LG4.5 Hyperuricemia/Nucleotide Metabolism – Dr. Hansen Flashcards
What is the most oxidized purine?
Uric Acid
Where do febuxostat and allopurinol inhibit uric acid production?
Xanthine oxidase
What is the underlying cause of gout?
-Nucleation and buildup of crystals of monsodium urate caused by hyperuricemia = “ high uric acid in blood.”
What is the structure of monosodium urate?
- 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
What is the most reduced purine?
Adensoine
What are sources of uric acid?
- 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.
How is uric acid eliminated from the body?
Excreted through urine/feces
What is the key regulating step of purine biosynthesis?
The key regulated step of purine biosynthesis is glutamine-phosphoribosylpyrophosphate aminotransferase (interpret nomenclature).
What is PRPP?
phosphoribosylpyrophosphate
What are the main functions of PRPP?
- 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
What precursor is activate to form PRPP?
Ribose-5-phosphate is the precursor that is activated to form PRPP by addition of a pyrophosphate group from ATP.
What activates PRPP synthetase?
Inorganic phosphate
What inhibit PRPP synthetase?
purine ribonucleotides
What two molecules are worked on by Xanthine oxidase?
- Hypoxanthine
- Xanthine
What does HPRT stand for?
HPRT =
Hypoxanthine-guanine
phosphoribosyltransferase
What is HPRT involved in?
Purine Salvage
What is Lesh-Nyhan?
- 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
What are the symptoms of Lesh-Nyhan?
Symptoms:
- Premature gout (early teens)
- Kidney stones (25% of patients)
- Mental retardation
- Cerebral palsy
- Self-mutilation/aggressive behavior
What with happen to purine metabolism if:
- ATP depletion
- AMP buildup
-Purine metabolism decreased
-purine degradation
uric acid buildup in blood
What will happen to purine metabolism if:
- High energy
- Fatty acid synthesis
- Fatty liver disease
- Purine metabolism increased
- New production of purines
Compare regulation of glucose verse fuctose
-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.
Unregulated, rapid, excessive phosphorylation of fructose
by fructokinase in the liver temprorarily depletes what?
ATP
What affect will a transient low level of nucleotide triphosphates and a high level of nucleotide monophosphates have on purine catabolism?
Increase purine degradation
