Biochem Lecture 37 (Pyrimidine Metabolism) Flashcards
What are the pyrimidine bases?
uracil, thymine, cytosine
What components go into the synthesis of a pyrimidine base?
C (from CO2) + NH-group (from glutamate) + aspartate (CCCN)
What is the end-product of initial pyrimidine base synthesis?
oroate
this will be used to form uridine-5’-monophosphate (UMP) from whence dUMP, CTP/dTTP and dTTP come
What is the regulated step in pyrimidine synthesis?
How is it regulated?
Where does step take place? (Compare to other isoform of this protein)
The first step with CPS II (carbamoyl phosphate synthetase II)
activated by ATP and PRPP; inactivated by UTP (i.e. end-product neg feedback)
This takes place in the cytosol (As compared to CPS I’s activiity in the mitochondria in the urea cycle; uses NH3 as an N source vs. glutamate here w/ CPS II)
At what point is the sugar added to the newly synthesize pyrimidine?
What is it added from?
Not ‘til later on once orotate ring has formed.
The ribose sugar is added from PRPP
How are nucleoside diphosphates formed? (both purine and pyrimidine)
How about nucleoside triphosphates?
There are specific nucleoside monophosphate kinases unique to each
There is one, universal nucleoside diphosphate kinase that phosphorylates all of them
How is CTP synthesize?
UDP—nucleoside diphosphate kinase—>UTP—CTP synthetase**—>CTP
**transamination
How are pyrimidines salvaged?
A phosphoribosyl group is reattached using pyrimidine phosphoribosyl transferase and a PRPP
Why is pyrimidine degradation less “tricky” than purine degradation?
B/c pyrimidines have only one ring, the ring can be opened and the now soluble products can be sent to the citric acid cycle
What is Uracil degraded to?
ß-alanine + CO2 + NH3
What is Thymine degraded to?
ß-aminoisobutyrate + CO2 + NH3
How do you synth dNDPs from NDPs?
ribonucleotide reductase + Thioredoxin co-factors
Works on UDP, ADP, CDP, GDP (i.e. not TDP)
Why is it important to regulate ribonucleotide reductase?
An imbalance in the dNTP pool can increase the rate of mutation
How is ribonucleotide reductase controlled?
activated by: ATP
overall activity of whole enzyme inhibited by dATP (i.e. not any other dNTPs; clinically relevant for some dzs, e.g. ADA)
fine-tune regulation of specific substrates by: ATP, dATP, dTTP, and dGTP
What is ADA (Adenosine Deaminase) deficiency?
Build-up of adenosine because broken:
adenosine—ADA—>inosine
diminished dNTP pools make T- and B-cell replication difficult; leads to SCID; kids usu. die before 2 y/o =(
