphate
- CPS-II
| - committed step
138
CPS-II inhibited by
- UTP
139
CPS0II activated by
- PRPP
140
formation of orotic acid
- aspartate -> carbamoyl aspartate -> orotic acid
141
how to form carbamoyl aspartate from aspartate
- aspartate + carbamoyl phosphate
142
first 3 activities of pyrimidine synthesis pathway resides on
- CAD
143
enzyme from aspartate to carbamoyl aspartate
- aspartate transcarbamoylase
144
enzyme from carbamoyl phosphate to orotic acid
- dihydroorotase
| - dihydroortate dehydrogenase
145
formation of UMP from orotic acid
- orotic acid -> OMP
| - OMP -> UMP
146
orotic acid -> OMP donor
- PRPP
147
orotic acid -> OMP donor reversibility of reaction
- irreversible
148
orotic acid -> OMP donor enzyme
- orotate phosphoribosyl transferase
149
OMP-UMP enzyme
- orotidine 5'-P decarboxylase
150
orotate phosphoribosyl transferase and orotidine 5'-P decarboxylase part of which enzyme
- UMP synthase
151
hereditary orotic aciduria caused by
- mutations in UMP synthase
152
symptoms of orotic aciduria
- poor growth
- anemia
- high levels of orotic acid in urine
153
how to treat orotic aciduria
- uridine
154
uridine pathway
- uridine -> UTP
| - UTP-CTP
155
what does UTP inhibit
results?
- CSPII
| - reduces de novo synthesis of orotic acid to normal levels
156
UMP -> UDP which enzyme
requires
- UMP kinase
ATP
157
UDP -> UTP which enzyme
requires
- NDP kinase
ATP
158
enzyme to produce CTP from UTP
also required
- CTP synthetase
| - glutamine
159
negative regulation of synthesis of CTP from UTP
- CTP is negative regulator
160
key regulated step of pyrimidine synthesis
- CSP II
161
CSP activated by
- PRPP
162
what is required for the first step of pyrimidine synthesis
why is this important?
- ATP
| - helps balance purine/pyrimidine ratio
163
inhibitors of CPS II
- UTP and UDP
164
inhibitor of OMP decarboxylase
- UMP
165
cytosine degradation pathway
- cytosine
- uracil
- beta alanine
166
thymine degradation pathway
- thymine
| - beta aminoisobutyrate
167
end result of B-alanine and B-aminoisobutyrate
- excreted in urine
- converted to malonyl-CoA and used in fatty acid biosynthesis
- HIGHLY SOLUBLE
168
salvage of pyrimidine bases
- salvaged to nucleosides -> nucleotides
169
uracil/thymine to uridine/thymidine via
also included
- nucleoside phosphorylase
- ribose-1-phosphate (U)
- deoxyribose-1-phosphate (T)
170
uridine to UMP via
also included
- nucleoside kinase
| - ATP
171
dNDPs are derived from
- NDPs
172
enzyme to reduce NDPs to dNDPs
- ribonucleotide reductase
173
cofactor required by ribonucleotide reductase
for what reason
- thioredoxin
| - supply H
174
purpose of NADPH in synthesis of dNDPs
- provides H to replenish thioredoxin
175
hydroxyurea MOA
- inhibits ribonucleotide reductase
- reduces dNTPs and dNDPs
- reduces DNA synthesis
176
enzyme for UDP to dUDP
- ribonucleotide reductase
177
why is dUTP quickly hydrolyzed to dUMP
- we don't use dUTP for DNA synthesis
178
alternative path to produce dUMP
- dCMP -> dUMP
179
dCMP -> dUMP enzyme
- dCMP deaminase
180
dCMP deaminase activated by
- dCTP
181
dCMP deaminase inhibited by
- dTTP
182
dUMP - dTTP by enzyme
also needs
- thymidylase synthase
| - N5,N10-methylene tetrahydrofolate
183
N5,N10-methylene tetrahydrofolate derived from
- dihydrofolate
184
what do we need for continued DNA replication
- regeneration of DHF by NADPH
185
activation of ribonucleotide reductase
- ATP
186
inhibition of ribonucleotide reductase
- dATP
187
cross regulation by dNTPs helps with
- balancing correct amounts of each dNTP
188
2 allosteric sites of ribonucleotide reductase
- controls activity
| - substrate specificity
189
5-fluorouracil MOA
- converted to 5-fluorodeoxyuridine monophosphate
190
5-fluorodeoxyuridine monophosphate purpose
- permanently binds thymidylate synthetase
191
5-fluorouracil result
- reduces conversion of dUMP to dTMP
192
methotrexate MOA
- competitive inhibitor of DHFR
193
methotrexate result
- reduces levels of THF and N5,N10-methylene
| - reduces conversion of dUMP to dTMP
194
6-mercaptopurine MOA
- negatively regulated PRPP amidotransferase
| - reduces nucleotides
195
6-mercaptopurine inhibits which pathways
- IMP-> AMP
| - IMP -> GMP
196
leflunomide MOA
- inhibits dihydroorotate dehydrogenase
197
importance of inhibiting dihydroorotate dehydrogenase
- blocks orotate and pyrimidine production
