The document outlines purine and pyrimidine metabolism, detailing the structural components of nucleotides and their synthesis pathways. It describes the roles of various nucleotides in metabolic functions, including energy metabolism and signal transduction, and discusses medical applications such as chemotherapy. Additionally, it examines the synthesis and salvage pathways of purines and pyrimidines, highlighting the implications of disorders like Lesch-Nyhan syndrome.

1. Purines and Pyrimidine
Metabolism
Dr. Apeksha Niraula
Assistant Professor
Institute of Medicine
TUTH
Maharajgunj

2. Nucleotides: ---- Nitrogenous Base
---- Pentose Monosachharides
---- One/Two or Three Phosphate
Groups
Nitrogeneous Bases PURINES
PYRIMIDINES

3. Purine and Pyrimidine Structure
 Both DNA and RNA contain the same Purine bases :
Adenine (A) and Guanine (G)
 Both DNA and RNA contain the same Pyrimidine
structure cytosine (C), differ in their second Thymidine base :
DNA contains Thymine (T)
RNA contains Uracil (U)
Nucleosides:
Addition of Pentose sugar to a base through a Glycosidic
bond produces a Nucleoside.
E.g: Ribonucleoside,Deoxyribonucleoside.

4. Functions
 Participate in metabolic functions as diverse as energy metabolism, protein
synthesis, regulation of enzyme activity, and signal transduction.
 Linked to vitamins or vitamin derivatives, nucleotides form a portion of many
coenzymes.
 ATP and ADP are the principal players in the energy transductions that accompany
metabolic interconversions and oxidative phosphorylation.
 Cyclic nucleotides cAMP and cGMP serve as the second messengers in hormonally
regulated events.
 Medical applications : Use of synthetic purine and pyrimidine analogs that contain
halogens, thiols, or additional nitrogen atoms in the chemotherapy of cancer and
AIDS, and as suppressors of the immune response during organ transplantation.

6. Can Cells Synthesize Purine Nucleotides??
 Nearly all organisms synthesize purines and
pyrimidines “denovo biosynthesis Pathway“.
 Many Organisms also “Salvage "purines from diet
and degradative pathways

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How do Cells synthesize the Purine
Nucleotides??

8. Synthesis of Purine Nucleotides
 denovo Synthesis Total Ten Steps in
synthesis of Purine
Nucleotide.
 Salvage Pathway

9. A. Synthesis of 5-Phosphoribosyl -1-
pyrophosphate

10. B. Synthesis of 5-Phosphoribosylamine
 Committed step in Purine Synthesis.

11. C. Synthesis of Inosine Monophosphate, the
“PARENT’ Purine Nucleotide
 Next Nine steps in Purine biosynthesis leads to
formation of Inosine Monophosphate(IMP).
 Four Steps require ATP as an energy source and two
steps in the pathway require N10
-formyltetrahydrofolate
as a one carbon donor.

12. Synthesis of Adenosine and Guanosine
Monophosphate
 Two step Energy-requiring pathway.
 Synthesis of AMP requires GTP and Synthesis
of GMP requires ATP Cross Regulation

14. Inosine monophosphate (IMP)

15.  If both AMP and GMP are present in adequate
amounts, the de-novo pathway of purine synthesis is
TURNED OFF at the Amidotransferase step.

17. Synthetic Inhibitors of Purine Synthesis
 Sulfonamides
 Methotrexate
 Designed to inhibit the growth of rapidly dividing
microorganisms without interfering with human cell
functions.

18. How is Pyrimidine synthesized????
 In contrast to Purine ring, Pyrimidine ring is completed
before the addition of 5-ribose Phosphate.
 Carbamoyl Phosphate and Aspartate are the precursors
of the Six-membered Pyrimidine Ring.

19. A. Synthesis of Carbomyl Phosphate
 Glutamine + CO2 C
Carbomyl Phosphate Synthetase II
Regulated Step in this
pathway.
Carbomyl Phosphate

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CPS I CPS II
Cellular Location Mitochondria Cytosol
Pathway Involved Urea Cycle Pyrimidine Synthesis
Source of
Nitrogen
Ammonia Glutamine
Regulators Acivator: N-acetyl-
Glutamate
Activator :PRPP
Inhibitor : UTP
Comparison between CPS I and CPS II

21. B. Synthesis of Orotic Acid
 Second Step Formation of
CarbomylAspartate.

22. C. Formation of a Pyrimidine Nucleotide
 Orotidine Monophosphate(OMP)
Parent Pyrimidine mononucleotide formed from Completed
Pyrimidine ring.
 OMP Orotidylate Decarboxylase Uridine
Monophosphate
(UMP)
removes carboxylic group.
 Orotate Phosphoribosyltransferase and Orotidylate
Decarboxylase are also catalytic domains of a single Polypeptide
chain called UMP Synthase.

23. Orotic Aciduria
 Deficiency of one or both activities of
the Bifunctional Enzyme
Orotic Acid in Urine.
 UMP thus formed is converted to UDP and UTP.

24. D. Synthesis of Cytidine Triphosphate
UTP Amination Cytidine
Triphosphate
(CTP)

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E. Synthesis of Deoxythymidine
Monophosphate
dUMP Thymidylate synthase dTMP

26. Salvage Pathways for Pyrimidine and Purine
Bases
 Denovo Synthesis of Nucleotides is Expensive in terms
of the use of high-energy phosphate bonds esp. for
Purine biosynthesis.
 All tissues are not capable of denovo synthesis of Purine
nucleotides such as Erythrocytes, Neutrophils,
Brain cells

27. Purine Salvage Pathway
 Two Pathways available.
I. One step Synthesis
 Formation of GMP and IMP
 Hypoxanthine Guanine Phosphoribosyltransferase (HGPRT)
catalyzes the One step nucleotide formation from either
Guanine or Hypoxanthine using PRPP as the donor of ribosyl
moiety.
Guanine Similarly, Hypoxanthine
PRPP HGPRT HGPRT
GMP + PPi Inosine + PPi

28. II. Two Step Synthesis
 Nucleoside Phosphorylase- Nucleoside
kinase pathway.
Adenine + Ribose-1-P
Nucleoside Phosphorylase
Adenosine + Pi
ATP
Adenosine Kinase
AMP + ADP
 Neither Guanosine nor Inosine Kinase has
been detected in mammalian cells.

29. In addition to the above cycle, there is another
salvage cycle for purines GMP, IMP as well as their
deoxyribonucleotides which is converted to their
respective nucleosides by a PURINE-NUCLEOTIDASE
Enzyme

30. Lesch-Nyhan syndrome:
 Rare, X-linked, recessive disorder.
 Virtually complete deficiency of HGPRT.
 Results in an inability to salvage hypo -xanthine
or guanine, from which excessive amounts of uric
acid is produced.
 Lack of the salvage pathway causes increased
PRPP levels and decreased IMP and GMP levels.
 Denovopurine synthesis is increased.

31.  A combination of decreased purine reutilization and
increased purine synthesis results in increased
degradation of purines and the production of large
amounts of uric acid, making Lesch-Nyhan a
heritable cause of hyperuricemia
 Hyperuricemia frequently results in the formation of
uric acid stones in the kidneys (urolithiasis) and the
deposition of urate crystals in the joints (gouty
arthritis) and soft tissues
 Syndrome is also characterized by motor
dysfunction, cognitive deficits, and behavioral
disturbances that include self-mutilation (biting of
lips and fingers)

34. Pyrimidine Base Salvage
 Pyrimidine Phosphoribosyl Transferase catalyses the
formation
of Pyrimidine Nucleotide using PRPP.
Pyrimidine Base
PRPP Pyrimidine Phosphoribosyl Transferase
Pyrimidine Nucleotide + PPi

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Q. The rate of DNA synthesis in a culture of cells could
be most accurately determined by measuring the
incorporation of which of the following radiolabeled
compounds?
A. Adenine.
B. Guanine.
C. Phosphate.
D. Thymidine.

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Q. A 1-year-old female patient is lethargic, weak, and
anemic. Her height and weight are both low for her
age. Her urine contains an elevated level of orotic
acid. The administration of which of the following
compounds is most likely to relieve her symptoms?
A. Adenine.
B. Guanine.
C. Hypoxanthine.
D. Thymidine.
E. Uridine.

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