Week 15 Objectives

Question 1

Compare and contrast the roles of dietary nucleic acids and of de novo biosynthesis in the production of purines and pyrimidines destined for polynucleotide biosynthesis, including the reaction by phosphoribosyl 1-pyrophosphate synthetase.

Answer 1

o Pyrimidines: Thymine (T), cytosine (C), uracil (U) (in RNA only) (CUT)
▪ Single ring structures
▪ Thymine base pairs with adenine
▪ Cytosine base pairs with guanine

o Purines: Guanine (G) and adenine (A)

Question 2

Explain why antifolate drugs and analogs of the amino acid glutamine inhibit purine biosynthesis.

Answer 2

Treatment for gout also include inhibition of xanthine oxidase by allopurinol
-Degradation of purines generates uric acid → insoluble and accumulation can cause gout

Question 3

Outline the sequence of reactions that convert inosine monophosphate (IMP), first to AMP and GMP, and subsequently to their corresponding nucleoside triphosphates.

Answer 3

Synthesis continues till the production of IMP (inosine monophosphate) which can be used to generate → AMP
and GMP

▪ High levels of GMP will inhibit the conversion of IMP to GMP
▪ High levels of AMP will inhibit the conversion of IMP to AMP

Question 4

Describe the formation from ribonucleotides of deoxyribonucleotides (dNTPs).

Answer 4

Bases can be converted to the deoxy form (for DNA replication)
o Ribonucleotide reductase converts ribose bases → deoxybases
▪ Enzyme is only active when DNA replication is occurring.

Question 5

Indicate the regulatory role of phosphoribosyl pyrophosphate (PRPP) in hepatic purine biosynthesis and the specific reaction of hepatic purine biosynthesis that is feedback inhibited by AMP and GMP.

Answer 5

Synthesis of 5-phosphoribosyl 1-pyrophosphate (PRPP)
o This is the conversion of ribose 5 –phosphate → PRPP by the enzyme PRPP synthetase
▪ Reaction is inhibited by purine bases (A and G)
o PRPP will be the active 5-carbon sugar used for the synthesis of both purines and pyrimidines

Question 6

Identify the reactions discussed that are inhibited by anticancer drugs.

Answer 6

Inhibitors of pyrimidine synthesis

o 5-fluorouracil (CANCER) inhibits thymidylate synthase which converts dUMP → dTMP

o Methotrexate (CANCER) inhibits the folate cycle by inhibiting dihydrofolate reductase

• Cytosine is the only nucleotide that does not require folate for its synthesis, otherwise folate required

Question 7

Describe the structure of the end product of purine catabolism. Comment on its solubility and indicate its role in gout, Lesch-Nyhan syndrome, and von Gierke disease.

Answer 7

o Disorders of purine salvage:
▪ Hyperuricemia – elevated uric acid.
▪ Lesch-Nyhan Syndrome - deficiency HGPRT
▪ Von Gierke Disease – over production due to increased flux through the Pentose phosphate
pathway

Question 8

Purine synthesis

Answer 8

PRPP is initially combined with glutamine
▪ This is the first committed step by enzyme PRPP Glutamyl Amidotransferase (GPAT)
▪ GPAT can be:
• Inhibited when GMP is elevated
• Activated by PRPP