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8/12/2019 5-2 Necleotide Metabolism (Pyrimidine)
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8/12/2019 5-2 Necleotide Metabolism (Pyrimidine)
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Cytidine MonophosphateCytosine Cytidine
Base Nucleotide
Base (P04ester)
Nucleoside*
Base
Nucleotidase
Phosphorylase
The nomenclature of pyrimidine depends
on their linkage to a pentose
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shorter pathway than for purines
base is made first, then attached to ribose-P
(unlike purine biosynthesis)
only 2 precursors (aspartate and glutamine, plusHCO3
-) contribute to the 6-membered ring
requires 6 steps (instead of 11 for purine)
the product is UMP (uridine monophosphate)
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Condensation of glutamine, bicarbonate in thepresence of ATP
Carbamoyl phosphate synthetase exists in 2 types:
CPS-Iwhich is a mitochondrial enzyme andis dedicated to the urea cycle and arginine
biosynthesis)CPS-II, a cytosolic enzyme used here
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CPS-II is the major site of regulation in animals: UDP and
UTP inhibit the enzyme and ATP and PRPP activate it
It is the committed step in animals
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enzyme is aspartate transcarbamoylase(ATCase)
catalyzes the condensation of carbamoylphosphate with aspartate with the release of Pi
ATCase is the major site of regulation inbacteria; it is activated by ATP and inhibited by
CTPcarbamoyl phosphate is an activatedcompound, so no energy input is needed at thisstep
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enzyme: dihydroorotase
forms a pyrimidine from carbamoylaspartate
water is released in this process
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In E. coli, the first 3 enzymatic reactions arecatalyzed by 3 separate proteins/enzymes
In animals, all 3 steps are found in a multifunctionalenzyme (210 kD).
The acronym CAD is used as a name for the
multienzyme: carbamoyl phosphate synthetase,aspartate transcarbamoylase and dihydroorotase
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An irreversible reaction
Enzyme: dihydroorotate dehydrogenase
Oxidizing power is derived from quinones(thru coenzyme Q)
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Enzyme: orotate phosphoribosyl transferase
Ribose phosphate originates from PRPP
product is orotidine-5-monophosphate(OMP)
orotate phosphoribosyl transferase is also
used in salvage of uracil and cytosine to theircorresponding nucleotide
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enzyme: OMP decarboxylase
product: uridine monophosphate (UMP)
In animals, steps 5 and 6 are catalyzed bya single polypeptide with 2 active sites
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OCH2 H
H
OH
O
OH
H
P O
O
O-
P
O
O-
O-
OPHO
O
OH
H
HN
N
O
O COO-
Horotate phosphoribosyl transferase
PRPP
PPi
O
CH2
H
OH
H
OH
H
OPHO
O
OH
N
HN
O
O COO-
H
orotidine monophosphate (OMP)
O
CH2
H
OH
H
OH
H
OPHO
O
OH
N
HN
O
O
HCO2
OMP decarboxylase
(uses no cofactors)
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An inherited human diseasecaused by a deficiencyin the multifunctional enzyme that catalyzes the last2 steps in the pyrimidine synthesis
large amounts of orotic acid in urine
retarded growth and severe anemia
treat by administration (injection) of uridine and/or
cytidine
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UMP + ATP UDP + ADP
UDP + ATP UTP + ADP
nucleoside diphosphate kinase
CTP synthase (cytidylate synthetase)
N
N
O
H
O
Ribose 3phosphate
N
NO
Ribose 3phosphate
NH2glutamine +
ATPGlutamate +
ADP +Pi
CTPUTP
(in bacteria, ammonia donates the amino group)
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Glutamine +
HCO3-
+ATP
Carbamoyl
phosphate
carbamoyl phosph.
synthetase
Orotate
OMPUMPUTP + CTP
orotate
phosphoribosy
transferase
UTP and CTP are feeback inhibitors of CPS II
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O
HH
OHOH
CH2
H H
OP
O
OH
OHBase
O
HH
HOH
CH2
H H
OP
O
OH
OHBase
ribonucleotide reductase
dADP, dGDP, dUDP and dCDP are all synthesized by the same enzyme
Synthesized from nucleoside diphosphate (not mono or triphosphate) by
ribonucleotide reductase
All pathways shown previously led to synthesis of ribonucleotides
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Methylation of d-UMP via N5,N10-
methylene THF
Reaction inhibited by 5-fluorouracil (Efudex)
O
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HN
N
O
H
HO
OCH2
H
OH
H
H
H
OP
O-
O
-O
H
H
OCH2
H
OH
H
H
H
OP
O-
O
-O
HN
N
O
CH3
HO
HN
N
N
NH2N
O N
H
H
H
RH
H
HN
N
N
NH2N
O N
H
H
RH
d-UMP
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Catabolism of a pyrimidine
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