Hóa sinh Axit Nucleic

Amide bond formation Glycinamide ribonucleotide GAR synthetaseFormyl group transfer Formylglycinamide ribonucleotide GAR transformylase Amino group transfer Formylglycinamidine ribonuc

1 Nomenclature and structure of

Page 3

PRPP SYNTHETASE

5 – PHOSPHORIBOSYL –

1- PYROPHOSPHATE

PRPP

PO 4

P P

glutamine

Glu phosphoribosyl amidotransferase

HO

NH2

Page 5

Glycine

Glutamine

N5 N10 – methenyltetrahydrofolate

PRPP

N

8 3

H2

CH

C C

INOSINE MONOPHOSPHATE

8 3

ATP

Amide bond formation Glycinamide ribonucleotide GAR synthetase

Formyl group transfer Formylglycinamide

ribonucleotide GAR transformylase

Amino group transfer Formylglycinamidine

ribonucleotide amidotransferase FGAR

Imidazole ring closure 5-aminoimidazole

ribonucleotide FGAM cyclase

Carboxylation of HCO 3 4–carboxy-5-aminoimidazole

ribonucleotide AIR Carboxylase

Amide group transfer SAICAR SAICAR synthetase

Release of fumarate AICAR SAICAR Lyase

transformylase

Ring closure INOSINE MONOPHOSPHATE IMP synthetase

C H

INOSINE MONOPHOSPHATE

IMP DEHYDROGENASE

P

H 2 N

GMP SYNTHETASE

H 2 N

Fumarate

RECIPROCAL SUBSTRATE EFFECT

H 2 N N

HN

C

C C

N

N

C

PO 4

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PURINE De Novo Synthesis- Summary

Committed step Conversion of PRPP to

5’-phosphoribosyl – 1- amine

Rate limiting

enzyme Glutamine PRPP Amidotransferase

End - products IMP

The purine and pyrimidine rings are synthesized de novo in mammalian cells utilizing amino acids as

as carbon donor.

The de novo pathway for purine nucleotide synthesis

consists of ten enzymatic reactions leading to

inosine monophosphate.

The de novo synthesis of pyrimidine nucleotide leads

to uridine monophosphate in six metabolic steps

Both pathways are expensive requiring the hydrolysis

of ATP molecules.

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DEOXYRIBONUCLEOTIDE

SYNTHESIS

SH SH

Thioredoxin

S S

Ribonucleotide reductase

Thioredoxin reductase

DEOXYRIBONUCLEOTIDE SYNTHESIS

Page 17

Lehninger 5 th ed

Ribonucleotide reductase: subunit structure

S

OH H

H

H

H

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D N A

NDP Kinase

dUTPase

1.DE NOVO SYNTHESIS 2.SALVAGE PATHWAY

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CH O

HN C

C C

N N C

N N C

Ribose – 5 - Phosphate

PRPP

Guanylic Acid Adenylic Acid Inosinic Acid

Guanine Hypoxanthine

CH O

HN

C

C C

N N C

PO 4

CN

H

HNC

CC

N

NH

C

O

O

CN

HNC

CC

N

NH

C

O

CN

H

HNC

CC

N

NH

HN C

C C

N N C

URIC ACID

XANTHINE

HYPOXANTHINE

diet

Xanthine oxidase

Purine overproduction and overexcretion

HGPRTase

Renal lithiasis, hypouricemia

CLINICAL CORRELATION

CLINICAL

DISORDER

ENZYMATIC DEFECTS

Purine overproduction and overexcretion

Purine overproduction and overexcretion

Mercaptopurine

Methotrexate

Uracil Hypoxanthine

Thymidylate synthase

Dihydrofolate

Adenylosuccinate synthase

DHF reductase

CLINICAL CORRELATION

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In Summary

Nomenclature and structure

Synthesis : De Novo and salvage pathways Degradation – uric acid

Clinical correlation

Thank you!

References:

1.Lehninger, Principles of Biochemistry, 5th ed, - Chap 22 2.Horton, Principles of Biochemistry, 4th ed – Chap18

3.Devlin, Textbook of Biochemistry, 6th ed - Chap 20

4.Stryer, Textbook of Biochemistry, 5th ed – Chap 25