LG4.5 Hyperuricemia/Nucleotide Metabolism – Dr. Hansen

Question 1

What is the most oxidized purine?

Answer 1

Uric Acid

Question 2

Where do febuxostat and allopurinol inhibit uric acid production?

Answer 2

Xanthine oxidase

Question 3

What is the underlying cause of gout?

Answer 3

-Nucleation and buildup of crystals of monsodium urate caused by hyperuricemia = “ high uric acid in blood.”

Question 4

What is the structure of monosodium urate?

Answer 4

• Each negatively charged urate is neutralized by one positively charged sodium ion.
• 6.8 mg/L of urate is the solubility limit of monosodium urate in blood.
• Crystals nucleate and grow at higher urate concentrations and dissolve at lower concentrations

Question 5

What is the most reduced purine?

Answer 5

Adensoine

Question 6

What are sources of uric acid?

Answer 6

• Dietary purines are oxidized to uric acid in the liver.
• Dietary purines are oxidized to uric acid in the liver.
• Reabsorption through the urate1 transporter decreases elimination.

Question 7

How is uric acid eliminated from the body?

Answer 7

Excreted through urine/feces

Question 8

What is the key regulating step of purine biosynthesis?

Answer 8

The key regulated step of purine biosynthesis is glutamine-phosphoribosylpyrophosphate aminotransferase (interpret nomenclature).

Question 9

What is PRPP?

Answer 9

phosphoribosylpyrophosphate

Question 10

What are the main functions of PRPP?

Answer 10

• PRPP is the foundation on which purine are built.
• PRPP is also the foundation used for purine salvage.
• PRPP is also used in a later step of pyrimidine synthesis

Question 11

What precursor is activate to form PRPP?

Answer 11

Ribose-5-phosphate is the precursor that is activated to form PRPP by addition of a pyrophosphate group from ATP.

Question 12

What activates PRPP synthetase?

Answer 12

Inorganic phosphate

Question 13

What inhibit PRPP synthetase?

Answer 13

purine ribonucleotides

Question 14

What two molecules are worked on by Xanthine oxidase?

Answer 14

• Hypoxanthine

- Xanthine

Question 15

What does HPRT stand for?

Answer 15

HPRT =
Hypoxanthine-guanine
phosphoribosyltransferase

Question 16

What is HPRT involved in?

Answer 16

Purine Salvage

Question 17

What is Lesh-Nyhan?

Answer 17

• HPRT is inactivated by x-linked recessive mutations

- inhibition of an enzyme leads to buildup of its upstream substrates and depletion of its downstream products

Question 18

What are the symptoms of Lesh-Nyhan?

Answer 18

Symptoms:

• Premature gout (early teens)
• Kidney stones (25% of patients)
• Mental retardation
• Cerebral palsy
• Self-mutilation/aggressive behavior

Question 19

What with happen to purine metabolism if:

• ATP depletion
• AMP buildup

Answer 19

-Purine metabolism decreased
-purine degradation
uric acid buildup in blood

Question 20

What will happen to purine metabolism if:

• High energy
• Fatty acid synthesis
• Fatty liver disease

Answer 20

• Purine metabolism increased

- New production of purines

Question 21

Compare regulation of glucose verse fuctose

Answer 21

-Glucose entry into glycolysis within the liver is highly regulated by: phosphofructoskinase
which in turn is regulated by insulin, glucagon, etc.
-Fructose enters glycolysis within the liver through fructokinase which is extremely rapid and unregulated.

Question 22

Unregulated, rapid, excessive phosphorylation of fructose

by fructokinase in the liver temprorarily depletes what?

Answer 22

ATP

Question 23

What affect will a transient low level of nucleotide triphosphates and a high level of nucleotide monophosphates have on purine catabolism?

Answer 23

Increase purine degradation