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Pyrimidine Synthesis and
Degradation
Unlike the synthesis of the purine ring,
which is constructed on a preexisting
ribose 5-phosphate donated by PRPP,
the pyrimidine ring is synthesized first
and the sources of the atoms are
glutamine, CO2, and aspartic acid
A. Synthesis of carbamoyl phosphate
This is the first (regulated) step of this
pathway.
Carbamoyl
phosphate
is
synthesized from glutamine and CO2,
catalyzed
by
carbamoyl
phosphate
synthetase (CPS) II. CPS II is inhibited by
UTP (the end product of this pathway) and is
activated by ATP and PRPP.
B. Synthesis of orotic acid
The second step in pyrimidine synthesis is the
formation of carbamoylaspartate, catalyzed
by [aspartate transcarbamoylase]. The
pyrimidine ring is then closed hydrolytically
by
dihydroorotase.
The
resulting
dihydroorotate is oxidized to produce orotic
acid
(orotate)
by
enzyme
called
[dihydroorotate dehydrogenase].
Note:
All enzymes that participate in pyrimidine
biosynthesis are cytoplasmic, except dihydroorotate
dehydrogenase which is attached to the inner
mitochondrial membrane.
C. Formation of a pyrimidine nucleotide
Following the completion of closure of
pyrimidine ring (orotate), the ring will be
converted to a pyrimidine nucleotide by an
enzyme called [orotate phosphoribosyl
transferase] utilizing PRPP again as a source
of ribose 5′-phosphate with liberation of
phosphate.
The resulting nucleotide is called OMP
(Orotidine 5′- monophosphate) which is the
parent pyrimidine nucleotide. OMP will finally
be decarboxylated by [OMP decarboxylase]
to UMP (uridine monophosphate). UMP is
phosphorylated to UTP.
The last 2 enzymes i.e. Orotate
phosphoribosyltransferase
and
orotidylate decarboxylase are catalytic
domains of a single polypeptide chain
called UMP Synthase.
Orotic aciduria— a rare genetic defect—is
caused by a deficiency of this bifunctional
enzyme, resulting in orotic acid to appear
in the urine in association to growth
impairment and megaloblastic anaemia.
Treatment is by administration of uridine
leading to inhibition of the 1st step
reaction (i.e CSP II) and reduction of
orotate production.
D. Synthesis of cytidine triphosphate (CTP)
E. Synthesis of thymidine monophosphate
(TMP) from dUMP
dUMP is converted to dTMP by [thymidylate
synthase], which uses N5,N10-methylene
tetrahydrofolate as the source of the methyl
group. Inhibitors of thymidylate synthase
include thymine analogs such as 5fluorouracil, which serve as successful
antitumor agents.
Salvage of pyrimidines
Few pyrimidine bases are salvaged in
human cells. However, the pyrimidine
nucleosides can be salvaged by
nucleoside kinases that utilize ATP in the
phosphorylation of the nucleosides to
nucleotides. [Note: The salvage of
pyrimidine nucleotides is the basis for
using uridine in the treatment of
hereditary orotic aciduria.]
Degradation of pyrimidine
nucleotides
Unlike the purine bases that are not in
cleaved human cells, the pyrimidine ring
is opened and degraded to highly
soluble products, β-alanine and βaminoisobutyrate, with the production of
NH3 and CO2.
Naturally Occurring free nucleotides that are
not part of nucleic acids but have important
biological functions:
Some nucleotides are not part of nucleic acids
but they freely present in the cell cytosole
and they have important functions like the
following:
1. ATP (Adenosine triphosphate):
It is the primary source of energy in too many energy
requiring biological processes. It is used and
converted to ADP+ Pi in the cytoplasm, however, the
inner mitochondrial membrane requires specialized
carriers to transport ADP and Pi from cytoplasm to
mitochondria where it is synthesized again by an
enzyme called ATP- synthetase. This enzyme
complex synthesizes ATP using the energy of one
proton gradient generated by [Electron Transport
Chain]. ATP is important in oxidative phosphorylation
reactions.
2. Cyclic Adenosine monophosphate (cAMP)
A membrane bound enzyme called (adenylate
cyclase) converts ATP to 3′,5′-adenosine
monophosphate (also called cyclic AMP or
cAMP). It is considered as a second
messenger for chemical signals like hormones
or neurotransmitters, each of which binds to a
unique type of membrane receptor and
considered
as
1st
messenger.
cAMP is rapidly hydrolyzed to 5′- AMP by an
enzyme called [c AMP Phosphodiesterase]
which cleaves the cyclic 3′,5 phosphodiester
bond. 5′- AMP is not an intracellular signaling
molecule,
thus
the
effects
of
neurotransmitters or hormone- mediated
increases of c AMP are rapidly terminated if
the extracellular signal (1st messenger) is
removed.
3UDPGLUCOSE,
UDP-GALACTOSE,
UDP-NACETYLGLUCOSAMINE
AND
UDPNACETYLGALACTOSAMINE
These are nucleotide sugars that are
considered as the
precursors of the
carbohydrate components of glycoproteins.
In addition, GDP-mannose, GDP-L-fucose
(which is synthesized from GDP-mannose),
and CMP-N-acetylneuraminic acid may
donate sugars to the growing glycoprotein
chain.
4. UDP- glucoronic acid
It is produced by the oxidation of UDPglucose. It is the active form of glucoronic
acid
that
donates
the
sugar
in
glycosaminoglycans synthesis and other
glucuronylation reactions. In addition, UDPglucoronic acid is involved in the conjugation
to less polar compounds like steroids, some
drugs, and bilirubin. Thus it is an important
detoxifying intermediate.
5- Flavine Adenine Dinucleotide (FAD)
and Nicotinamide Adenine
Dinucleotide (NAD):
These are important co-enzymes that play
important roles in certain metabolic
processes like citric acid cycle and
electron transport system