Metabolism of Purine and Pyrimidine and disorders

Dr. Ashok Kumar J

International Medical School

Malaysia

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Bases present in nucleic acids•Nitrogen-containing heterocyclic compounds•Purines and pyrimidines

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N

N

NCH

CH

C

CCH

NH N

N

CH

CH

CHCH

1

2

3

4

5

6 7

8

9 1

2

3

4

5

6

Purine Pyrimidine

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Ribose or

Deoxyribose

BASE

Phosphate

Nucleotide

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Base linked to Sugar byN- glycosidic linkage

(Nucleoside)

Sugar is phosphorylated

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α-D - RibosePhosphoribosyl pyrophosphate (PRPP)

ATP AMP

De novo synthesis of Purine Nucleotide

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Phosphoribosylpyrophosphate (PRPP)

Glutamine Glutamate

5-phospho-β-D ribosylamine

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α

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Glycine

N5, N10 Methenyl THFA

Glutamine

CO2

Aspartate

N10 Formyl THFA

Inosine Monophosphate(IMP)

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Adenosine Monophosphate (AMP)

IMP

Formation of AMP from IMP

Fumarate

Aspartate Glutamine

GuanosineMonophosphate (GMP)

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Synthesis of Purine nucleotide

C

C C

C

CH N

NN

N

Ribose

GLYCINECO2

Aspartate

N5 N10 MethenylTHFA

GLUTAMINE

N10 FormylTHFA

1

2

34

5

6 7

8

9

P6/23/2014

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9GMPAMP

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Adenine

Adenosine Monophosphate

PRPP PPi

Purine Salvage

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PPi

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PRPP PPi

PRPP

Hypoxanthine

Guanine

Inosine Monophosphate

Guanosine Monophosphate6/23/2014

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Adenosine Monophosphate

Adenosine

ATP ADP

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PurineDegradation

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Pi

Adenosine

Inosine Xanthine

H2O

NH3

Guanosine

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Uric acid acts as antioxidant

Monosodium urate salts are present in body fluids

As the temperature decreases

solubility of the uric acid decreases

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Sodium urate crystallizes in soft tissues and joints; uratestones in the kidneys - Gout

Normal blood level is 3 – 7 mg/dl (<5mg/dl)In females slightly lower than in males

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Inherited defect in the metabolism of purines or transport of uric acid in the renal tubules

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PRPP synthesis increasedIncreased production and

degradation of purinenucleotides

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N

N

CH

CH

CH

1

2

3

4

5

6

Pyrimidine

CHCO2

Aspartate

Pyrimidine Biosynthesis

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CO2 + Glutamine + ATP

Carbamoyl phosphate synthetase II(cytosol)

AspartateCarbamoyl aspartic acid

Aspartate Trans carbamoylase

Pi

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Carbamoyl phosphate

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Orotic AcidOrotidine Monophosphate

(OMP)

PRPP

Orotatephosphoribosyl

transferase

UMP

CO2

Orotidylic acid decarboxylase

UDP

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N5 N10 MethyleneTHFA

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UDP

dTMP

CTP

CTP Synthetase

Thymidylate synthase

THFA

ATP

ADP

Glutamine

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Regulation

Aspartate TranscarbamoylaseAllosteric Inhibitor is CTP Allostearic activator is ATP

CO2 + NH3

β – Alanine and β-Aminoisobutyrate

Catabolism of Pyramidines

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Anticancer Drug Targets Thymidylate synthase and dihydrofolate reductase

N5 N10 MethyleneTHFA

dUMP

dTMP

Thymidylate synthase

THFA DihydrofolateDihydrofolate Reductase

Aminopterin and

Methotrexate

Inhibit

Fluorouracil

Fluorodeoxyuridylate(Sucide inhibitor)

Inhibit

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Disorders of pyrimidine metabolism

Orotic aciduria

Type I orotic aciduriaDeficiency of both orotate phosphoribosyltransferase and orotidylate decarboxylase

Type II orotic aciduria is due to a deficiency Orotidylate decarboxylase

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Good of Luck

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