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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
low solubility


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)
renal disease
lactic acidosis
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?

enzyme replacement

bone marrow transplants

gene therapy


purine nucleoside phosphorylase (PNP) deficiency?

Less common

less severe; only impacts T-cells
repeated infections
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


pyrimidine biosynthesis

1. HCO3 and glutamine

2. carbamoyl phosphate synthetase-II (CPS-II)

3. carbamoyl phosphate

4. carbamoyl aspartate

5. dihydroorotate

6. orotate

7. OPRT enzyme

8. OMP

9. OMP decarboxylase

10. UMP

11. UDP

12. UTP


What is the regulatory step of pyrimidine synthesis?



What is CPS-II inhibited by ?

a lot of UTP will inhibit the process

feedback inhibition


what activates CPS-II?



How is CTP formed?

1. UTP

2. CTP synthetase

3. CTP

4. CDP


How are ribonucleosides converted to deoxyribonucleosides?

ribonucleotide reductase


How is thymidine synthesized?

Thymidine monophosphate synthesized from dUMP by
thymidylate synthase

ONLY pyrimidine that needs methylene tetrahydrofolate (one carbon donor)


what is the action of 5-flurouracil?

Irreversibly binds thymidylate synthase and inactivates it

anticancer drug


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?

uridine administration


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


How can one determine if the orotic aciduria is due to urea cycle defect or biosynthesis defect?

by looking at the blood ammonia levels