Purine/Pyrimidines

Question 1

What is 6-mercaptopurine used for?

Function

Answer 1

Treat some forms of leukemia.

Fx: inhibition of the purine biosynthetic pathway which is needed for formation of nucleotides and thus production of DNA/RNA.
Slows proliferation

A reduced dose must be given to homozygous genetic variants or they will overdose

Question 2

PRPP Synthetase function

Answer 2

Synthesis of PRPP for purine and pyrimidine nucleotide synthesis

Question 3

Phosphoribosyl amidotransferase

Answer 3

Regulated/committed enzyme of purine nucleotide synthesis.
Activators: PRPP
Inhibitors: ATP and GTP

Question 4

Xanthine Oxidase

Answer 4

Enzyme of purine degradation. Forms uric acid and xanthine from hypoxanthine

Inhibitor: Allopurinol

Question 5

HGPRT

Hypoxanthine Guanine Phosphoribosyl Transferase

Answer 5

Enzyme of Purine salvage pathway.
Deficiency causes: Lesch Nyhan Syndrome-self mutilation, hyperuricemia

Salvage pathway important for brain as it uses less energy

Question 6

CPS-II

Answer 6

Regulated enzyme of pyrmidine biosynthesis

Inhibited by: UTP
Activated by: PRPP, cytosolic enzymes

Question 7

UMP Synthase (OPRT and OMP decarboxylase)

Answer 7

Enzyme of pyrmidine biosynthesis

Deficiency causes Orotic aciduria

Question 8

Ribonucleotide Reductase

Answer 8

Converts ribonucleotides to deoxyribonucleotides.

Inhibitor: Hydroxyurea

Requires Thioredoxin (protein coenzyme), NADPH+, H+

Regulated to ensure equivalent concentrations of dATP, dGTP, dCTP, and dUTP during S phase of cell cycle

Question 9

Adenosine Deaminase

ADA

Answer 9

Converts adenosine to inosine in purine degradation pathway.

Deficiency results in SCID (T and B cell deficiency)

Question 10

Purine nucleoside phosphylase (PNP)

Answer 10

Converts purine nucleoside to free purine base in purine degradation pathway.

Deficiency results in T-cell immunodeficiency

Question 11

How many carbon atoms come from tetrahydrofolate (folic acid) in purine nucleotide denovo synthesis?

Answer 11

2 C

Question 12

What are the precursors to purine de novo synthesis?

Answer 12

Amino Acids:
1. Glutamine
2. Aspartate
3. Glycine

Formyl Tetrahydrofolate (cofactor)

and CO2

Question 13

What is the first regulated step?

Purine de novo synthesis

Answer 13

Ribose phosphate to Phosphoriboysl pyrophosphate (PRPP) by
PRPP synthetase

Question 14

What is the committed step in denovo purine synthesis?

Answer 14

PRPP to Phosphoribosylamine by
Phosphoribosylamidotransferase

Question 15

What inhibits conversion of IMP to GMP?

Answer 15

Mycophenolic Acid by inhibiting IMP dehydrogenase

Used post transplantation to prevent rejection

Question 16

How do humans obtain folate (Vit B9)

Answer 16

From our diet

It is essential for DNA synthesis during S phase and critical for rapidly dividing cells

IF deficient: Macrocytic anemia and decreased cell division.
Higher risk of neural tube defects

Question 17

What is uric acid and why is it important to know?

Answer 17

End product of purine breakdown
Has a low solubility which then can cause deposits (tophi) that can cause gouty arthritis, renal stones…

Blood uric levels are close to saturation limits

Question 18

Hyperuricemia two causes

Answer 18

1. Underexcretion-most common. Due to males/obesity/beer/meat, renal disease, lactic acidosis, inherited disorders (Von Gierke disease, Hereditary Fructose Intolerance)
2. Overproduction: Overactive enzyme (PRPP synthetase gene mutation where enzyme actually works better). HGPRT Deficinecy- Lesch Nyhan syndrome-less recycling which causes increase in PRPP. Lastly, chemotherapy patients

Question 19

Gout

Causes/Treatment

Answer 19

Hyperuricemia: underexcretion leads to deposition of monosodium urate crystals=acute athritic joint pain

Tx: allopurinol inhibits xanthine oxidase. Increased levels of hypoxanthine and xanthine which are more soluble and can be excreted in urine

Question 20

Adenosine Deaminase Deficiency (ADA)

Answer 20

Autosomal recessive cause of SCID.

If untreated kids die before age 2 d/t overwhelming infection

Question 21

Purine Nucleoside Phosphorylase Deficiency (PNP)

Answer 21

Autosomal recessive

T-cell deficiency
Therapy: Erythrocyte transfusion Hematopoietic stem cell transplant

Question 22

When are primidine rings synthesized?

Answer 22

Pyrmidine rings are initially synthesized before attachment to the ribose-5-phosphate (donated by PRPP)
No folic acid is required to make the ring however later in the synthesis thmidine requires one-carbon group donation from methylenetetrahydrofolate (THF)

Question 23

What is the regulation of Pyrmidine Synthesis?

Answer 23

CPS II domain-activated by PRPP and ATP
Inhibited by: UTP

CPS I is in Urea Cycle

Question 24

What is the regulated domain of bacterial prymidine nucleotide synthesis?

Answer 24

Aspartate transcarbamoylase

Question 25

How do you differentiate between orotic aciduria d/t to Urea Cycle defect or prymidine biosynthesis defect?

Answer 25

Check blood ammonia levels

Question 26

What is the only pyrmidine that needs methylene thetrahydrofolate?

Answer 26

dTMP