Pyrimidine Metabollism

Question 1

what molecules are pyrimidines

Answer 1

-thymine cytosine and uracil

Question 2

difference between the association of the purine skeleton with PRPP and the pyrimidine skeleton and PRPP

Answer 2

• the purine skeleton is assembled ON the PRPP molecule

- whereas the pyrimidine skeleton is assembled prior to being attached to PRPP

Question 3

what is a major regulatory step in the formation of pyrimidines? what are the products and the reactants

Answer 3

-formation of carbamoyl phosphate which happens in the cytoplasm and is ctalyzed by CPS2 from 2ATP, HCO3-, and glutamine

Question 4

N carbamoyl aspartate is formed from what using what

Answer 4

-formed from carbamoyl phosphate and aspartate using aspartate transcarbamoylase

Question 5

which reactions form the pyrimidine ring?

Answer 5

• dihydroorotase using N carbamoylaspartate, creating dihydroorotate
• dihydroorotate dehydrogenase using dihydroorotate to creat orotate

Question 6

where does the ribose phosphate group come from? what molecule is it added to? and what enxyme does this? what happens next?

Answer 6

• comes from PRPP
• added to orotate
• catalyzed by orotate phosphoribosyl transferase
• orotidyl decarboxylase removes a carboxyl group from orotidylate (orotate + PRPP), creating uridylate (UMP)

Question 7

adding phosphates to UMP

Answer 7

• forst uridylate kinase

- then the nonspecific nuclesoide diphosphate kinase

Question 8

formation of CTP

Answer 8

-CTP synthase uses UTP, glutamine and ATP to produce CTP

Question 9

where do the carbons come from on the pyrimidine ring

Answer 9

• 3 carbons and an N come from aspartate
• 1 C from bicarbonate
• 1 N from glutamine

Question 10

what are the first threee enzymes in the pyrimidine biosynthesis pathway
-what is special about them

Answer 10

• 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

Question 11

how is pyrimidine salvage done?

Answer 11

• reversible conversion of bases to nucleosides catalyzed by a phosphorylase
• and then a nucleoside to a nucleotide via a kinase

Question 12

why do we care less about pyrimidine catabolism?

Answer 12

-because in contrast to the uric acid produce in purine catabolism, pyrimidine catablsim doenst have any dangerous intermediates

Question 13

during catabolism, nucleotides are first converted into what by what

Answer 13

-nucleosides by phosphotases

Question 14

cytidine is converted to what by what during catabolism?

Answer 14

uridine by cytosine deaminase

Question 15

uridine and thymidine are converted to what by what in catabolism

Answer 15

-free bases by pyrimidine nucleoside phosphorylase

Question 16

how can you estimate the turnover of DNA in cancer patients which are undergoing a lot of DNA degradation during chemotherapy

Answer 16

-measure B-aminoisobuturate

Question 17

what enzyme catalyzes the reaction producing deoxynucleosides?
-what does it need to do this and how is this cofactor formed?

Answer 17

• ribonucleotide reductase (RNR)

- thioredoxin, which is replenished by thioredoxin redcutase using NADPH

Question 18

what is a inhibitor of tyrosyl radicals and what can this accomplish

Answer 18

• 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

Question 19

what regulates CPS2?

Answer 19

• inhibited by UTP

- activated by ATP, PRPP

Question 20

what regulates OMP decarboxylase

Answer 20

-inhibited by UMP

Question 21

orotic aciduria

• cause
• characterization
• treatment

Answer 21

• 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

Question 22

control of the biosynthesis of dNTP’s

Answer 22

• 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

Question 23

adenosine deaminase deficiency

Answer 23

• 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

Question 24

methotrexate

Answer 24

• 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

Question 25

consderation when treating someone with methotreate

Answer 25

• 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

Question 26

FdUMP

Answer 26

-this inhibits the enzyme thymiylate synthase which is directly responsible for the formation of dTMP using dUMP and methylene THF