Pyrimidine Metabolism pdf - DNA

Lec. 6 Pyrimidine Metabolism

Pyrimidine biosynthetic pathway

de Novo Synthesis of Pyrimidines



The ring is assembled from bicarbonate, aspartate and

glutamate.



The ring is synthesized first and then added to the ribose.

1) Step 1: Carbamoyl Phosphate synthesis

 Carbamoyl phosphate for pyrimidine synthesis is made by

carbamoyl phosphate synthetase II (CPS II)

 Substrates are HCO

, glutamine ,2 ATP

 CPS-II can be viewed as the committed step in pyrimidine

synthesis

2) Step 2: Aspartate transcarbamoylase (ATCase)

catalyzes the condensation of carbamoyl phosphate with
aspartate to form carbamoyl-aspartate

3) Step 3: dihydrootase

ring closure and dehydration via condensation Produce
dihydroorotate

4) Step 4: dihydroorotate dehydrogenase

Synthesis of a pyrimidine (orotate)

5) Step 5: orotate phosphoribosyltransferase

Orotate is joined with a ribose-P to form orotidine-5’-
phosphate (OMP)

6) Step 6: OMP decarboxylase

OMP decarboxylase makes UMP (uridine-5’-
monophposphate)

Synthesis of uridine and cytidine triphosphate



Nucleoside monophosphate kinase



UMP + ATP → UDP + ADP



Nucleoside diphosphate kinase



UDP + ATP → UTP + ADP



CTP sythetase forms CTP from UTP and ATP

Synthesis of dTMP



Methylation of d-UMP by N

-methylene THF



Nucleotide mono-, di-, and triphospahtes are



interconvertible



Nucleoside monophosphate kinases



UMP is converted to UTP before going on to produce CTP



CTP is formed by amination of UTP.

Regulation of pyrimidine nucleotide biosynthesis

UTP and CTP are feeback inhibitors of CPS II

Orotic aciduria



An inherited human disease caused by a deficiency in the

multifunctional enzyme that catalyzes the last 2 steps in the
pyrimidine synthesis



large amounts of orotic acid in urine



retarded growth and severe anemia



treat by administration of uridine and/or cytidine

Novo versus salvage pathways

Regulation of pyrimidine biosynthesis



UDP and UTP are feedback inhibitors of CPS II



PRPP and ATP are activators

Salvage of pyrimidine



Pyrimidine nucleosides can be salvaged by



Nucleoside kinase that use atp in the phosphorylation of the

nucleoside to nucleotide.

How Are Pyrimidines Degraded?



Pyrimindine rings can be fully degraded to soluble structures

(Compare to purines that make uric acid)



pyrimidines ring is opened and degraded to highly soluble

products as B-alanine,



-aminoisobutyric acid, ammonium,

and CO



Degradation pathways are quite distinct for purines and

pyrimidines, but salvage pathways are quite similar



CMP and UMP degraded to bases similarly to purines

  Dephosphorylation
  Deamination
  Glycosidic bond cleavage



Uracil reduced in liver, forming b-alanine

 Converted to malonyl-CoA  fatty acid synthesis for

energy metabolism



What are the major differences between purine and

pyrimidine pathways? What are the similarities?

 similarities:

o both start with R-5-P
o PRPP synthetase catalyzes rate limiting step, most active

during DNA replication

 differences:

o pyrimidines use carbomoyl phosphate synthetase II

(CPSII) for the first committed step whereas purines use
glutamine-PRPP-amidotransferase,

o pyrimidine pathway is 4 steps whereas purines is 11



What enzyme catalyzes the rate limiting step and the first

committed step in pyrimidine synthesis?

 PRPP synthetase is rate limiting,
 carbamoyl phosphate synthetase II (CPSII) is 1

committed



What is the first pyrimidine and first pyrimidine

nucleotide formed in pyrimidine synthesis?

orotate is first pyrimidine, OMP is first pyrimidine nucleotide



How is CPS II regulated?

Positive effectors: PRPP, ATP

negative effector: UTP



From OMP, what is the process that leads to the formation

of UTP, CTP?
OMP → UMP (Orodylate decarboxylase) → UDP → UTP
(CTP synthetase) → CTP



What percentage of pyrimidines are recycled, and how

does this compare to purines?

30% of pyrimidines are recycled compared to 90% in purines



At what level are pyrimidines recycled and how does this

differ from purines?
pyrimidines are recycled at the level of nucleosides while
purines are recycled as free bases



Do pyrimidine degradation products cause any

pathologies? Why?
No, pyrimidine degradation products are highly water soluble
and excreted in urine



Which nucleotide is an important target in cancer

treatment?
Thymidine (it is only found in DNA, its inhibition will inhibit
replication)



Purine/Pyrimidine

degradation

are

the

same

for

ribonucleotides and deoxyribonucleotides



Biosynthetic pathways are only for ribonucleotide production



Deoxyribonucleotides are synthesized from corresponding

ribonucleotides

Synthesis of deoxyribonucleotides from
ribonucleotides



The nucleotides synthesized all contain

ribose(ribonucleotides)



to synthesize DNA we need nucleotides that contain

deoxyribose



ribonucleotide reductase reduce ribonucleotides to

deoxyribonucleotides.(by reduction of ribose sugar )



As UDP to dUDP,GDP to dGDP

Regulation of Nucleotide Biosynthesis

Anticancer Drugs

Inhibition of the synthesis of dexoyribonucleotides or
thymidylate will selectively inhibit fast growing cells.