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45 Cards in this Set
- Front
- Back
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What are the purine bases?
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-Adenine
-Guanine - Hypoxanthine |
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What are the pyrimidine bases?
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- Cytosine
- Thymine - Uracil |
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Where is the primary site of de novo synthesis of nucleotides?
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Liver and bone marrow
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What is the structure of nucleosides?
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- Base with a sugar
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What is the structure of a nucleotide?
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- Base + sugar + phosphate (1-3)
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In purines are the base or sugar built first?
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Sugar (ribose)
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What are the 2 enzymes involved in Purine Synthesis I?
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- PPRP Synthetase
- Glutamate PPRP Amido-transferase (committed step) |
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How is PPRP Synthetase (of purine synthesis I) regulated?
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- Inhibited by ADP/GDP or variants
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How is Glutamate PPRP Amido-transferase (of Purine Synthesis I) regulated?
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- Inhibited by GMP/AMP/IMP
- Increased by PRPP |
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What is the product of Purine Synthesis II?
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- IMP
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What is required to convert IMP to GMP?
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- ATP hydrolysis
- NH3 from Gln - IMP dehydrogenase and GMP Synthase - GMP negatively inhibits |
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What is required to convert IMP to AMP?
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- GTP hydrolysis
- NH3 from Asp - Adenylsuccinate Synthase and Adenylsuccinase - AMP negatively inhibits |
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What promotes the active form of PRPP? the inactive form of PRPP?
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- Active: high amounts of PRPP
- Inactive: high amounts of IMP/GMP/AMP |
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What enzyme is responsible for the conversion of free Guanine to GMP?
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- HGRT
- Uses PRPP - Negatively inhibited by GMP |
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What enzyme is responsible for the conversion of free Adenine to AMP?
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- APRT
- Uses PRPP - Negatively inhibited by AMP |
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What enzyme is responsible for the conversion of free hypoxanthine to IMP?
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-HGPRT
- Uses PRPP - Negatively inhibited by IMP |
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What are the general steps of purine base degradation?
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1) converted to nucleosides by nucleotidases
2) converted to free bases by phosphorylase 3) converted to Xanthene by oxidase 4) converted to Uric Acid by Xanthene Oxidase 5) excreted |
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How does the degradation of AMP differ from GMP/IMP?
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AMP breaks down into its nucleoside then converts to Inosin via Adenosine Deaminase
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SCIDS is caused by?
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- Defect in Adenosine Deaminase
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What are the symptoms of SCIDS?
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- no T or B cells (no immunity)
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What causes hyperuricema/gout?
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- Increased purine nucleotide degradation (MI or chemo)
- Reduced uric acid excretion (starvation, diabetic ketoacidosis) - Inborn enzyme deficiencies in purine metabolism |
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What are symptoms of gout?
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Hyperuricemia
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What specific enzymes problems could cause gout?
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- PRPP synthetase
- PRPP amido-transferase (both these defects prevent feedback inhibition so excess uric acid is created) |
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What are treatments for gout?
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- Allopurinol: inhibits Xanthine oxidase to suppress synthesis of uric acid
- Uricosuric agents: increase urinary excretion of uric acid - Anti-inflammatories/ oral corticosteroids - PEG-uricase: oxidation of uric acid to more soluble form (expensive, may have severe allergic reaction) |
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What enzyme is deficient in Lesch-Nyan Syndrome?
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- HGPRT
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What are the symptoms of Lesch-Nyan Syndrome?
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- Hyperuricemia
- Anemia -Neuropathy (chewing fingers/toes, aggression) - Nephropathy (obstructive kidney disease) - Mental/growth retardation |
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What metabolites are increased/decreased in Lesch-Nyhan Syndrome?
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- Increased: PRPP
- Decreased: IMP/GMP |
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What enzyme is deficient in SCID?
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- Adenine Deaminase
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What metabolites increase/decrease in SCID?
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- Increase: ATP and dATP
- Decrease: any other dNTP |
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What are the symptoms/results of SCID?
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- DNA synthesis is suppressed
- No T or B cells = no immune |
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What enzyme is deficient in Xanthinuria?
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Xanthine oxidase
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What metabolites are increased/decreased in Xanthinuria?
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- hyperxanthinuria
- hypouricemia - xanthine renal lithiasis |
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What enzyme is defective in Von Gierke's Disease?
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- Glucose-6-Phosphatase
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What is the result of the defective enzyme in Von Gierke's Disease?
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- Increase of flux through pentose phosphate pathway, which increases ribose-5-P and PRPP
- this stimulates production of purines and thus the production of uric acid |
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What are the symptoms of Von Gierke's Disease?
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- Hyperuricemia
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In the synthesis of pyrimidine is the base or ribose synthesized first?
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- base (then add on sugar)
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What are the 3 enzymes associated with pyrimidine synthesis?
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- Carbamoyl Phosphate Synthetase II (CPSII, regulated step)
- UMP Synthase (PRPP cofactor) - CTP Synthase |
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How is CPSII regulated in pyrimidine synthesis?
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- Inhibited by UMP
- Increased by PRPP |
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How is UMP Synthetase regulated?
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- Inhibited by UMP
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How is CTP Synthase regulated?
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- Inhibited by CTP
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What is hereditary orotic aciduria caused by?
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- Defect in UMP Synthetase
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What are symptoms of Hereditary Orotic Aciduria?
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- Orotic aciduria
- Orotic acid crystalluria - kidney disease decrease in dCTP and dTTP synthesis= megoblastic anemia - increased excretion of pyrimidine precursors - Immune dysfunction, growth deficiency, skeletal weakness, developmental delay (possible) |
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What are some potential causes of Hereditary Orotic Aciduria other than defective enzyme?
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- Hyperammonemia
- Arginine deficiency - Lysine toxicity - Fatty liver b/c alcoholism |
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Why would Nucleotide analogs be important anti-cancer drugs?
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- Cancer/tumor cells grow more rapidly than normal cells are are more sensitive to DNA changes
- Analogus prevent DNA polymerization |
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How does affinity play a role in Nucleotide analogs and medication?
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- Some nucleotide analogs have a higher affinity for specific viral enzymes over human enzymes
- are more specific for HIV/Herpes than human |
