Pyrimidine Metabollism Flashcards
what molecules are pyrimidines
-thymine cytosine and uracil
difference between the association of the purine skeleton with PRPP and the pyrimidine skeleton and PRPP
- the purine skeleton is assembled ON the PRPP molecule
- whereas the pyrimidine skeleton is assembled prior to being attached to PRPP
what is a major regulatory step in the formation of pyrimidines? what are the products and the reactants
-formation of carbamoyl phosphate which happens in the cytoplasm and is ctalyzed by CPS2 from 2ATP, HCO3-, and glutamine
N carbamoyl aspartate is formed from what using what
-formed from carbamoyl phosphate and aspartate using aspartate transcarbamoylase
which reactions form the pyrimidine ring?
- dihydroorotase using N carbamoylaspartate, creating dihydroorotate
- dihydroorotate dehydrogenase using dihydroorotate to creat orotate
where does the ribose phosphate group come from? what molecule is it added to? and what enxyme does this? what happens next?
- comes from PRPP
- added to orotate
- catalyzed by orotate phosphoribosyl transferase
- orotidyl decarboxylase removes a carboxyl group from orotidylate (orotate + PRPP), creating uridylate (UMP)
adding phosphates to UMP
- forst uridylate kinase
- then the nonspecific nuclesoide diphosphate kinase
formation of CTP
-CTP synthase uses UTP, glutamine and ATP to produce CTP
where do the carbons come from on the pyrimidine ring
- 3 carbons and an N come from aspartate
- 1 C from bicarbonate
- 1 N from glutamine
what are the first threee enzymes in the pyrimidine biosynthesis pathway
-what is special about them
- CPS2, aspartate transcarbamoylase
- they are all domains of the same polypeptide chain
- this is a multienzyme complex that facilitates the ordered synthesis of important compounds
how is pyrimidine salvage done?
- reversible conversion of bases to nucleosides catalyzed by a phosphorylase
- and then a nucleoside to a nucleotide via a kinase
why do we care less about pyrimidine catabolism?
-because in contrast to the uric acid produce in purine catabolism, pyrimidine catablsim doenst have any dangerous intermediates
during catabolism, nucleotides are first converted into what by what
-nucleosides by phosphotases
cytidine is converted to what by what during catabolism?
uridine by cytosine deaminase
uridine and thymidine are converted to what by what in catabolism
-free bases by pyrimidine nucleoside phosphorylase
how can you estimate the turnover of DNA in cancer patients which are undergoing a lot of DNA degradation during chemotherapy
-measure B-aminoisobuturate
what enzyme catalyzes the reaction producing deoxynucleosides?
-what does it need to do this and how is this cofactor formed?
- ribonucleotide reductase (RNR)
- thioredoxin, which is replenished by thioredoxin redcutase using NADPH
what is a inhibitor of tyrosyl radicals and what can this accomplish
- hydroxyurea
- this is given to cancer patients hoping that the cell can not produce deoxys in order to replicate its DNA
- inhibits the RNR step
what regulates CPS2?
- inhibited by UTP
- activated by ATP, PRPP
what regulates OMP decarboxylase
-inhibited by UMP
orotic aciduria
- cause
- characterization
- treatment
- caused by the absence of either or both of the enzymes OPRT or orotidylate decarboxylase
- characterized by failure of normal growth and severe anemia due to inhibition of DNA replication due to lack of pyrimidines
- can treat by bipassing the block with either orotidylate (OMP) or UMP depending on the deficiency
control of the biosynthesis of dNTP’s
- reduction of ribonucleotide diphosphates is controlled allosterically
- dATP inhibits RNR and ATP activates RNR
- this allows for fine tuning of the dNTP pool for DNA synthesis
adenosine deaminase deficiency
- causes death from infection before the age of 2
- patients lack both B and T lymphocyte function
- reason for immune dysfunction unknown
- associated with large build up of dATP (inhibitor of RNR), this may block activation of the immune systems since lymphocytes can not proliferate
methotrexate
- inhibits DHF reductase which catalyzes the reformation of THF which is used to make dTMP from dUMP
- anologue of folic acid, has a high affinity for DHF reductase
- valuable drug in the treatment of many rapidly growing tumors such as acute leukemia
consderation when treating someone with methotreate
- all rapidly dividing cells are vulnerable
- however they can be rescued by adding an alternative source of THF
- prolonged usage leads to resistance
- this means the dose should be sufficiently high in order to avoid the survival of mutant cells that become resistant
FdUMP
-this inhibits the enzyme thymiylate synthase which is directly responsible for the formation of dTMP using dUMP and methylene THF
