Download - Nucleic acid metabolism lecture nam02
Dr. Aga Syed SameerCSIR Lecturer (Demonstrator)
Department of Biochemistry,
Medical College,
Sher-I-Kashmir Institute of Medical Sciences,
Bemina, Srinagar, Kashmir, 190010. India.
Nucleic Acid MetabolismPyrimidine Metabolism
IMP Pathway
AMP and GMP Pathway
• Important for those cells which are not capable of de novo synthesis of purine nucleotides
• Brain
• RBCs
• Leukocytes
Salvage Pathway
Salvage Pathway
Hypoxanthine
Guanine
Adenine
PRPP
IMP
GMP
AMP
PPi
HGPRTase
AGPRTase
Kinases for Interconversion
AMP
+
GMP
ATP
2ADP
GDP + ADP
Adenylate Kinase
Guanylate Kinase
Pyrimidine Biosynthesis
• UMP (Uridine Monophosphate)• Precursor to
• TMP and CTP
• Utilizes (Substrates)• One Aspartate
• γ-NH3 of Glutamine
• CO2 is recycled (Used in 1st step and released back in last)
• Water molecule
• NAD+
• ATP’s (Two : Till UMP Synthesis)
• Methyl group of THF + GTP {dTMP Synthesis}
• NH3 of Glutamine + ATP (2 Equivalent) {CTP Synthesis}
2 ATP + HCO3- + Glutamine + H2O
CO
O PO3-2
NH2
Carbamoyl Phosphate
NH2
C
N
H
CH
CH2
C
COOO
HO
O
Carbamoyl Aspartate
HN
C
N
H
CH
CH2
C
COOO
O
Dihydroorotate
HN
C
N
H
C
CH
C
COOO
O
Orotate
HN
C
N
C
CH
C
COOO
O
HH
CH2
OH OH
H H
OO
2-O3P
Orotidine-5'-monophosphate
(OMP)
HN
C
N
CH
CH
C
O
O
HH
CH2
OH OH
H H
OO
2-O3P
Uridine Monophosphate
(UMP)
2 ADP +
Glutamate +
Pi
Carbamoyl
Phosphate
Synthetase II
Aspartate
Transcarbamoylase
(ATCase)
Aspartate
Pi
H2O
Dihydroorotase
Quinone
Reduced
QuinoneDihydroorotate
Dehydrogenase
PRPP PPi
Orotate Phosphoribosyl
Transferase
CO2
OMP
Decarboxylase
Pyrimidine Biosynthesis
Enzymes and Reactions• 2 condensation Rxns: form carbamoyl aspartate and
dihydroorotate (intramolecular)
• Dihydroorotate dehydrogenase (FMN) is an intra-mitochondrial enzyme; oxidizing power comes from ubiquinone reduction
• Attachment of base to ribose ring is catalyzed by OPRT; PRPP provides ribose-5-P.
• OMP Decarboxylase enhances the rate of decarboxylation by a factor of 2x1023
• Channeling: • Enzymes 1, 2, and 3 are on same chain;
• Enzymes 5 and 6 are on same chain
CTP and UTP synthesis• UMP is then converted UDP &
UTP
• The conversion takes place by the action of Nucleoside Mono/Di Phosphate Kinases.
• CTP formed from UTP via CTP Synthetase driven by ATP hydrolysis • Glutamine provides amide
nitrogen
Conversion of Ribonucleotidesto Deoxyribonucleotides• Ribonucleotide reductase
• NADP
• Thioredoxin reductase
Regulation of RNR’s
• ATP activates
• dATP Inhibits
dTMP synthesis• dUMP formed; produces dTMP via Thymidylate
Synthetase• N5,N10 Methylene THF provides methyl group
• THF is first reduced and then methylated
dTMP synthesis
dTMP synthesis
Regulation• Differs between bacteria and animals
• Bacteria – regulation at ATCase rxn
• Animals – regulation at carbamoyl phosphate synthetaseII
• UDP and UTP inhibit enzyme;
• ATP and PRPP activate it
• Also UMP and CMP competitively inhibit OMP Decarboxylase
Degradation of Pyrimidines• CMP and UMP degraded to bases similarly to purines
• Dephosphorylation
• Deamination
• Glycosidic bond cleavage
• Uracil reduced in liver, forming β-Alanine
• Is then converted to malonyl-CoA used in fatty acid synthesis for energy metabolism
• dTMP is degraded to β-Amino Isobutyrate
• Is then converted to methyl malonyl-CoA used in fatty acid synthesis for energy metabolism