Nucleotide Metabolism Flashcards
(130 cards)
1
Q
What is a nucleoside?
A
base linked to 1’ of ribose
2
Q
What is a nucleotide?
A
nucleoside esterified to a phosphate at 5’ of ribose ring
3
Q
What two components are fused to make a pyrimidine?
A
purine and imidazole ring
4
Q
Where are the enzymes for purine synthesis located?
A
cytoplasm
5
Q
At what base is purine synthesis initiated?
A
PRPP
5-phosphoribosyl-1-pyrophosphate
6
Q
What is the first step in purine synthesis? What enzyme catalyzes this reaction?
A
generation of PRPP
PRPP Synthetase
7
Q
Is PRPP synthesis specific to purine synthesis?
A
No.
PRPP is required for both purine and pyrimidine synthesis
8
Q
What is PRPP derived from?
A
ribose-5-phosphate
9
Q
What is the committed step of de novo purine synthesis? What enzyme catalyzes this reaction?
A
formation of 5-phosphoribosylamine (5-PRA)
enzyme = amidophosphoribosyltransferase
10
Q
What is the first purine to be produced during de novo synthesis?
A
inosine-5-monophosphate
IMP
11
Q
IMP serves as a precursor for what two other purines?
A
AMP and GMP
12
Q
What donate carbon and nitrogen atoms to purine synthesis?
A
amino acids
13
Q
Specifically, what amino acids donate carbon and nitrogen to purine synthesis?
A
glycine, glutamine and aspartate
14
Q
What does CO2 provide in purine synthesis?
A
carbon and oxygen
15
Q
What does N10-formyl-THF provide in purine synthesis?
A
donor of one-carbon
16
Q
What are the roles of nucleoside monophosphate kinases and nucleoside diphosphate kinases?
A
generation of nucleotide triphosphates
17
Q
Which, NMPK orNDPK have a more specific or more general substrate specificity?
A
NMPK = more specific
NDPK = more broad
18
Q
Why is GTP an ‘ATP Equivalent’?
A
the more are readily interconverted
19
Q
What are the most effective inhibitors of PRPP Synthetase?
A
ADP and GDP
20
Q
What serves to inhibit amidophosphoribosyltransferase activity?
A
AMP and GMP
21
Q
What serves as an allosteric activator of amidophosphoribosyltransferase?
A
PRPP
22
Q
Where does the bulk of purine nucleotide degradation occur?
A
the liver
23
Q
How is the degrdation of GMP initiated?
A
5’-nucleotidases
24
Q
What is the 2nd step of guanosine degradation? What two molecules are liberated?
A
purine nucleoside phosphorylase
guanosine –> guanine and ribose
25
How does AMP degradation begin?
by the action of AMP deaminase and adenosine deaminase
26
What does the action of AMP deaminase produce?
IMP from AMP
27
What enzyme converts AMP to adenosine?
5'-nucleotidases
28
What enzyme converts AMP to IMP?
AMP deaminase
29
What enzyme converts adenosine to inosine?
adenosine deaminase
30
What enzyme converts IMP to inosine?
5'-nucleotidases
31
What enzyme converts inosine to hypoxanthine?
purine nucleoside phosphorylase
32
What enzyme converts hypoxanthine to xanthine?
xanthine oxidase
33
What enzyme converts GMP to guanosine?
5'nucleosidases
34
What enzyme converts guanosine to guanine?
purine nucleoside phosphorylase
35
What enzyme converts guanine to xanthine?
guanine deaminase
36
What two conditions can lead to a decrease in uric acid secretion?
real insufficiency and metabolic acidosis
37
What two conditions can cause an increase in nucleotide turnover that can exacerbate gout?
increased nucleotide turnover
diets rich in purine
38
How does alcohol consumption exacerbate gout?
alcohol consumption causes ATP turnover and increase in serum lactic acid
39
What are gout crystals?
sodium urate
40
What is it called when gout precipitates in the kidney?
uric acid urolithiasis
41
What is allopurinol oxidized to?
oxypurinol
42
How does oxypurinol aid in the treatment of gout?
oxypurinol is a competitive inhibitor of xanthine oxidase
43
How does pyrimidine synthesis differ from that of purine synthesis?
pyrimidines are synthesized as bases then attached to ribose
44
What is the first enzyme of pyrimidine synthesis?
Carbamoyl Phosphate Synthetase II
45
What is the product of carbamoyl synthetase II?
carbamoyl phosphate
46
What enzyme acts on carbamoyl phosphate? What does this produce?
Aspartate Transcarbamoylase
N-carbamoyl aspartate
47
What enzyme works on N-carbamoyl aspartate?
Dihydroorotase
48
What does dihydroorotase produce?
dihydroorotate
49
What enzyme of pyrimidine synthesis is expressed in the mitochondria?
Dihydroorotate Dehydrogenase
50
What does dihydroorotate dehydrogenase work on? What does dihydroorotase produce?
dihydroorotate
orotate
51
What enzyme works on orotate? What is the product of this enzyme?
orotate phosphoribosyl transferase
OMP
52
What enzyme works on OMP? What is the product of this enzyme?
OMP decarboxylase
UMP
53
What enzyme catalyzes the transfer of R5P to orotate?
orotate phosphoribosyltransferase
54
What is OMP also known as?
orotidine 5 monophosphate
55
What is CAD?
carbamoyl phosphate synthetase, aspartate transcarbamoylase, dihydroorotase
56
What two enzymes make up UMP synthase?
OMP decarboxylase and orotate phosphoribosyl transferase
57
Orotic aciduria features a defect in what enzyme?
UMP synthase
58
What three symptoms do patients with orotic aciduria present with?
orotic acid in urine
megaloblastic anemia
occasional defect in cellular immunity
59
What is the treatment for orotic aciduria?
pyrimidine supplementation
60
What does CTP synthase use as an amino donor?
glutamine
61
Where is de novo synthesis of pyrimidines most regulated?
carbamoyl phosphate synthetase II
62
Regarding CTP synthase, what kind of effector is CTP?
negative effector
63
What kind of kinetics does CTP synthase display regarding UTP levels?
sigmoidal kinetics
64
Activity of carbamoyl phosphate synthetase II is affected by what two molecules?
inhibited by UTP
activated by PRPP
65
What enzyme produces deoxyribonucleotides?
ribonucleotide reductase
66
What is the substrate for ribonucleotide reductase?
nucleoside 5' Di-phosphates
67
What is the product of ribonucleotide reductase?
2'-deoxyribonucleotide -5'-diphosphates
68
How are ribonucleotide reductase levels regulated?
transcription
69
What is a common and important pharmacological inhibitor of ribonucleotide reductase?
hydroxyurea
70
Mutations in adenosine deaminase are implicated in what disease?
severe combined immunodeficiency disease
71
Why is adenosine deaminase believed to cause SCID?
back-up of adenosine metabolites inhibits ribonucleotide reductase
72
How is dTMP converted to dTDP?
dTMP kinase
73
What is the classic inhibitor of thymidylate synthase?
5-fluorouracil
74
In the body, what is 5-FU converted to?
fUMP
75
What form of 5-fluorouracil is a substrate for ribonucleotide reductase?
fUDP
76
Dephosphorylation of what producs fdUMP?
fdUDP
77
Specifically, how does 5-FU inhibit thymidylate synthase?
FdUMP and N5N10 THF form a permanent and irreversible complex with thymidylate synthase
78
Degradation of pyrimidines yield what two products?
beta-alanine
beta-aminoisobutyrate
79
Where are nucleosides taken up?
intestinal epithelial cells
80
Why is adenosine interesting?
adenosine can be directly phosphorylated by adenosine kinase to produce AMP
81
What does Lesch-Nyhan Syndrome result from?
defective HGPRTase
82
How do salvage pathways decrease de novo synthesis?
By sequestering PRPP and lowering activity of amidophosphoribosyl transferase
83
What is the one pyrimidine that is not salvaged in humans?
cytosine
84
What enzyme do fungi express that make them susceptible to analogs?
cytosine deaminase
85
How does probenecid work?
inhibits renal uptake of uric acid
86
What enzyme in pyrimidine synthesis uses PRPP?
orotate phosphoribosyltransferase
87
What disease is UMP synthase defective in?
orotic aciduria
88
How is orotic aciduria treated?
uridine administration
89
What does CTP synthase use as a nitrogen source?
glutamine
90
What is CPS II inhibited by?
UTP
91
What is CPS II activated by?
PRPP
92
What is CTP synthase inhibited by?
CTP
93
What is CTP synthase activated by?
UTP
94
What is an important inhibitor of ribonucleotide reductase?
hydroxyurea
95
What does ribonucleotide reductase work on?
5'-nucleoside diphosphates
96
What enzyme is deficient in patients with SCID?
adenosine deaminase
97
What kind, oxy or deoxy, form of thymine exists?
Only deoxy
98
What is another inhibitor of thymidylate synthase?
methotrexate
99
How does methotrexate inhibit thymidylate synthase?
inhibitor of dihydrofolate reductase
100
What is beta-alanine metabolized into?
acetyl-CoA
101
What is dTMP metabolized into?
beta-aminoisobutyrate
102
What is the function of adenosine kinase?
to phosphorylate adenosine to AMP
103
What is the pyrimidine that IS NOT salvaged in humans?
cytosine
104
What do fungi express that make them vulnerable to 5-fluorocytosine?
cytosine deaminase
105
What does cytosine deaminase synthesize from 5-fluorouracil?
FUMP
106
What structures provide carbon and nitrogen for IMP synthesis?
glycine, glutamine and aspartate
107
What form of THF is used for purine synthesis?
N10-formyl-THF
108
What is the ATP consumption required to synthesize the first purine, IMP?
four ATPs consumed
109
What is the rate limiting step of AMP synthesis?
adenylosuccinate synthetase
110
What it the rate limiting step of IMP synthesis?
IMP dehydrogenase
111
What is amidophosphoribosyltransferase inhibited by?
AMP and GMP
112
What is PRPP synthetase inhibited by?
ADP and GDP
113
What serves as an allosteric activator of amidophosphoribosyltransferase?
PRPP
114
What is the function of AMP deaminase?
AMP --> IMP
115
What is the function of adenosine deaminase?
adenosine --> Inosine
116
What is more common, reduced excretion of uric acid or increased production of uric acid?
reduced excretion
117
How does alcohol contribute to gout?
increases serum lactic acid
uric acid competes with other organic acids for excretion
118
What enzyme converts dUMP to dTMP?
thymidylate synthase
119
What products get degraded to beta-alanine?
dCMP, CMP, UMP, uracil
120
What products get degraded to beta-aminoisobutyrate?
dTMP, thymine
121
Pyrimidine degradation requires what reducing agent?
NADPH
122
How are beta-alanine and beta-isobutyrate excreted?
urine
123
What is the function of adenosine kinase?
Adenosine --> AMP
124
What enzyme is deficient in Lesch-Nyhan Syndrome?
HGPRTase
125
What enzyme is responsible for pyrimidine salvage?
Pyrimidine Phosphoribosyltransferase
126
What is the one pyrimidine that is not salvaged in humans?
cytosine
127
How are the activities of HGPRTase and APRTase regulated?
the activity is inhibited by their products (IMP, GMP, AMP)
128
What is beta-alanine metabolized to?
acetyl-CoA
129
What is beta-aminoisobutyrate metabolized into?
succinyl-CoA
130
What metabolite of pyrimidine degradation is unique to pyrimdine degradation?
beta-aminoisobutyrate
