Ch. 25 Nucleotide Metabolism

Question 1

Lesch-Nyhan Syndrome

Answer 1

X linked
No HGPRT -> Can’t do salvage pathway Hypoxanthine to IMP and Guanine to GMP -> accumulate PRPP -> shunted toward de novo synthesis -> increase purine nucleotide sun via de novo -> increase uric acid formation -> hyperuricemia
Signs: CNS abnormalities (mental retardation)

Question 2

Adenine Phosphoribosyltransferase (APRT) Defiency

Answer 2

Autosomal Recessive
Salvage pathway
Unable to salvage adenine to AMP -> increase adenine -> oxidized to 2,8 dihydroxyadenine by XO -> excrete as insoluble material (gravel)
Treatment: allopurinol + low-purine diet

Question 3

Adenosine Deaminase (ADA) Deficiency

Answer 3

Autosomal Recessive
Purine Catabolism
No ADA -> no adenosine to inosine -> accumulate adenosine -> increase dATP -> inhibit ribonucleotide reductase -> decrease dNTP production -> SCID (B/T lymphocyte destruction)

Question 4

Purine Nucleoside Phosphorylase (PNP) deficiency

Answer 4

Autosomal Recessive
Purine Catabolism
No PNP -> accumulate GMP, GDP, GTP -> inhibit ribonucleotide reductase -> decrease dNTP production -> less severe immuno deficiecy (only T lymphocyte dysfunction)

Question 5

Myoadenylate (AMP) Deaminase Deficiency

Answer 5

Autosomal Recessive
Purine nucleotide cycle in exercising muscle
No AMP deaminase -> can’t convert AMP (adenylic acid) to inosinic acid (IMP)
Benign muscle disorder characterized by fatigue/exercise-induced muscle aches due to increase flux thru cycle during exercise

Question 6

Xanthine Oxidase Deficiency

Answer 6

Autosomal Recessive

No conversion of hypoxanthine to xanthine to uric acid -> accumulate hypoxanthine -> hypouricemia + hypoxanthuria

Question 7

What are pyrimidines used for?

Answer 7

DNA/RNA synthesis
Intermediary metabolism (glycogen/phospholipid synthesis)

Question 8

De Novo Synthesis of Pyrimidines

Answer 8

Step 1: Form UMP

Step 2: Form other pyrimidines from UMP

Question 9

Stage 1: Formation of UMP

Answer 9

Gln, ATP, CO2 -> Carbamoyl phosphate (CP synthetase II)
Carbamoyl + Asp ->Carbamoyl Asp (Asp transcarbamoylase)
-> Dihydroorotate (dihydroorotase)
-> orotate (dihydroorotate dehydrogenase)
-> orotidine 5’ monophosphate (orotate phosphoribosyl transferase)
-> UMP (orotidylate decarboxylase)

Question 10

3 genes involved in UMP formation

Answer 10

Cytosol multifunctional polypeptide (contains enzymes 1-3)
Inner mitochondrial membrane (enzyme 4)
UMP synthase in cytoplasm (enzyme 5-6)

Question 11

Stage 2: Formation of Other Pyrimidines

Answer 11

UMP + ATP => UDP + ADP (uridylate kinase)
UDP + ATP => UTP + ADP (nucleoside diphosphate kinase)

UTP + ATP + Gln => CTP + ADP + Glu (CTP synthase)

UDP => dUDP (ribonucleotide reductase) => dUTP (deoxyuridylate kinase) => dUMP (dUTPase) => TMP (thymidylate synthase)

Question 12

FUDRP

Answer 12

Inhibits thymidylate synthase
Anti-cancer
From exogenous 5-FU or FUDR

Question 13

Salvage Pathway of Pyrimidines

Answer 13

From dietary/exogenous sources

Pyrimidine + ribose 5P) => pyrimidine-ribose (phosphorylase) + ATP => pyrimidine-ribose-phosphate (kinase)

Question 14

Pyrimidine Analogs used to:

Answer 14

Can treat: Neoplastic disease, psoriasis, final infections, and DNA viral infections

Question 15

Cytarabine

Answer 15

Analog of 2’ deoxycytidine
Inhibit nucleic acid synthesis
Trans position of OH causes steric hindrance of base rotation

Question 16

6 azauridine & azarabine

Answer 16

Inhibit orotidylate decarboxylase => Inhibit UMP formation (pyrimidine synthesis)

Question 17

5-Azacytidine

Answer 17

Hypomethylation => Arrest DNA synthesis

Question 18

AZT (Azathymidine)

Answer 18

Inhibit viral reverse transcriptase

HIV drug

Question 19

Regulation of De Novo Pyrimidine synthesis

Answer 19

In Prokaryotes, Asp trans