Purine Metabolism Flashcards
What are the three sources of nucleotides?
- Dietary (endogenous)
(Exogenous)
- De Novo Pathway (produced in the liver primarily)
- Salvage Pathway (energetically most favorable)
4 Key Steps in Purine Synthesis
- Ribose 5-phopsphate –> PRPP by PRPP synthetase
- PRPP –> 5-phosphoribosyl amine
- Stepwise generation of purine rings
- Formation of IMP (which later becomes AMP + GMP)
Purine is degraded into
Uric Acid
produced in the liver and is transported to the kidneys for excretion through urine.
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
Gout
Major regulated step in purine biosynthesis inhibited by High levels of end-product (AMP,GMP,IMP)
PRPP –> 5-phosphoribosyl amine
IMP, AMP, XMP, and GMP inhibit which enzyme when they are expressed at high levels
Glutamine PR-Amidotransferase
The committed step in the synthesis of purines is addition of the first N in the purine ring by which enzyme
Glutamine PR-Amidotransferase
What pathway converts purine bases (A/G/H) into purine nucleotides (AMP/GMP/IMP)?
Salvage Pathway
Adenine is converted to AMP via which enzyme?
Adenine phosphoribosyltransferase (APRT)
Hypoxanthine and Guanine are converted to IMP and GMP respectively via which enzyme?
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
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?
Lesch-Nyhan syndrome
High levels of AMP, GMP, or IMP negatively inhibit feedback of what enzyme by shifting it to inactive dimer form?
Glutamine Phosphoribosyl amidotransferase (rate limiting enzyme)
High levels of PRPP shift what enzyme to its active monomer form?
Glutamine Phosphoribosyl amidotransferase (rate limiting enzyme)
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.
True
PRPP synthetase gets inhibited allosterically by
ADP and GDP
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)?
G174R
What is the name of regulation that prevents excess puring nucleotides by inhibiting their own pathways?
negative feedback regulation
For Example, AMP and GMP inhibit their own pathways by inhibiting glutamin-PR-amidotransferase
What is the name of regulation that maintains purine balance through cross-stimulation of other pathway?
positive cross regulation
For Example, ATP cross stimulates GMP production; GTP cross stimulates AMP production
What enzyme carries out the conversion of xanthine to uric acid in purine degradation?
Xanthine Oxidase
What two steps are carried out by Xanthine Oxidase?
- The conversion of hypoxanthine (or guanine) to xanthine.
2. The conversion of xanthine to uric acid.
What are the two drugs that inhibit xanthine oxidase by lowering uric acid and increase hypoxanthine and guanine levels?
Allopurinol and Febuxostat
What are possible outcomes of hypoxanthine and guanine that couldn’t be converted into xanthine by allopurinol and febuxostat?
- they are soluble so excreted in the urine
2. can be salvaged to nucleotides (AMP or GMP)
All nitrogen in purines comes from
amino acids
The goal of purine synthesis is to create
AMP and GMP
CO2, Glycine, Tetrahydrofolate are sources of
carbon in purines
What are three purine bases we have to know?
adenine, guanine, hypoxanthine
What are the common classical features of lesch-nyhan syndrome?
neurologic impairment, self-mutilating behavior
