Pyrimidine Metabolism Flashcards
What are the pyrimidines?
Thymine 2,4 deoxy 5 methyl
Cytosine 2 oxy 4 amino
Uracil 2,4 deoxy
Orotic Acid 2,4 deoxy 6 carboxy
Nomenclature of of pyrimidines
ex: cytosine (base)
nucleoside: Base + ribose
end with IDINE ~ therefore cytidine
nucleotide: base + ribose + PO4 ester
cytidine monophosphate
What step of pyrimidine synthesis is the rate limiting step?
Rate limiting step: inhibited by UTP, activated by ATP & PRPP. This allows balance in the amounts of purines and pyrimidines
glutamine + HCO3- + 2 ATP (carbamoyle phosphate synthase 2) => carbamoyle phosphate + glutamine + 2 ADP + Pi
occurs in the cytosol
What are the steps of pyrimidine synthesis?
1: make carbamoyle phosphate using CPS2
2: carbamoyle phosphate + aspartate (aspartate transcarbamylase) => carbamoyle aspartate + Pi
3: carbamoyle aspartate + H+ (dihydroorotase) => dihydroorotate + H20
4: dihidroorotate + NAD+ (dihydroorotate dehydrogenase) => orotate + NADH + H+
orotate- first made pyrimidine
Where do the atoms from pyrimidines come from?
aspartate gives 3 C and one N
glutamine gives one N
carbon dioxide gives one C
What is CAD
multifunctional enzyme: one polypeptide with 3 domains and 3 activities.
catalyzes first three steps of pyrimidine synthesis:
CPS2
Aspartate transcarbamylase
Dihydroorotase
What contributes N atoms to both purines and pyrimidines?
aspartic acid
glutamine
How do you make UMP?
de novo: start with orotate which undergoes a “salvage like pathway”
orotate+ PRPP (orotate phosphoribosyl transferase) => OMP + Pi
OMP ( OMP decarboxylase) => UMP + CO2
what is UMP synthase?
multifunctional enzyme: one polypeptide, 3 domains, 3 activities
orotate phosphoribosyl transferase
OMP decarboxylase
What is orotic aciduria?
abnormal growth, megaloblastic anemia
caused by low UMP activity, more specifically OPRT. Build up of orotic acid.
treat with uridine rich diet
How do you synthesis cytosine (CTP)?
from uracil + glutamine:
uracil + glutamin+ ATP (CTP synthetase) => cytosine + glutamate + ADP+ Pi
What is ribonucleotide reductase?
How is it regulated?
What reverts its action?
converts ribonucleoside diphosphate + thioredoxine (2SH) => deoxyribonucleoside diphosphate + thioredoxin (S-S)
REDOX reaction
dATP inhibits; ATP activates
thioredoxin reductase with NADPH + H+ converts deoxyribonucleoside diphosphate back to ribonucleoside diphosphate
which nucleotides are acted upon by ribonucleotide reductase?
ADP GDP CDP UDP turned into: dADP dGDP dCDP dUDP ATP -> ADP converts them into dATP dGTP dCTP dUTP
How do you make thymine
from dUTP:
dUTP + H2O => dUMP + PPi
dUMP + ATP + 5,10 THF => dTMP + DHF
dTMP + ATP => dTTP + ADP
*it is the rate limiting step of DNA synthesis
What is the mechanism behind the dUMP -> dTMP reaction?
the enzyme is thymidylate synthase
it is a redox reaction:
5,10 THF goes from reduced to oxidized DHF when converting dUMP -> dTMP
DHF is reduced by DHF reductase -> THF (tetrahydrofolate)
THF is given back its carbon via serine transhydroxymethylase -> 5,10 THF
*note THF also known as FH4
