Lecture 7 (4A) - Purine Biosynthesis Regulation

Question 1

Need balance

Answer 1

between bases (purines and pyrimidines)

Question 2

Purine biosynthesis regulation

Answer 2

• tight control, critical balance needed
  
  • ATP to GTP
• IMP pathway
  
  • regulated at first 2 priming step reactioins
    
    • regulation of first and second steps, by products that you get → excess/required product
    • 2 sites of allosteric control

Question 3

IMP pathway

Answer 3

regulated at first 2 priming steps

Question 4

First reaction (Primer 1)

Answer 4

PRPP production (important product)

• feedback inhibition at this step
• by IMP, AMP, GMP

Question 5

Second reactioni (Primer 2)

Answer 5

5-phosphoribosyl-1-amine production

• flux-generating step
• feedback inhibition here too
  
  • by AMP, ADP, ATP at one site in the enzyme
  • by GMP, GDP, and XMP at ANOTHER site in the enzyme

(feedback inhibition at different sites in the enzyme)

Question 6

IMP - competitive inhibition

Answer 6

by AMP and GMP if concentration of AMP high

• inibits AMP production
• same for GMP

Question 7

Activation

Answer 7

feed forward activation

• by PRPP to create β-5-phosphoribosylamine
  
  • PRPP activates
• ​powering steps
  
  • step 1A (in biosynthesis of AMP, addition of aspartate)
  • step 2B (in biosynthesis of GMP, oxygen replaced on C2 atom)
  • GTP required to form AMP
  • ATP requried to form GMP
  • can get back inhibition to prevent concentration from getting too high

Question 8

GTP requied to form

Answer 8

AMP

Question 9

ATP required to form

Answer 9

GMP

Question 10

Salvage pathways

Answer 10

• cells degrade nucleic acids (often RNA)
• free purines produced, salvaged for reuse
• very important processes

Question 11

Salvage pathway

processes differ in different species

Answer 11

mammals - 2 principle enzymes

• adenine phosphoriboxyl transferase

adenine + PRPP → AMP + PPi

• hypoxanthine phosphoriboxyl transferase** (HPRT/HGPRT)**

hypoxanthine + PRPP → IMP + PPi

guanine + PRPP → GMP + PPi

• deficiency in HGPRT → Lesch-Nyhan syndrome

Question 12

Adenine phosphoribosyl transferase

Answer 12

adenine + PRPP → AMP + PPi

Question 13

Hypoxanthine phosphoribosyl transferase

(HPRT or HGPRT)

Answer 13

hypoxanthine + PRPP → IMP + PPi

guanine + PRPP → GMP + PPi

deficiency = Lesch-Nyhan syndrome