nucleotide metabolism- Brar

Question 1

what is the difference between a nucleoside and a nucleotide?

Answer 1

Nucleoside
• Sugar + base (purine or pyrimidine)
• Linked thru an N-glycosidic linkage.
• Purines bond to the C1’ carbon of the sugar at their N9 atoms.
• Pyrimidines bond to the C1’ carbon of the sugar at their N1 atoms.

Nucleotide
• Nucleoside + phosphate(s)
• Phosphate attached to the 5’ end thru esterification.—> mono, di, or tri phosphates
-RNA=polymer of ribonucleotides
-DNA=polymer of deoxyribonucleotides
-not all are polymers-> nucleoside triphosphates (ATP/GTP) are important energy carriers.
-also FAD, NAD+ and CoA

Question 2

Purine synthesis

Answer 2

first purine formed is IMP (inosine monophosphate), and AMP and GMP are formed from there. the purine base is hypoxanthine

Nitrogen in purine formation are from: glycine, aspartate and glutamine. N10-formyl tetrahydrofolate contributes both a N and 2 Cs. 1 C from CO2. glycine also contributes 2 Cs.

Question 3

how is IMP synthesized? and what activates/inhibits IMP synthesis?

Answer 3

• (5’-phophoribosyl-1-pyrophosphate (PRPP) → IMP)
• Glutamine contributes N1 and N4.
• Glycine contributes N2 and 2Cs
• CO2 contributes C5
• Aspartate contributes N6.
• THF contributes C3 and C7.
o Sulfa drugs and folic acid analogs inhibit THF synthesis. –> slow down DNA synthesis

• Cofactors required:
o Mg2+, K+, Mn2+ and H2O.
• 4 ATPs required.

• Inhibitors:
o AMP, GMP and IMP.

•	Activators:
o	PRPP (starting substrate)

Question 4

what is required for the conversion of IMP–> AMP or GMP?

Answer 4

• IMP → AMP
o Requires aspartic acid and GTP. produces fumarate

• IMP → GMP
o Requires glutamine and ATP.
o Produces NADH.
• Inhibitors: AMP and GMP respectively.

Question 5

what is the role of mycophenolic acid?

Answer 5

• Reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase.–> prevents the formation of GMP
• Deprives rapidly proliferating T and B cells of key components of nucleic acids.
• This drug is used to prevent graft rejection.

Question 6

how are purines degraded and what does their degradation lead to?

Answer 6

All purine degradation leads to uric acid
• Nucleic acids → nucleotides by pancreatic nucleases and intestinal phophodiesterases.
• Nucleotides → Nucleosides by group-specific nucleotidases and non-specific phosphatases.
• Nucleosides can be directly absorbed or further degraded.
• First, phosphate and ribose are removed.
• Then, nitrogenous base is oxidized.

Question 7

How are pyrimidines synthesized?

Answer 7

• Pyrimidine ring synthesis completed first; then attached to ribose-5-phosphate.
• UMP synthesized first.
o CTP synthesized from UMP.
• UTP inhibits carbamoyl synthetase II (1st enzyme in synthesis).
• PRPP activates synthesis

3 Cs and a N are from aseptic acid, one N is from glutamine and 1 C is from CO2

it requires 2 ATP to produce UMP

Question 8

What are pyrimidines degraded to?

Answer 8

soluble products:
Alanine
Aminoisobutyrate
Ammonia and carbon dioxide is produced

Question 9

What are the features of ADA deficiency?

Answer 9

Adenosine deaminase (ADA) deficiency.
• This enzyme converts adenosine → inosine.
• Causes a type of severe combined immunodeficiency (SCID), involving T-cell and B-cell depletion.
• dATP accumulates in blood cells which inhibits DNA synthesis.
• Kids die before 2 years old.

Question 10

What are the features of gout?

Answer 10

Gout
• Characterized by hyperuricemia w/ recurrent attacks of acute arthritic joint inflammation, caused by deposition of monosodium urate crystals.
• Results from underexcretion of uric acid.
• Treatment w/ allopurinol inhibits xanthine oxidase resulting in accumulation of hypoxanthine and xanthine which are more soluble