Hóa sinh Axit Nucleic

Name of presentation
by Mr X

Nucleotide Metabolism
Part II
Lecturer:
MARIA MILAGROS U. MAGAT, MD,MEM,FPPS,FPAPP
1. Nomenclature and structure of nucleotides
2. Nucleotide synthesis : De Novo and salvage pathways
3. Degradation of nucleotides
4. Clinical correlation
OBJECTIVES:
PRPP
SYNTHETASE
OH
RIBOSE 5 - PHOSPHATE
5 – PHOSPHORIBOSYL – 1- PYROPHOSPHATE
PRPP
SYNTHESIS – PRPP
glutamine
Glu phosphoribosyl amidotransferase
NH2
SYNTHESIS – P-ribose-NH2
Glycine
Glutamine
N5 N10 – methenyl
tetrahydrofolate
PRPP
N
8
3
2
1
6
9
DE NOVO SYNTHESIS - PURINE
H2
CH
H
H2
H
ATP
Glutamine
N
H
ATP
ATP
CO2
Aspartate
ATP
N10 – Formyl
tetrahydrofolate
INOSINE MONOPHOSPHATE
Glycine
DE NOVO SYNTHESIS
Glutamine
CO2
Aspartate
N10 – Formyltetrahydrofolate
INOSINE MONOPHOSPHATE
Glutamine
N5 N10 – methenyl
tetrahydrofolate
ATP
ATP
ATP
ATP
DE NOVO SYNTHESIS
H
H
INOSINE MONOPHOSPHATE
IMP
DEHYDROGENASE
NAD
XANTHYLATE
GUANYLATE
Glutamine
H2N
GMP SYNTHETASE
DE NOVO SYNTHESIS - GMP
INOSINE MONOPHOSPHATE
ADENYLOSUCCINATE
LYASE
ADENYLOSUCCINATE
ADENYLATE
Aspartate
ADENYLOSUCCINATE
SYNTHETASE
DE NOVO SYNTHESIS - AMP
Fumarate
RECIPROCAL SUBSTRATE EFFECT
IMP
XANTHYLATE
GUANYLATE
ADENYLOSUCCINATE
ADENYLATE
ATP
GTP
Glutamine
AMP
GDP
Aspartate
PURINE De Novo Synthesis- Summary
Committed step
Conversion of PRPP to 5’-phosphoribosyl – 1- amine
Rate limiting enzyme
Glutamine PRPP Amidotransferase
End - products
IMP
GMP
Amino group to C2 of IMP
ATP
AMP
Substitution of oxygen by amino group at C6
GTP
Regulation
Reciprocal substrate effect
ATP in GMP synthesis
GTP in AMP synthesis
-
-
-
-
PURINE De Novo Synthesis- REGULATION
De Novo Synthesis- Summary
The purine and pyrimidine rings are synthesized de novo in mammalian cells utilizing amino acids as carbon and nitrogen donors and carbon dioxide also 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.
De Novo Synthesis- Summary
DEOXYRIBONUCLEOTIDE
SYNTHESIS
NADP+
NADP+
H+
+
Ribonucleotide reductase
Thioredoxin reductase
DEOXYRIBONUCLEOTIDE SYNTHESIS
Lehninger 5th ed
Ribonucleotide reductase: subunit structure
Ribonucleotide reductase: MOA
Lehninger 5th ed
H
H
X
H
H
S
S
OH
H
H
H
H
D
N
A
dUMP
dTMP
UDP
dUDP
dUTP
dTTP
Ribonucleotide reductase
Ribonucleotide reductase
Ribonucleotide reductase
Ribonucleotide reductase
NDP Kinase
NDP Kinase
NDP Kinase
Deaminase
thymidylateSynthetase
NDP Kinase
dUTPase
SYNTHESIS:

DE NOVO SYNTHESIS
SALVAGE PATHWAY
Guanylate
Adenylate
INOSINE
ADENOSNE
ADENNE
HYPOXANTHINE
XANTHINE
GUANOSINE
GUANINE
APRT
HGPRT
SALVAGE PATHWAY
Ribose – 5 - Phosphate
PRPP
Guanylic Acid
Adenylic Acid
Inosinic Acid
Guanine
Hypoxanthine
Adenine
PRPP
Synthetase
INTERMEDIATES
De Novo Synthesis
Salvage Pathways
PURINE METABOLISM
APRT
HGPRT
Degradation of Purines
Guanylic Acid
Adenylic Acid
Inosinic Acid
Uric Acid
Degradation of Pyrimidines
Cytidilic Acid
Uridylic acid
Thymidylic Acid
b-alanine
b-aminoisobutyrate
CATABOLISM
Formation of Uric Acid
Guanylate
Guanosine
URIC ACID
XANTHINE
HYPOXANTHINE
diet
Gout
Gout
Lesch-Nyhan
Xanthinuria
Characteristics
PRPP Synthetase
HGPRTase
Xanthine oxidase
Purine overproduction and overexcretion
HGPRTase
Renal lithiasis, hypouricemia
CLINICAL CORRELATION
CLINICAL
DISORDER
ENZYMATIC
DEFECTS
Purine overproduction and overexcretion
Purine overproduction and overexcretion
Inhibitor
Fluorouracil
Mercaptopurine
Methotrexate
Metabolite
Enzyme
Uracil
Hypoxanthine
Thymidylate synthase
Dihydrofolate
Adenylosuccinate synthase
DHF reductase
CLINICAL CORRELATION
Nucleotides
In Summary
Nomenclature and structure

Synthesis : De Novo and salvage pathways

Degradation – uric acid

Clinical correlation
Thank you!
References:
Lehninger, Principles of Biochemistry, 5th ed, - Chap 22
Horton, Principles of Biochemistry, 4th ed – Chap18
Devlin, Textbook of Biochemistry, 6th ed - Chap 20
Stryer, Textbook of Biochemistry, 5th ed. – Chap. 25