10.08.18 Nucleotide Metabolism Flashcards
Adenine, Xanthine, Guanine, Hypoxanthine, Uric Acid, and Inosine are examples of what?
Purines
Cytosine, Thymine, and Uracil are examples of what?
Pyrimidines
What is a nucleoside made of?
Base+Sugar
What is nucleotide made of?
Base+Sugar+ Phosphate group
What is the difference between RNA and DNA?
-OH instead of -H at second carbon of sugar
RNA is less stable
What are the sources of nucleotides?
- Dietary
- De novo synth
- Salvage pathway
____ is the precursor to PRPP
Ribose 5-phosphate
an activated form of ribose that initiates synthesis
PRPP
common precursor to purine nucleotides and the branch point for the synthesis of different purines
IMP
Ribose 5-phosphate is derived from ___ via PPP or salvage pathway
Glucose
Pentose molecule that participates in synthesis and salvage of purines and pyrimidines
5-phosphoribosyl-1-pyrophosphate (PRPP)
What enzyme converts Ribose 5-phosphate + ATP –> PRPP
PRPP synthetase
What upregulates PRPP synthetase what downregulates it?
+: Ribose 5-phosphate, Pi (indicates low nt levels)
-: purine nt, ADP, GDP
X-linked disorder associated with severe nervous system abnormalities and decreases in PRPP synthetase activity
Arts Syndrome
What happens when PRPP synthetase activity reduces?
What happens when PRPP synthetase is increased?
Reduced purine levels; hypoxanthine absent from urine/uric acid is reduced in serum
Increased purine and gout
This enzyme action is irreversible (committed step) in purine synthesis
Glutamin phosphoribosyl amidotransferase
What reaction does glutamine phosphoribosyl amidotransferase catalyze?
Glutamine + PRPP –> 5-Phosphoribosylamine
What upregulates the commited in purine synth and what downregulates it?
+: PRPP
-: AMP, GMP, IMP, XMP (products)
What form of glutamine phosphoribosyl amidotransferase is active and which is inactive
Active= monomer
Inactive = dimer
How does glutamine affect the rate of glutamine phosphoribosyl amidotransferase?
Doesn’t
What does the rate of phosophorylrybosylamine depend on?
PRPP
Inhibited by products and has distinct binding sites
In how many steps is tetrahydrofolate the carbon donor in purine synth?
2
What rxns does dihydrofolate reductase (DHFR) carry out?
- Folate –> Dihydrofolate
2. Dihydrofolate –> THF
an anti-tumor drug that reduces the synthesis of THF by inhibiting DHFR
Methotrexate
What is the base for IMP?
Hypoxanthine
What is the precursor for both AMP and GMP?
IMP
AMP synthesis requires what for energy?
GMP synthesis requires what for energy?
What is this called?
GTP
ATP
Positive cross-regulation
What are AMP and GMP inhibitors of in their own synthesis?
AMP- adenylosuccinate synthetase
GMP- IMP dehydrogenase
What does mycophenolic acid inhibit and what is it used in?
inhibits IMP dehydrogenase (GMP formation)
reduces lymphocyte proliferation and prevents graft rejection
Other than mycophenolic acid, what is also used to inhibit IMP dehydrogenase?
RIbavarin
What are the base specific kinases and what are the nonspecific kinases?
What do all these kinases require?
Base specific:
- Adenylate kinase
- Guanylate kinase
Nonspecific:
Nucleoside diphosphate kinase
ATP
What is the basic pathway for purine degradation?
Nucleic acids –> Bases –> Uric acid
What digest nucleic acids in the stomach?
Pepsin
What is secreted by the pancreas to digest RNA/DNA into oligonucleotides?
RNAses and DNAses
What degrades oligonucleotides to NMPs and dNMPs?
Phosphodiesterases
What removes the phosphate groups from nucleotides to make nucleosides?
Nucleotidases (or phosphatases)
What degrades nucleosides into free bases plus ribose/deoxyribose?
Nucleosidases
How can hyperuricemia occur?
- Overproduction or uric acid
2. Limited excretion (90% of cases)
Where does purine degradation occur?
Liver
What does allopurinol do and what is used to treat?
Inhibits xantine oxidase
Treats Gout
What are the 2 pathways AMP can become inosine?
- AMP – AMP deaminase –> IMP – 5’nucleotidase–> Inosine
2. AMP –5’nuclotidase–> Adenoside – Adenosine deaminase –> Inosine
What does inhibition of adenosine deaminase lead to?
Why?
SCID
Used to make inosine and deoxyinosine; high levels of dATP inhibits ribonucleotide reductase which reduces DNA synthesis and low lymph count; high levels of deoxyadenosine levels may also be toxic
What can an AMP deaminase deficiency lead to?
Why?
- Skeletal muscle myopathy
- Excercise-induced fatigue/cramps
- Asymptomatic
Function only in skeletal muscle and selective for only AMP (not dAMP)
building nucleotides from bases/nucleosides (energetically advantageous)
Nucleotide salvage pathways
What enzyme facilitates free base to nucleotide by adding phosphoribose using PRPP
What takes adenine to AMP?
What takes Guanine/hypoxanthine to IMP/GMP?
phosphoribosyl transferases
Adenine phosphoribosyltransferase (APRT)
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
What enzyme converts a purine nucleoside into purine + ribose 1-phosphate?
Purine nucleoside phosphorylase
What does a deficiency of purine nucleoside phosphorylase lead to?
T-cell immunodeficiency
Decreased salvage of hypoxanthine and guanine and increased levels of PRPP
Lesch-Nyhan syndrome
What are some factors that increase PRPP synthetase?
- Increased levels of PRPP
- Increased glutamine phosphoribosyl amidotransferase activity
- Increase in production of 5-phosphylribosyl 1-amine and nt
What disease is from a deficiency of glucose-6-phosphatase?
Von Gierke disease
How does Von Gierke disease contribute to gout uric acid overproduction?
G6P shunted to PPP pathway stimulates more nt synthesis
X-linked recessive disorder with a deficiency of HGPRT
- neurological/behavioral abnormalities; gout
Lesch-Nyhan Syndrome
What can you use to treat gout?
Acute gout: anti inflammatory agents, colchicine (for symptoms)
Chronic gout:
Allopurinol/Febuxostate- inhibit xanthine oxidase
Pegloticase/Rasburicase- convert uric acid to soluble allantoin
Probenecid, Lesinurad- promotes renal excretion of uric acid
Why do cancer patients undergoing treatment have high levels of uric acid? What is this called?
Tumor Lysis Syndrome
- destruction of tumor cells/nucleic acid
Treat with allopurinol or Rasburicase
What 2 AA and byproduct are needed for pyrimidine synthesis?
- Glutamine
- Aspartate
- CO2
Which synthesis has ribose 5-phosphate backbone added later?
Pyrimidine
What enzyme is used to convert glutamine and CO2 to carbamoyl phosphate?
Carbamoyl Phosphate Synthetase II (CPS II)
What is carbamoyl phosphate inhibited by and activated by?
- UTP
+ PRPP
What enzyme converts carbamoyl phosphate and asparatate to carbamoyl aspartate?
Aspartate transcarbamoylase
What enzyme converst dihydroorotate to orotate?
Dihydroorotate dehydrogenase
Mutations in UMP Synthase results in poor growth, anemia, and high levels of orotic acid in urine due to lack of pyrimidines
Orotic Aciduria
What is the committed step in pyrimidine synthesis?
CPS II
What are the products of purine degradation
Malonyl CoA and Methylmalonyl CoA
What cofactor is needed by ribonucleotide reductase?
Thioredoxin
What is an anti-tumor compound that inhibits ribonucleotide reductase?
Hydroxyurea
What drug permanently binds thymidylate synthase?
5-Fluorouracil
What drug negatively inhibits PRPP amidotransferase and inhibits AMP and GMP production from IMP?
6-Mercaptopurine
What drug inhibits dihydroorotate dehydrogenase?
Leflunomide
