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17 Cards in this Set

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pyrimidine synthesis
starts with carbamoyl phosphate and converges on UMP
pyrimidine synthesis step by step
carbamoyl phosphate + Asp -> pyrimidine dihyroorotate
dihyroorotate goes in mitochondria and oxidized to orotate and put back in cytosol
orotate couples with PRPP then decarboxylated to be UMP
how is pyrimidine synthesis different from purine synthesis?

what about carbamoyl phosphate is different?
purines assembled on PRA scaffold, but pyrimidines get PRPP at the end added.

purines did everything in cytosol only

no folate derivatives needed
C's made from U's at UTP level (Not IMP)

in urea cycle the carbamoyl phosphate was made in the mitochondria
What aa's are used in pyrimidine synthesis?

How does this compare to purines?
Gln Asp

purines also used Gly
What enzyme does formation of carbamoyl phosphate?

And it's combo with Asp and loss of water to _____
carbamoyl phosphate synthestase II, but really ATCase which has mulitple functions

dihydroorotate which gets oxidized to orotate in mitochondria
What significance is orotate?
it's how we saw the OTC deficiency in urea cycle
What allosteric regulators are involved in pyrimidine synthesis?
UMP (the end product) (-)
ATP (+) (basepairs with these; purine controls pyrimidines)

CTP (-) (a product even further downstream than UMP)
what happens after orotate is made?
PRPP comes in and it gets decarboxylated

done by UMP synthase (bifunctional enzyme)
Orotic aciduria
problem
symptoms
treatment
deficiency in UMP synthase
occurs early in life: anemia unresponsive to normal therapy, **crystalluria (crystal levels orotate in urine)
add U series or CMP- these have feedback inhibition
We have UMP. How do we make the others?
C series
regulation
UTP + Gln made into --CTP synthase -> CTP using ATP
GTP allosteric activator (another balancer of pyrimidine and purine)

dUMP gets methylated by --thymidylate synthase--> dTMP
Where all do purines regulate pyrimidines?
GTP regulates CTP synthase
ATP + and UMP, CTP - regulates ATCase
what's the purpose of dUTPase?
hydrolyzes dUTP to dUMP.
it wastes energy but don't want dUTP competing with dTTP for DNA
How do we make our T series?
thymidylate synthase
dUMP methylation to dTMP
(NOT SAM; uses folate!)
What does 5-Fluorouracil do?
targets thymidylate synthase
a suicide inhibitor converted to FdUMP and blocks folate-driven methylation
Methotrexate
dihydrofolate reductase
competitive inhibitor

dihydrofolate is output of thymidylate synthase when dUMP goes to dTMP. It needs to be recycled by dihydrofolate reductase to cycle back as folate.

as dihydrofolate levels rise, it inhibits thymidylate synthase
Acyclovir
antivirals.
usually thymine -> thymine phosphorylase ->dTMP -thymidine kinase-> dTTP
Acyclovir gets taken in instead, made into acycloGTP, taken into DNA, no 3' OH.
How to catabolize pyrimidine?
Endo and exo RNases Dnases and nucleotidases and nucleosidases
all the unmethylated ones converge on U and dU and then phosphate taken off which is then Beta-alanine which is ketogenic
the methylated ones (T's) go to T -> methylmalonyl CoA and succinyl CoA (glucogenic)