Catabolism of Purines and
Pyrimidines

Recapitulation….
• Nucleotides..
• Nitrogenous base
• Structure
• Pathways
• Committed Step
• Synthetic analogs

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
They lack PRPP Amido
transferase

Purine Salvage Pathway
 Two Pathways available.
I. One step Synthesis
 Formation of GMP and IMP
 Hypoxanthine Guanine Phosphoribosyltransferase (HGPRT)
catalyses 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

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.

 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

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.

 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)

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

Catabolism of Purines
 Adenine and Guanine nucleotides are converted to various
compounds catalyzed by their respective enzymes until the
final common product Xanthine is produced.
Xanthine
Xanthine Oxidase
Uric Acid

A. Adenine Nucleotide Metabolism
 In Liver and Heart Muscle
Purine 5’- Nucleotidase
I. AMP Adenosine
Adenosine Deaminase
II. Adenosine Inosine
Purine Nucleoside Phosphorylase
III. Inosine Ribose-1-P
+
Hypoxanthine
Xanthine Oxidase
IV. Hypoxanthine Xanthine
XO
URIC ACID

 In Skeletal Muscle:
I. AMP Adenylate Deaminase IMP
Purine 5’- Nucleotidase
II. IMP Inosine
Xanthine Oxidase
III. Inosine Uric Acid

B. Guanosine Metabolism
i) In Liver, Kidney, Spleen, Pancreas
GMP Guanosine
Purine 5’-Nucleotidase
Guanosine R-1-P + Guanine
Purine Nucleoside Phosphorylase
Guanine Xanthine + NH3
Guanine Deaminase
Xanthine Uric Acid
Xanthine Oxidase

Liver (Mainly)
Guanosine Guanine Deaminase Xanthosine
Xanthosine R-1-P + Xanthine
Purine Ribonucleoside Phosphorylase
Xanthine Uric Acid

Further catabolism of Uric Acid
Uric Acid
Uricase
Allantoin
Allantoic Acid
Allantoinase
Ureidoglycolate
Ureidoglycolase
Urea + Glyoxylate
UREA NH3 + CO2

Catabolism of Pyrimidines
I. Cytosine and Uracil
Pyrimidine Dephosphorylated Pyrimidine
5’-Nucleotidase
Nucleosides
Dihydrouracil
Uracil 5,6 - Dihydrouracil
Dehydrogenase
Cytosine Uracil
Deamination

5,6 Dihydrouracil Beta-ureidoprorionic
Hydropyrimidine Hydrase acid
Beta-Ureidoproprionic acid
CO2, NH3,and Alanine
can be oxidized to
Acetate
Acetyl CoA

II. Thymine
 Released from Thymidine or produced from deamination of 5- “
Methylcytosine.
Thymine
NADPH dependent dehydrogenase
Dihydrothymine
Hydrase
Beta-Ureidoisobutyric Acid
CO2, NH3, Beta aminoisobutyrate