Purine and Pyrimidine Metabolism

Question 1

What creates a nucleotide?

Answer 1

Base, sugar, phosphate groups
N-glycosidic bond
Phosphoric acid ester bond
and phosphoric acid anydride bonds

Question 2

Define nucleoside, nucleotide and deoxynucleotide

Answer 2

a. sugar and the base
b. sugar, base and phosphate
c. deoxyribose sugar, base and phosphate (loss of O)

Question 3

What breaks up the RNA polymers into short oligomers?

Answer 3

Ribonucleases

Question 4

What breaks up the DNA polymers into short oligomers?

Answer 4

Deoxyribonucleases

Question 5

Short DNA oligomer is unable to be broken down into a nucleotide monophosphates. What enzyme is defective?

Answer 5

Phosphodiesterase

Question 6

What breaks down nucleotides into base and sugar?

Answer 6

First nucleotidase and then nucleosidase

Question 7

What are “sulfa” drugs?

Answer 7

Antibacterial agents in the sulfonanilamide family act as a competitive inhibitor of the bacterial enzyme that incorporates PABA into folate. This inhibition disrupts DNA replication in bacteria. Wont effect humans bc they acquire folate as a vitamin

Question 8

How can methotrrexate be helpful but also harmful in humans?

Answer 8

It targets dihydrofolate reductase that converts dietary folate to tetrahydrofolate in the liver. This inhibition disrupts DNA replication in rapidly dividing cancer cells. But the drug can also attack normal cells

Question 9

What is the metabolic end point in the catabolism (oxygen added to a molecule to make it more polar) of purines and in most oxidized member of the common purines?

Answer 9

Uric acid: has an acidic hydrogen and limited aqueous solubility. The limited solubility of urate is a factor that plays a key role in gout

Question 10

How does the inhibition of IMP dehydrogenase used for preventing graft rejection?

Answer 10

By inhibiting IMP dehydrogenase, it disrupts the DNA replication in B and T cells by depriving them of adequate supplies of GMP and hence dGTP

Question 11

What is needed to convert a nucleotide diphosphate into a 2-deoxynucleotide diphosphate?

Answer 11

NADPH and ribonucleotide reductase

Question 12

What important molecules can nucleotides contribute to?

Answer 12

Coenzyme A
NAD
FAD

Question 13

What does ADA play a role in?

Answer 13

ADA (adenosine Deaminase) plays an important role in adensoine homeostasis and modulates signaling by extracellular adenosine.

Question 14

What happens when there is an over production of ADA?

Answer 14

An erythrocyte form - causes hemolytic anemia (rare). increased degradation of adenosine depletes adenine nucleotide pool and triggers premature destruction of RBCs

Question 15

What happens when there is an underproduction of ADA?

Answer 15

SCID: severe combined immunodeficiency
Results in high amounts of adenosine which is then converted into dATP, high levels bloc synthesis of all other dNDP’s and dNTPs. Impaired DNA synthesis and compromised immune system

Question 16

What role does xanthine oxidase play?

Answer 16

Catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid

• has two FADs, 2 Mo atoms, and 8 Fe
• drug target for gout

Question 17

What is a “bubble boy”?

Answer 17

SCID: Patients need to be protected from environment
Fatal genetic disorder in which B and T cells are defective
Most commonly X-linked; males
Mutations affect a protein needed by receptor for ILs involved in development and differentiation of both cells

Question 18

Patient has intense pain and inflammation of the 1st metatarsal pharangeal joint. Diagnosis

Answer 18

Gout

Question 19

What is the cause of gout symptoms?

Answer 19

overproduction of uric acid (primary hyperuricemia)
Under-excretion of uric acid (secondary)
Sodium urate crystals precipitate in synovial fluid of joints = pain
Phagocytic cells engulf crystals and release factors that initiate an acute inflammatory response

*deposits in kidney can cause kidney damage

Question 20

What type of lifestyle causes gout?

Answer 20

Diet rich in purines (beans, lentils, spinach) together with meat, seafood, and alcohol

• beer has elevated purine
• alcohol metabolism increases uric acid production

Question 21

What is the treatment of gout?

Answer 21

colchicine (decreases movement of granulocites to the affected area) and allopurinol that inhibits xanthine oxidase

• probenecid - increases excretion of uric acid
• urate oxidase - converts uric acid to soluble allantoin

Question 22

What nucleotide can be catabolized to form Malonyl CoA?

Answer 22

Ketogenic uracil

Question 23

What nucleotide can be catabolized to form succinyl CoA and Methylmalonyl CoA?

Answer 23

Thymine: glucogenic

Question 24

What are the sources of ring atoms of purine bases?

Answer 24

CO2, Gln, Gly, Asp, formyl THF

Question 25

What are the sources of ring atoms of pyrimidine bases?

Answer 25

HCO3-, Gln, Asp, N5, N10-methylene THF

Question 26

What are the purine bases?

Answer 26

Adenine, Guanine, Xanthine, Hypoxanthine

Question 27

What are the pyrimidine bases?

Answer 27

Cytosine, Thymine, Uracil, Orotate

Question 28

What is the committed step in purine synthesis?

Answer 28

The formation of the pohsphoribosyl amine

Question 29

What are two salvage enzymes of purine biosynthesis?

Answer 29

Hypoxanthine guanine phosphoribosyl transferase

Adenine phosphoribosyl transferase

Question 30

What molecule begins the purine biosynthesis De Novo?

Answer 30

Alpha D-ribose 5-phosphate from the pentose pathway

Question 31

What are the major products of the De Novo synthesis of purine nucleotides?

Answer 31

Fumerate
IMP
AMP
GMP

Question 32

What is the pyrimidine ring synthesized from?

Answer 32

Carbamoyl phosphate and aspartate by aspartate-transcarbamoylase
*committed step

Question 33

The pyrimidine ring reacts with PRPP which is catalyzed by what?

Answer 33

Orotate phosphoribosyl transferase

*disease Orotic aciduria

Question 34

What is the immediate hydrogen donor for the reduction of robonucleoside diphosphate into deoxyribonucleotide?

Answer 34

Thioredoxin or glutaredoxin

Question 35

The synthesis of purine nucleotides is controlled with what feedback inhibition?

Answer 35

IMP, AMP, GMP

Question 36

What are two major control points of pyrimidine biosynthesis?

Answer 36

Carbamoyl phosphate synthetase is inhibited by UMP and purines and stimulated by PRPP
Aspartate transcarbamoylase is feedback inhibited by CTP

Question 37

Concentration of what dNTP is the limiting factor of DNA synthesis?

Answer 37

dTTP

Question 38

Describe the adenine salvage pathway

Answer 38

Adenine+ PRPP converted to AMP

• Enzyme APRT
• Disease: Renal lithiasis

Question 39

Describe the guanine or hypoxanthine salvage pathway

Answer 39

guanine/hypoxanthine + PRPP = GMP or IMP

Enzyme: HGPRT

Question 40

What causes Lesch-Nyhan syndrome?

Answer 40

Defect in HGPRT enzyme in purine salvage pathway. There is an overproduction of uric acid

Question 41

What are the symptoms of Lesh-Nyhan syndrome?

Answer 41

Patients have primary hyperuricemia and hyperuricosuria (leading to gout)
Urate kidney stones, poor muscle control, mental retardation and tendency of self mutilation

Question 42

What is the function of thymidine kinase?

Answer 42

phosphorylates the nucleoside dT to generate dTMP using ATP as a phosphoryl donor

Question 43

What does acyclovir cause?

Answer 43

It resembles guanine rather than dT and undergoes phosphorylation by viral thymidine kinase at a rate that exceeds that of cellular thymidine kinase
Viral thymidine kinase converts acyclovir to acyclo GMP. Acyclo GMP is converted to acyclo GTP which is incorportated into DNA and terminates replication