nucleotide 1

Question 1

1. Identify the key elements of the structures of purines and pyrimidines and give examples of each.

Answer 1

ribose sugar, rings structures, 3’OH

Purines- AG
Pyrimidines- CTU

Question 2

2. List two key differences between the synthesis of purine and pyrimidine nucleotides.

Answer 2

1. purines are made on the ribose sugar, initial nucleotide product is IMP I is then converted to G and A as a monophosphate
2. pyrimidines a base ring is syntheisized and then attached to a ribose sugar, initial nucleotide is UMP, U is converted to C as a triphosphate

Question 3

3. Name the key regulated steps and feedback loops within the de novo purine synthesis

Answer 3

1. ribose 5 P–>PRPP, PRPP Synthetase
   - purines down regulate this, Pi upregulates it
2. PRPP —> 5’-ribophophosylamine, Glutamine-PRPP-amido transferase. AMP, GMP, IMP inhibit it, PRPP activates it
3. Ends in IMP
4. IMP–> AMP by adeno succinate synthetase etc, uses GTP, inhibited by AMP
   IMP–>GMP by IMP dehydrogenase, uses ATP, inhibited by GMP
5. Kinases get GMP and AMP to GDP and ADP
   - ATP is the P donor in both
6. Kinases get from GDP and ADP to GTP and ATP by dinucleoside kinases that also uses ATP

Question 4

4. Identify the enzyme that reduces ribose to deoxyribose, describe the strategy this enzyme uses for catalysis, and name its substrates.

Answer 4

ribonucleotide reductase

uses Thioredoxin (similar to glutathione) to reduce the RNA to DNA and then regenerates itself by NADPH and thioredoxin reductase

• on/off switch- process inhibited by deoxyATP (end product inhibition, activated by ATP
• there is a specific site on the enzyme for each nucleotide

Question 5

5. List the enzyme deficiencies and describe the pathophysiology of: Gout, Severe Combined immunodeficiency syndrome, and Lesch-Nyhan syndrome.

Answer 5

Gout- too much uric acid is being made, so drugs like allopurinol inhibit xanthine oxidase to decrease uric acid production

SCID–>Adenonsine or deoxy adenosine can tbe broken down to inosine by adenosine deaminase, causing build up of dATP which inhibits ribonucleoside reductase, which turns it off and disallowes DNA base synthesis

• -> rapidly tuening over cells are affected like T and B cells
• -> treatment is gene therapy

Lesch Nyhan- taking guanine back to GMP or hypoxanthine to IMP uses Hypoxanthine-Guanine PRPP transferase. this XLR dirorder, creates inability to recyle and excess uraic acid production
-neurological issues, chorea, and self mutilation

Question 6

6. Describe how 5-fluorouracil and similar drugs inhibit nucleotide synthesis.

Answer 6

they disable the ability to make dTMP from dUMP because they inhibit thymidilate synthase

Question 7

A 6 year old child presents to clinic for evaluation of mental retardation, uric acid kidney stones, self mutilating behavior, pain and swelling of his joint. This disorder is the result of which of the following?

A. Failure to break down pyrimadine bases
B. Failure to recycle/salvage purine bases
C. A defect in the synthesis of pyrimadine bases
D. Inhibition of the conversion of ribo-nucleosides to deoxyribonucleosides

Answer 7

B. Failure to recycle/salvage purine bases

Question 8

sources of atoms for purine synthesis

Answer 8

Glutamine, glycine, aspartate, THF, CO2

Question 9

3. Name the key regulated steps and feedback loops within the de novo pyrimidine synthesis pathways.

Answer 9

1. CO2 + Glutamine + 2 ATP–> Carbamoyl Phosphat, by carbamoyl phosphate synthetase 2 (cytosol)
2. Through a number of steps we get UMP
   - inhibited by UTP, activated by ATP and PRPP
3. UMP–>UTP, by two kinases using ATP
4. UTP–> CTP, by CTP synthetase using ATP and Glutamine as the amine donor

Question 10

3. Name the key regulated steps and feedback loops within the purine degradation pathways.

Answer 10

starts with AMP or GMP and ends with uric acid

1. AMP can be turned to IMP or Adenosine
2. GMP-> Guanosine->Guanine-> Xanthine
3. Adenosine becomes Inosine by Adenosine Deaminase. (SCID)
4. IMP also becomes Inosine
5. Inosine goes to Hypoxanthine
6. Hypoxanthine becomes xanthine by xanthine oxidase
7. xanthine–> uric acid by xanthine oxidase as well (target for allopurinol)

Question 11

3. Name the key regulated steps and feedback loops within the pyrimidine degradation pathways.

Answer 11

T–> succinyl coa
C–> malonyl coa
U–> acetyl coa

Question 12

sources of atoms for Pyrimidine synthesis

Answer 12

PRPP, CO2, glutamine, aspartate, ribose sugar added last

Question 13

how to get from dUMP–> to dTMP

Answer 13

Thymidylate synthase using THF as the methyl donor

inhibited by 5-flourouracil

DHF reductase recycle the THF, that is inhibited by methotrexate