Purine Metabolism

Question 1

What are the three sources of nucleotides?

Answer 1

1. Dietary (endogenous)

(Exogenous)

2. De Novo Pathway (produced in the liver primarily)
3. Salvage Pathway (energetically most favorable)

Question 2

4 Key Steps in Purine Synthesis

Answer 2

1. Ribose 5-phopsphate –> PRPP by PRPP synthetase
2. PRPP –> 5-phosphoribosyl amine
3. Stepwise generation of purine rings
4. Formation of IMP (which later becomes AMP + GMP)

Question 3

Purine is degraded into

Answer 3

Uric Acid

produced in the liver and is transported to the kidneys for excretion through urine.

Question 4

This disease causes monosodium urate crystals in joints resulting in a inflammatory response due to hyperuricemia from 1. underexcretion of uric acid by kidney and 2. increased PRPP synthetase activity

Answer 4

Gout

Question 5

Major regulated step in purine biosynthesis inhibited by High levels of end-product (AMP,GMP,IMP)

Answer 5

PRPP –> 5-phosphoribosyl amine

Question 6

IMP, AMP, XMP, and GMP inhibit which enzyme when they are expressed at high levels

Answer 6

Glutamine PR-Amidotransferase

Question 7

The committed step in the synthesis of purines is addition of the first N in the purine ring by which enzyme

Answer 7

Glutamine PR-Amidotransferase

Question 8

What pathway converts purine bases (A/G/H) into purine nucleotides (AMP/GMP/IMP)?

Answer 8

Salvage Pathway

Question 9

Adenine is converted to AMP via which enzyme?

Answer 9

Adenine phosphoribosyltransferase (APRT)

Question 10

Hypoxanthine and Guanine are converted to IMP and GMP respectively via which enzyme?

Answer 10

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

Question 11

What is the disorder that is x-linked and is due to absence of HGPRT that leads to decreased salvage of hypoxanthine and guanine and increased levels of PRPP?

Answer 11

Lesch-Nyhan syndrome

Question 12

High levels of AMP, GMP, or IMP negatively inhibit feedback of what enzyme by shifting it to inactive dimer form?

Answer 12

Glutamine Phosphoribosyl amidotransferase (rate limiting enzyme)

Question 13

High levels of PRPP shift what enzyme to its active monomer form?

Answer 13

Glutamine Phosphoribosyl amidotransferase (rate limiting enzyme)

Question 14

T/F: Glutamine phosphoribosyl amidotransferase gets inhibited even greater in the presence of AMP plus GMP or IMP because there are distinct regulatory binding sites for AMP and GMP/IMP.

Answer 14

True

Question 15

PRPP synthetase gets inhibited allosterically by

Answer 15

ADP and GDP

Question 16

What mutation in PRPP synthetase decrease its activity but also reduces its feedback inhibition by ADP or GDP leading to excess of PRPP (can cause hyperuricemia)?

Answer 16

G174R

Question 17

What is the name of regulation that prevents excess puring nucleotides by inhibiting their own pathways?

Answer 17

negative feedback regulation

For Example, AMP and GMP inhibit their own pathways by inhibiting glutamin-PR-amidotransferase

Question 18

What is the name of regulation that maintains purine balance through cross-stimulation of other pathway?

Answer 18

positive cross regulation

For Example, ATP cross stimulates GMP production; GTP cross stimulates AMP production

Question 19

What enzyme carries out the conversion of xanthine to uric acid in purine degradation?

Answer 19

Xanthine Oxidase

Question 20

What two steps are carried out by Xanthine Oxidase?

Answer 20

1. The conversion of hypoxanthine (or guanine) to xanthine.

2. The conversion of xanthine to uric acid.

Question 21

What are the two drugs that inhibit xanthine oxidase by lowering uric acid and increase hypoxanthine and guanine levels?

Answer 21

Allopurinol and Febuxostat

Question 22

What are possible outcomes of hypoxanthine and guanine that couldn’t be converted into xanthine by allopurinol and febuxostat?

Answer 22

1. they are soluble so excreted in the urine

2. can be salvaged to nucleotides (AMP or GMP)

Question 23

All nitrogen in purines comes from

Answer 23

amino acids

Question 24

The goal of purine synthesis is to create

Answer 24

AMP and GMP

Question 25

CO2, Glycine, Tetrahydrofolate are sources of

Answer 25

carbon in purines

Question 26

What are three purine bases we have to know?

Answer 26

adenine, guanine, hypoxanthine

Question 27

What are the common classical features of lesch-nyhan syndrome?

Answer 27

neurologic impairment, self-mutilating behavior