5-2 Necleotide Metabolism (pyrimidine) - Home

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Transcript 5-2 Necleotide Metabolism (pyrimidine) - Home

The nomenclature of pyrimidine depends
on their linkage to a pentose
Nucleotidase
Phosphorylase
Cytosine
Base
Cytidine
Nucleoside*
Base
Cytidine Monophosphate
Nucleotide
Base (P04 ester)

shorter pathway than for purines

base is made first, then attached to ribose-P
(unlike purine biosynthesis)

only 2 precursors (aspartate and glutamine, plus
HCO3-) contribute to the 6-membered ring

requires 6 steps (instead of 11 for purine)

the product is UMP (uridine monophosphate)

Condensation of glutamine, bicarbonate in the
presence of ATP

Carbamoyl phosphate synthetase exists in 2 types:
CPS-I which is a mitochondrial enzyme and
is dedicated to the urea cycle and arginine
biosynthesis)
CPS-II, a cytosolic enzyme used here
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
•enzyme
(ATCase)
is
aspartate
transcarbamoylase
•catalyzes the condensation of carbamoyl
phosphate with aspartate with the release of Pi
•ATCase is the major site of regulation in
bacteria; it is activated by ATP and inhibited by
CTP
•carbamoyl
phosphate
is
an
“activated”
compound, so no energy input is needed at this
step

enzyme: dihydroorotase

forms a pyrimidine from carbamoyl
aspartate

water is released in this process

In E. coli, the first 3 enzymatic reactions are
catalyzed by 3 separate proteins/enzymes

In animals, all 3 steps are found in a multifunctional
enzyme (210 kD).

The acronym CAD is used as a name for the
multienzyme: carbamoyl phosphate synthetase,
aspartate transcarbamoylase and dihydroorotase

An irreversible reaction

Enzyme: dihydroorotate dehydrogenase

Oxidizing power is derived from quinones
(thru coenzyme Q)

Enzyme: orotate phosphoribosyl transferase

Ribose phosphate originates from PRPP

product
(OMP)

orotate phosphoribosyl transferase is also
used in salvage of uracil and cytosine to their
corresponding nucleotide
is
orotidine-5’-monophosphate

enzyme: OMP decarboxylase

product: uridine monophosphate (UMP)

In animals, steps 5 and 6 are catalyzed by
a single polypeptide with 2 active sites
PRPP
O
HO
P
O
H
CH 2
O
OH
H
O
O
O
H
O
H
P
O
P
O-
HN
OH
O
N
O-
O-
OH
COOPPi
orotate phosphoribosyl transferase
H
O
O
HN
HN
O
HO
P
O
O
O
CH 2
N
COOHO
O
OH
H
CO 2
P
O
CH 2
O
H
H
OH
orotidine monophosphate (OMP)
N
OH
H
H
OH
O
OMP decarboxylase
(uses no cofactors)
H
H
H
OH
OH
An inherited human disease caused by a deficiency
in the multifunctional enzyme that catalyzes the last
2 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
UMP + ATP
UDP + ADP
nucleoside diphosphate kinase
UTP + ADP
UDP + ATP
CTP synthase (cytidylate synthetase)
O
H
glutamine +
ATP
Glutamate +
ADP +Pi
NH2
N
O
N
N
Ribose 3 phosphate
UTP
(in bacteria, ammonia donates the amino group)
O
N
Ribose 3 phosphate
CTP
Glutamine +
HCO 3- +
ATP
carbamoyl phosph.
synthetase
Carbamoyl
phosphate
Orotate
orotate
phosphoribosyl
transferase
UTP + CTP
UMP
UTP and CTP are feeback inhibitors of CPS II
OMP
All pathways shown previously led to synthesis of ribonucleotides
ribonucleotide reductase
OH
OH
P
Base
O
CH 2
O
OH
O
H
H
OH
P
Base
O
CH 2
O
H
H
OH
OH
O
H
H
H
H
OH
H
dADP, dGDP, dUDP and dCDP are all synthesized by the same enzyme
Synthesized from nucleoside diphosphate (not mono or triphosphate) by
ribonucleotide reductase
Methylation of d-UMP via N5,N10methylene THF
Reaction
inhibited
fluorouracil (Efudex)
by
5-
O
H
H
HN
N
H2 N
N
H
H
O
O-O
P
O
N
HN
H
N
O
CH 2 O
O
N
H
H
H
R
H
H
H
OH
H
d-UMP
O
CH 3
H
HN
N
H2 N
O
O-O
P
O
N
H
H
N
O
H
H
H
OH
H
HN
CH 2 O
O
N
H
H
N
R
Catabolism of a pyrimidine