Biochem Lecture 35 (Purine Metabolism)

Question 1

Which bases are the purines?

Answer 1

PUR as AG (gold)

Adenine and Guanine

Question 2

Nuceloside vs. Nucleotide?

Answer 2

nucleoside = base + sugar (either ribose or deoxyribose)

nucleotide = base + sugar + phosphate(s)

Question 3

What products are required to produce a purine de novo?

Answer 3

glutamine, glycine, 2 of 10-formyl-THF, CO2 and asparate

*problem if folic acid deficient

Question 4

What is the end product of purine de novo synthesis?

Answer 4

IMP

Question 5

What is the fate of IMP? What regulates that (those) fate(s)?

Answer 5

AMP and GMP

Levels of AMP and GMP inhibit their own synthesis

this is important because if the NTP/dNTP pool gets out of whack, there is an increased risk for mutation

Question 6

What are the reg’d steps in de novo purine synthesis?

Answer 6

1) 5-phosphoribosyl-1-pyrophosphate (PRPP) Synthase:

Ribose-5-P—PRPP Synthase—>PRPP

( + ) by Pi

( - )by purine ribonucleotides

2) PRPP amidotransferase:

PRPP—PRPP amidotransferase—>5’-Phosphoribosylamine

( + ) elevated PRPP [mass action AND allosterically]

( - ) AMP, GMP, IMP

Question 7

How do cells salvages purines?

Co-factor req’d?

Enzymes?

Answer 7

cell turnover and diet provide bases that can be salvages and re-used in the body

pathways require PRPP—>PPi and phosphoribosyltransferases (PRTs):

guanine and/or hypoxanthine—HGPRT—>GMP/IMP

adenine—APRT—>AMP

Question 8

What is Lesch-Nyhan disease?

Answer 8

Lesch-Nyhan is an x-linked genetic disease caused by a mutation in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) enzyme and leads to an inability to salvage hypoxanthine and guanine.

S/Sx: MR, spasticity, compulsive self-injury (e.g. biting—> loss of lips, fingers), hyperuricemia (b/c of elevated hypoxanthine)—>gout

Tx: allopurinol for gout; restraints to prevent self-injury =(

Question 9

How are excess purines degraded?

Answer 9

Excess purines are degraded to uric acid. The final, and most important step in this pathway is:

xanthine—xanthine oxidase—>uric acid

Question 10

Describe the pathogenesis of gout

Answer 10

Gout results from hyperuricemia which can be do to hpyeractivity of the purine degradation pathway, particularly with the xanthine oxidase enzyme involved in oxidation of xanthine to uric acid potentially due to high protein diets.

It can also be caused by an inability to excrete uric acid in the kidneys.

Question 11

Why does Lesch-Nyhan dz cause gout?

Answer 11

Lesch-Nyhan = problem with HGPRT (hypoxanthine-guanine phosphoribosyl transferase) enzyme that regenerates IMP and GMP from hypoxanthine and guanine bases, respectively.

incr [hypoxanthine] —> incr uric acid production (via mass action) [hypoxanthine—>xanthinine—xanthine oxidase—>uric acid]

Question 12

What is elevated in gout?

Answer 12

uric acid

Question 13

What are the mutation-level causes of gout?

Answer 13

1. Unregulated PRPP (phosphoribosylpyrophosphate) synthesis which is req’d of de novo synthesis of purines; they build-up upregulating the breakdown pathway
2. Lesch-Nyhan dz (loss of HGPRT): causes increased PRPP, also increased availability of purine bases
3. under excretion in the kidneys

Question 14

How does allopurinol treat gout?

Answer 14

inhibits xanthine oxidase inhibitor

purine bases—xanthine oxidase—>uric acid