Uric acid metabolism

Question 1

what are the 3 roles of purines?

Answer 1

○ Genetic code (A & G)
○ Second messengers for hormone action (e.g. cAMP)
○ Energy transfer (e.g. ATP)

precursors for urate

Question 2

outline the process of purine catabolism?

list the eznyme involved

Answer 2

Purine** -> Hypo Xanthine ->* Xanthine ->* Urate

• eznyme = xanthine oxidase

** note; adenine and guanine both undergo DIFFERENT reaction pathways where they are converted into the common INOSINE which is then converted to hypoxanthine

Question 3

why is it that animals dont get gout?

list the eznyme involved

Answer 3

this reaction occurs:
Urate -> Allantoin

enzyme: uricase

allantoin, is more easily excreted by the kidney because of its water-soluble compound.

In humans, a mutation during evolution resulted in an inactivated gene encoding uricase

Question 4

what causes formation of gout?

whihc is most common joint ?why at certain locations?

Answer 4

crystalisation of urate:

• cooler temperature
• higher concentration of urate
• acidic pH

(there are limits of solubility)

first metatarsophalangeal joint - periphery so cooler.

Question 5

what is the Fractional Excretion of Uric Acid (FEUA)?

why

Answer 5

10%

urat = antioxidant to protect us against oxidative stress

Question 6

where us urate excreted?

Answer 6

kidneys/nephrons

Question 7

outline the process of renla urate handling

Answer 7

urate is reabsorbeed AND excreeted in the Prxomial Convoluted tubule PCT

only 10% excreted 90% reabsorbs

Question 8

what are the 2 pathways involved in purine synthesis/metabolism?

what are their charcateristics, which area in body uses them?

Answer 8

1. De novo synthesis pathway
   - make purines from scratch
   - Bone marrow uses this to make purines
   - inefficient, meetabolically demanding
   - BM has high demand for purines so no.2 not enough
2. Salvage pathway
   - used by most cells in body
   - energy efficient
   - Recycles partially catabolised purines to make purines

Question 9

how does the salvage pathway make purines?

main enzyme?

Answer 9

Recycles partially catabolised purines to make purines

main reactions:
§ Hypoxanthine –> IMP (inosinic acid)
§ Guanine –> GMP - guanylic acid

Main enzyme:
• HPRT (aka HGPRT)
○ Hypoxanthine-guanine phosphoribosyltransferase

Question 10

how does the de novo s pathway make purines?

Answer 10

uses atp and other compounds to make IMP - inosinic acid

Uses IMP to make AMP and GMP

enzyme: PAT (pprp amido transferase)

Question 11

what is the rate-limiting step in the de novo s pathway?

what are the outputs of this reaction?

Answer 11

5 phosphoribosyl-1 pyrophosphate (PRPP) -> 5 phosphoribosyl-1 amine (PRA)

catalysed by PAT enzyme :phosphoribosyl-1 aminotransferase

outputs: IMP AMP GMP

Question 12

what is the output of the:

A. de novo pathway
B. salvage pathway

Answer 12

de novo pathway: IMP, AMP, GMP

salvage pathway: IMP, GMP

Question 13

what is the feedback inhibition in de novo pathway?

Answer 13

AMP and GMP exert Negative feeback to PAT to slow down rate of purine output

PPRP (5-phosphorybosil…) exerts Positive feedback to increase reaction rate

Question 14

what is the pathology of Lesch nyhan diseasee?

Answer 14

This is an X-linked disease (almost exclusively affects boys)

• It is caused by absolute deficiency of HPRT

1. this means there is no/less negative feedback inhibition on PAT, so the DE NOVO pathway goes into overdrive, makes lots of IMP
2. also PPRP builds up to = more IMP

which means salvage pathway makes lots of urate

Question 15

wahta are the clinical features of Lesch nyhan disease?

Answer 15

○ Normal at birth 
		○ Developmental delay at 6 months 
		○ Hyperuricaemia (rarer in children)
		○ Choreiform movements (at 1 year) 
		○ Spasticity and mental retardation 
		○ KEY FEATURE: Self-mutilation in 85% of patients at ages 1-16 (e.g. biting lips very hard)

Question 16

list some causes of hyperuricaemia

Answer 16

1. Increased urate production
   primary: lesh nyhan, glycogen storage disorders etc
   secondary: anything leading to increesaed cell turnover around the body eg leukaemia, psoriasis
2. Decreased urate excretion
   diuretics, aspirin, downs syndrome etc

Question 17

what results from an intense inflammatory reaction in the Synovium of the joint ?

Answer 17

gout

Question 18

what are the 2 presentations of gout?

Answer 18

Can be acute (podagra) or chronic (tophaceous)

Question 19

list some locations of tophi?

implicatoins of this?

Answer 19

fingers
- get periosteal erosion due to the presence of a tophus

pinna of ear

Question 20

which type of gout presents as:

‘exquisite’ pain
○ Affected joint is red, hot and swollen

Answer 20

acute gout

Question 21

how is gout diagnosed?

Answer 21

history, examination and uric acid levels

get synovial fluid sample -> polarised light + red filter/compensator

Urate - Needle-shaped and Negatively birefringent :
- appear BLUE and at 90 degrees

Question 22

Rhomboid-shaped and positively birefringent crystal is pathognomic of?

Answer 22

Calcium Pyrophosphate

• appear BLUE and parralell to compensator

Question 23

how is gout treated?

Answer 23

1. reduced inflammation (ACUTELY)
			§ NSAIDs 
			§ Colchicine - 1st
			§ Glucocorticoids 
(believe all 3 are first)

2. Reduce hyperuricaemia - post acute attack (Not acute)
   - Allopurinol : urate synthesis
   - Probenecid : urate excretion
   - Drink water
   - Stop diuretics : urate levels

Question 24

what is the MOA of colchicine?

Answer 24

inhibiting the manufacture of tubulin (microtubules)

this reduce the motility of neutrophils

so less neutrophils in joint for inflammation

Question 25

what is the MOA of allopurinol?

Answer 25

xanthine oxidase inhibitor reduce urate synthesis

Question 26

what is the MOA of probenecid

Answer 26

increase renal urate excretion

Question 27

what are the caveats of allopurinol use?

Answer 27

NEVER give it to someone who is on azathioprine azathipoprine -> mercaptopurine -> .. -> interferes with purine metabolism end result: suppression of bone marrow