Chapter 18: Purine and Pyrimidine Metabolism Flashcards
Ribose 5 phosphate uses what enzymes, etc to create PRPP?
ribose 5-P uses addition of pyrophosphate from ATP and PRPP synthetase to create PRPP (phosphoribosyl pyrophosphate)
Cells synthesize nucleotides in what 2 ways?
- de novo synthesis
- salvage pathway
Where does de novo synthesis of nucleotides occur?
What organ?
predominantly in the liver
What is a nucleoside?
consisting of a purine or pyrimidine base linked to a sugar.
Explain de novo synthesis of purines and pyrimidines.
purines and pyrimidines are synthesized from smaller precursors, and PRPP is added to the pathway at some point
Explain the salvage pathway in synthesis of nucleotides.
preformed purine and pyrimidine bases can be converted into nucleotides by salvage enzymes distinct from those of de novo synthesis
Where do purine and pyrimidine bases for salvage enzymes arise from in the salvage pathway?
- synthesis in the liver and transport to other tissues
- digestion of endogenous nucleic acids (cell death, RNA turnover)
Which pathway, de novo or salvage, is most essential for adequate nucleotide synthesis?
salvage pathway
What is the absent or deficient enzyme in Lesch Nyhan disease?
hypoxanthine guanine phosphoribosyl pyrophosphate transferase, (HGPRT)
aka (HPRT)
What are some symptoms of Lesch Nyhan disease?
CNS deterioration,
intellectual disability,
and spastic cerebral palsy
associated with compulsive self mutilation (biting of hands and lips)
hyperuricemia
death usually in first decade
Why do patients have CNS dysfunction with Lesch-Nyhan disease?
cells in the basal ganglia of the brain (fine motor control) normally have very high HGPRT activity
Why do patients with Lesch-Nyhan disease have hyperuricemia?
because purines cannot be salvaged causing gout
Draw out a diagram for nucleotide synthesis by salvage and de novo pathways.
Refer to diagram
Pyrimidines are synthesized de novo in what part of the cell?
cytoplasm
Where is CPS I located in cells compared to CPS II?
CPS I in the mitochondria of cells while CPS II is in the cytoplasm
What can be added to an infants formula to aid in UMP synthase deficiency?
uridine
Orotic aciduria inheritance pattern?
AR
How does addition of uridine to baby formula help relieve orotic acid formation in the urine of an infant with orotic aciduria?
uridine is salvaged to UMP, which feedback-inhibits carbamoyl phosphate synthetase -2, preventing orotic acid formation
DD of orotic aciduria with hyperammonemia (no megaloblastic anemia). Name the pathway involved and the deficient enzyme.
Pathway: urea cycle
Enzyme deficient: OTC
What is the DD of orotic aciduria with megaloblastic anemia (no hyperammonemia). Name the pathway and enzyme that is deficient.
Pathway: pyrimidine synthesis
Enzyme deficient: UMP synthase
DD of megaloblastic anemia with no orotic aciduria?
folate or B12 deficiency
Be able to create a diagram for de novo pyrimidine synthesis. (include where antineoplastic drugs work)
Refer to diagram
Cotrimoxazole is a mix of what antibiotics that act synergistically?
sulfamethoxazole and trimethoprim
What enzyme does sulfamethoxazole inhibit?
dihydropteroate synthase (we don’t have this enzyme we need folic acid from diet.)
What enzyme does trimethoprim inhibit?
bacterial dihydrofolate reductase (DHFR),
Draw out a schematic on bacterial transformation of PABA to THF.
What is the function of ribonucleotide reductase?
reduces all NDPs to dNDPs for DNA synthesis
What is the function of thymidylate synthase?
methylates dUMP to dTMP
What is the function of dihydrofolate reductase? Synthesis of what product would stop without this enzyme?
converts DHF to THF without DHFR, thymidylate synthesis will eventually stop
What does thymidylate synthase require to work?
requires THF
Drugs that inhibit ribonucleotide reductase?
hydroxyurea (S phase)
Drugs that inhibit thymidylate synthase?
5-fluorouracil (S phase)
Drugs that inhibit DHFR?
Methotrexate (eukaryotic) (S phase)
Trimethoprim (prokaryotic)
Pyrimethamine (protozoal)
What are some nucleotide substrates that inhibit ribonucleotide reductase?
dADP and dATP
Draw out a diagram on ribonucleotide reductase inhbitors and function specifically.
Refer to diagram
Describe pyrimidine catabolism.
may be completely catabolized (NH4+ is produced) or recycled by pyrimidine salvage enzymes
What is the most important enzyme in de novo purine synthesis?
PRPP amidotransferase
PRPP amidotransferase is inhibited by what 3 purine nucleotide end products?
AMP, GMP, and IMP
What are some drugs that inhibit PRPP amidotransferase?
allopurinol and 6-mercaptopurine
Allopurinol and 6-mercaptopurine are purine or pyrimidine analogs?
purine analogs
The drugs, allopurinol and 6-mercaptopurine are purine analogs which must be converted to their respective nucleotides by what enzyme in cells?
HGPRT
Create a diagram on the de novo synthesis of purines.
refer to diagram
Why are protozoan and multicellular parasites and many obligate parasites, such as Chlamydia, not able to synthesize purines de novo.
Because they lack the genes in the purine pathway necessary to do so
Therefore have elaborate salvage mechanisms for acquiring purines from the host
What amino acids are used in purine synthesis?
glycine, aspartate, and glutamine
Is THF required for synthesis of purines?
yes
IMP stands for what?
inosine monophosphate
IMP contains what purine base?
hypoxanthine
Hypoxanthine is the precursor for what purine bases?
AMP and GMP
Create a diagram on purine excretion and salvage pathways.
Refer to diagram
What are times when excess nucleoside monophosphates may accumulate?
- RNA is normally digested by nucleases (mRNAs and other types of RNAs are continuously turned over in normal cells
- Dying cells release DNA and RNA, which is digested by nucleases
- The concentration of free Pi decreases as it may in galactosemia, hereditary fructose intolerance, and glucose-6-phosphatase deficiency
