Flashcards in Lecture 40 Deck (27)
How to diagnose gout?
joint fluid aspirations
needle-like crystals urate crystals can be seen microscopically
pain and warmth of the area
most commonly seen on the big toe
What is uric acid?
It is the end product of purine breakdown
normally excreted in the urine
How is uric acid formed? AMP pathway
1. nucleic acid goes to AMP
2. AMP is converted to adenosine
3. adenosine is converted to inosine by adenosine deeaminase
4. inosine is converted to hypoxanthine by purine nucleoside phosphorylase
5. hypoxanthine is converted to xanthine by xanthine oxidase
6. xanthine is converted to uric acid
How is uric acid formed? GMP pathway
1. GMP is converted to guanosine by 5' nucleotidase
2. guanosine is converted to guanine by purine nucleoside phosphorylase
3. guanine is converted to xanthine by guanase
4. xanthine is converted to uric acid
what are the diet restrictions of those that have hyperuricemia?
they should avoid meat and alcohol
both these foods have DNA/RNA presence, thus would further increase urate levels in the patients blood.
what are the reasons for the formation of hyperuricemia?
1. underexcretion (most common)
2. overproduction of uric acid
how does a PRPP gene mutation impact urate levels in the blood?
elevated PRPP; meaning an over active enzyme would lead an excessive turnover of purines
meaning more uric acid
How does a HGPRT deficiency impact urate levels?
less recycling of the purines and elevated PRPP; thus increases turnover of purines
more uric acid
How can hyperuricemia be managed?
with the use of drugs:
1. allopurinol - inhibits xanthine oxidase (thus uric acid cannot be formed)
2. febuxostat - inhibits xanthine oxidase
decrease intake of meat and alcohol
What occurs during an adenosine deaminase deficiency?
how to dignose:
serum ig levels are extremely low
T and B cell function severely compromised
Adenosine deaminase (ADA) deficiency affects lymphocytes Adenosine accumulates → Increased [dATP] levels → Inhibits ribonucleotide reductase → Reduced lymphocyte cell division
Treatments of SCID?
bone marrow transplants
purine nucleoside phosphorylase (PNP) deficiency?
less severe; only impacts T-cells
lab tests will show T-cell deficiency
overview of pyrimidine metabolism?
aspartate, glutamate, and CO2 are precursors
UTP and CTP...... RNA
UTP and CTP..... dUMP...... methylene tetrahydrofolate........dTMP and dCTP..... DNA
1. HCO3 and glutamine
2. carbamoyl phosphate synthetase-II (CPS-II)
3. carbamoyl phosphate
4. carbamoyl aspartate
7. OPRT enzyme
9. OMP decarboxylase
What is the regulatory step of pyrimidine synthesis?
What is CPS-II inhibited by ?
a lot of UTP will inhibit the process
what activates CPS-II?
ATP and PRPP
How is CTP formed?
2. CTP synthetase
How are ribonucleosides converted to deoxyribonucleosides?
How is thymidine synthesized?
Thymidine monophosphate synthesized from dUMP by
ONLY pyrimidine that needs methylene tetrahydrofolate (one carbon donor)
what is the action of 5-flurouracil?
Irreversibly binds thymidylate synthase and inactivates it
what is the action of methotrexate?
competitively inhibits dihydrofolate reductase and prevents THF formation
(Methotrexate inhibits purine and thymidine biosynthesis)
what is orotic aciduria? (biosynthesis effect)
OPRT and/or OMP decarboxylase deficiency (UMP synthase)
symptoms: poor growth, megaloblastic anemia, and orotic acidura
normal blood ammonia levels
what happens when one has a pyrimidine deficiency?
decreased RBC formation
reduced DNA synthesis and cell division
what helps with orotic aciduria?
orotic aciduria due to urea cycle defect?
Orotic aciduria is also found in Hyperammonemia Type II (deficiency of ornithine transcarbamoylase of urea cycle)
Increased amounts of carbamoyl phosphate formed in the mitochondria (urea cycle), diffuses into cytosol and
is used for pyrimidine biosynthesis, causing increased formation of orotic acid and orotic aciduria