Purine and Pyrimidine Metabolism

Question 1

Purine de novo synthesis: Sources of atoms

Answer 1

The atoms that make up purine bases come from:

1. Amino Acids (aspartate, glycine and glutamine),
2. CO2
3. N10-formyltetrahydrofolate.

Purines are synthesized by building the base directly on the ribose sugar.

Uses PRPP

Question 2

Purine de novo synthesis: Key co-factors

Answer 2

1. Ribose 5-phosphate is formed via HMP shunt
2. PRPP is synthesized from ribose 5-phosphate and ATP
   a. Cofactor: Magnesium
   b. PRPP synthetase catalyzes the reaction
   c. ATP
3. 5’-phosphoribosylamine is synthesized from PRPP and glutamine. RATE-LIMITING STEP
   a. Cofactor: Magnesium
   b. Glutamine:phosphoribosyl pyrophosphate amidotransferate. Inhibited by the end products of synthesis

*AMP, GMP, IMP. Activated by PRPP

4. IMP (inosine mono-phosphate). XXXXXXXXXXXXXXXXXXXXXXXXX

Question 3

Purine de novo synthesis: Sources of energy

Answer 3

ATP

Question 4

Pyrimidine de novo synthesis: Sources of atoms

Answer 4

The atoms that make up pyrimidine bases come from

1. Amino Acids (glutamine, aspartate),
2. CO2
3. N10-formyltetrahydrofolate.

Pyrimidines are synthesized by building the base de novo and then attaching it to a ribose sugar.

Uses PRPP

Question 5

Pyrimidine de novo synthesis: Key cofactors, enzymes and energy sources

Answer 5

1. Carbamoyl phosphate is synthesized from glutamine, CO2 and 2 ATP.
   a. Carbamoyl phosphate synthetase II is the enzyme and it is inhibited by UTP and activated by ATP and PRPP.
   b. Energy source: 2 ATP
   c. Key regulated step
2. A series of steps follows with the end product being UMP.
   a. Cofactors: NAD+
   b. PRPP serves as the ribose 5-phosphate donor
3. UMP is phosphorylated to UTP.
4. CTP is produced by the deamination of UTP by CTP synthetase

Question 6

Regulation of key steps in purine synthesis

Answer 6

Key step is first step

PRPP and glutamine are used to add Nitrogen to PRPP

IMPs, GIMPs and AMPs (end products) inhibit the first step

Question 7

Regulation of key steps of pyrimidine synthesis

Answer 7

Key step is first step

CPS-2 is activated by PRPP and inhibited by UTP

Question 8

Describe the pathophysiology and clinical presentation of Gout

Answer 8

Purine degradation disorder

Question 9

Describe the pathophysiology and clinical presentation of SCID

Answer 9

Adensosine aminotransferase deficiencies

Step in nucleic acid degredation, will have build of of d-ATP in the blood. Inhibits DNA synthesis, so cells that are rapidly synthesizing DNA (ie immune cells) die

Question 10

Describe the pathophysiology and clinical presentation of Lesch-Nyhan

Answer 10

Can’t use recycling of purines, have to use denovo synthesis

HGPRT deficiency

Can’t salvage guanine. Rely on denovo syntheses, which leads to buildup of PRPP

Question 11

Describe the overall pathways of purine breakdown (source of carbons, products, key intermediates and key steps)

Answer 11

Degraded and excreted by the intestine

Remove base from sugar leaving free base. Base is broken down to uric acid to be excreted (renally)

Question 12

Describe the overall pathway of pyrimidine breakdown (source of carbons, products, key intermediates, key steps)

Answer 12

Degraded and excreted by the intestine

Remove base from sugar, but open up base ring and break it down into “stuff” like succinyl-CoA, malonyl-coA, acetyl CoA

Question 13

Describe how 5-fluorouracil and similar drugs inhibit nucleotide synthesis

Answer 13

Targets folate metabolism (anti-cancer)

Question 14

Da basic differences between Purine and Pyrimidine de novo synthesis

Answer 14

Purines:
Purine base is made on the ribose
Initial nucleotides product is IMP
I is converted to G and A as a monophosphate

Pyrimidines:
Base ring is synthesized then attached to the ribosome
Initial nucleoside product is UMP
U is converted to C as a triphosphate