13. Nucleotide degradation Flashcards
What are the 3 general steps involved in nucleotide degradation? State chemical equation (also state if any other products are released) and enzymes catalysing each reaction
1) Nucleoside triphosphate / nucleotide → nucleoside monophosphate
- Enzyme : DNAse / RNAse
2) Nucleoside monophosphate → nucleoside (ribose + base) + Pi
- Enzyme : nucleotidase*
3) Nucleoside + Pi → Purine / pyrimidine + ribose-1-phosphate
- Enzyme : nucleoside phosphorylase
Alternatively, last step could be : Nucleoside + H2O → Purine / pyrimidine + ribose ;; catalysed by nucleosidase
In the last step of degradation : Nucleoside + Pi → Purine / pyrimidine + ribose-1-phosphate
Ribose-1-phosphate then enters the pentose phosphate pathway (PPP) to be utilised as an intermediate. true or false?
False. Ribose-5-phosphate is the intermediate for PPP, not R1P!!
Purine degradation
Outline how purines are degraded. Draw out diagram, starting from the nucleoside monophosphate level (AMP, GMP, IMP, XMP)
Refer to notes
Purine degradation
What are the 3 key enzymes that are important in purine degradation (that could lead to metabolic diseases)? Write down the reactions they catalyse
- AMP deaminase (AMP → IMP)
- Adenosine deaminase (adenosine → inosine ;; nucleoside level)
- Xanthine oxidase (hypoxanthine → xanthine → uric acid)
Purine degradation
What condition can AMP deaminase deficiency in muscle result in?
Hint : AMP deaminase important in muscles ;; AMP → IMP → …. → AMP (cycle)
AMP will not be able to be deaminated into IMP, and IMP cannot go through subsequent recycling to regenerate AMP.
In the cycle, aspartate is converted into fumarate, which enters TCA cycle to generate more energy.
Thus, with AMP deaminase deficiency in muscle, during exercise, muscles get fatigued easily
Purine degradation
In the reaction : AMP → IMP →adenoylosuccinate → AMP (AMP deaminase involved), ___ is converted into ___ to be utilised in the TCA cycle for energy (ATP) production
Aspartate ;; fumarate
Pyrimidine degradation
What is the final products for pyrimidine degradation, and what pathways do they undergo? [2]
- Malonyl CoA : precursor for FA synthesis
- Methylmalonyl CoA : converted into succinyl CoA, which undergoes TCA cycle to produce energy (ATP)
Purine degradation
What reaction does adenosine deaminase catalyse? What metabolic disease results due to adenosine deaminase (ADA) deficiency, especially in lymphocytes?
Adenosine → inosine or deoxyadenosine → deoxyinosine
<br></br>
When there is a deficiency in adenosine deaminase, deoxyadenosine cannot be degraded. Since lymphocytes are high in kinases, deoxyadenosine can be phosphorylated to eventually form dAMP → dADP → dATP → dATP. High levels of dATP then ** inactivates RNR** and inhibits DNA synthesis, leading to lymophotoxicity
Purine degradation
Xanthine oxidase is an enzyme which oxidises its substrate (xanthine). Explain where the electrons from xanthine goes to, and end products formed by the reaction of xanthine oxidase.
Xanthine oxidase oxidises substrates by accepting electrons from susbtrates. The electrons are then transported within XO via Mo complexes → Fe-S clusters → FAD → Oxygen (final electron acceptor)
- After O2 accepts electrons from XO, it forms H2O2-, which are reactive species (ROS) → need to get reduced by GSH (reduced glutathione) into harmless products like water
Purine degradation
What metabolic conditions arises from excess uric acid production? Explain them in detail [2]
1) Gout: painful arthrithis due to deposition of sodium urate crystals. Sodium urate can also deposit in kidneys and urinary tract, leading to kidney stones and urinary tract obstruction (more common in males, 3/1000)
<br></br>
2) Lesch Nyhan Syndrome : due to deficiency in HGPRT → purine cannot be salvaged → excess PRPP → excess biosynthesis of purine nucleotide → excess breakdown into purines → accumulation of uric acid (repeat)
- neurological and behavioural problems
Purine degradation
What is a solution to prevent metabolic diseases due to excess uric acid production?
Use of allopurinol , which acts as a competitive inhibitor of hypoxanthine, binding to xanthine oxidase
- inhibition of hypoxanthine → xanthine → uric acid
Pyrimidine degradation
Outline how pyrimidies are degraded, starting from the nucleoside monophosphate level (CMP, UMP/dTMP)
Refer to notes
Pyrimidine degradation
Cytidine can be degraded into cytosine, which is then converted into final degradation products. True or False?
False. Like adenosine, cytidine needs to be converted into uridine through cytidine deaminase
Pyrimidine degradation
Uracil (or thymine for DNA) is oxidised / reduced into dihydrouracil (dihydrothymine). What enzyme catalyses this reaction
Reduced ;; dihydrouracil (dihydrothymine) dehydrogenase
Pyrimidine degradation
What does it mean by “pyrimidine degradation contributes to energy metabolism of the cell to a small extent”?
In pyrimidine degradation, Methylmalonyl CoA can be converted into succinyl CoA, which undergoes TCA cycle to produce energy (ATP)
What is the key differences in purine nucleotide and pyrimidine nucleotide degradation?
In purine nucleotide degradation, xanthine is oxidised into uric acid
In pyrmidine nucleotide degradation, dihydrouracil / dihydrothymine is reduced into malonyl CoA (uracil)/ methyl malonyl CoA (thymine)
**recall : thymine has additional -CH3 group as compared to uracil **
