How Do Cells Synthesize Pyrimidines

How Do Cells Synthesize Pyrimidines?
In contrast to purines, pyrimidines are not synthesized as nucleotide derivatives. Instead, the pyrimidine ring
system is constructed before a ribose-5-P moiety is attached. Also, only two precursors, carbamoyl-P and
aspartate, contribute atoms to the six-membered pyrimidine ring (Figure 1), compared to seven precursors
for the nine purine atoms.
Figure 1. The metabolic origin of the six atoms of the pyrimidine ring.
In mammals have two enzymes for carbamoyl phosphate synthesis. Carbamoyl phosphate for pyrimidine
biosynthesis is formed by a carbamoyl phosphate synthetase II (CPS-II), a cytosolic enzyme. The substrates of
carbamoyl phosphate synthetase II are HCO3–, H2O, glutamine, and two ATPs (Figure 2). Thus, the N atom in
carbamoyl phosphate made by CPS-II comes from the amide group of glutamine. The first ATP is used to form
carboxy phosphate, an activated form of CO 2 (step 1, Figure 2). The glutamine amide displaces phosphate
from carboxy phosphate to give carbamate (step 2). Phosphorylation of carbamate by the second ATP in the
overall reaction yields carbamoyl phosphate (step 3). Because carbamoyl phosphate made by CPS-II in
mammals has no fate other than incorporation into pyrimidines, mammalian CPS-II can be viewed as the
committed step in the pyrimidine de novo pathway (Figure 3, step 1). Bacteria and plants have but one CPS,
and its carbamoyl phosphate product is incorporated into arginine as well as pyrimidines. Thus, the
committed step in bacterial pyrimidine synthesis is the next reaction, which is mediated by aspartate
transcarbamoylase (ATCase).
Figure 2. The carbamoyl phosphate synthetase II (CPS-II) reaction.

Figure 3. The de novo pyrimidine biosynthetic pathway.
ATCase catalyzes the condensation of carbamoyl phosphate with aspartate to form carbamoyl
aspartate (Figure 3, step 2). No ATP input is required at this step because carbamoyl phosphate represents an
“activated” carbamoyl group.
Step 3 of pyrimidine synthesis involves a ring closure and dehydration via linkage of the —NH 2 group
introduced by a carbamoyl phosphate with the former β-COO – of aspartate; this reaction is mediated by the
enzyme dihydroorotase. The product of the reaction is dihydroorotate (DHO), a six-membered ring
compound. Dihydroorotate is not a true pyrimidine, but its oxidation yields orotate, which is. This oxidation
(in step 4) is catalyzed by dihydroorotate (DHO) dehydrogenase. Bacterial dihydroorotate dehydrogenases are
NAD+-linked flavoproteins which are somewhat unusual in possessing both FAD and FMN; these enzymes
also have non-heme Fe-S centers as additional redox prosthetic groups. Whereas, the eukaryotic version of
dihydroorotate dehydrogenase is a protein component of the inner mitochondrial membrane; its immediate
e– acceptor is a quinone, and oxidation of the reduced quinone by the mitochondrial e– transport chain can
drive ATP synthesis via oxidative phosphorylation. At this stage, ribose-5-phosphate is joined to N-1 of
orotate in appropriate N-β -glycosidic configuration, giving the pyrimidine nucleotide orotidine-5’-
monophosphate, or OMP (step 5). The ribose phosphate donor is PRPP; the enzyme is orotate
phosphoribosyltransferase. Next reaction is catalyzed by OMP decarboxylase. Decarboxylation of OMP gives
UMP (uridine-5’-monophosphate, or uridylic acid), one of the two common pyrimidine ribonucleotides.
The reaction catalyzed by carbamoyl phosphate synthetase II (CPS-II), in which uses the amide of glutamine
to form carbamoyl-P (Figure 2).
Step 1: The first ATP consumed in carbamoyl phosphate synthesis is used in forming carboxy-phosphate,
an activated form of CO2.
Step 2: Carboxy-phosphate (also called carbonyl-phosphate) then reacts with the glutamine amide to yield
carbamate and glutamate.
Step 3: Carbamate is phosphorylated by the second ATP to give ADP and carbamoyl phosphate
The de novo pyrimidine biosynthetic pathway (Figure 3):
Step 1: Carbamoyl-P synthesis.
Step 2: Condensation of carbamoyl phosphate and aspartate to yield carbamoyl-aspartate is catalyzed by

aspartate transcarbamoylase (ATCase).
Step 3: An intramolecular condensation catalyzed by dihydroorotase gives the six-membered heterocyclic

ring
characteristic of pyrimidines. The product is dihydroorotate (DHO).
Step 4: The oxidation of DHO by dihydroorotate dehydrogenase gives orotate.
Step 5: PRPP provides the ribose-5-phosphate moiety that transforms orotate into orotidine-5'-monophosphate,
a pyrimidine nucleotide. Note that orotate phosphoribosyltransferase joins N-1 of the pyrimidine to
the
ribosyl group in appropriate β-configuration. PPi hydrolysis renders this reaction thermodynamically
favorable.
Step 6: Decarboxylation of OMP by OMP decarboxylase yields UMP.
References
CliffsNotes. (n.d.). Pyrimidine Metabolism. Retrieved from https://www.cliffsnotes.com/study-guides/biology/

biochemistry-ii/purines-and-pyrimidines/pyrimidine-metabolism
Creative Proteomics. (n.d.). Pyrimidine Biosynthesis Analysis Service. Retrieved from https://www.creative-
proteomics.com/services/pyrimidine-biosynthesis-analysis-service.htm
Garrett, R. H. & Grisham, C. M. (2011). Biochemistry (5th ed.). Cengage Learning.
Moffatt, B. A., & Ashihara, H. (2002). Purine and Pyrimidine Nucleotide Synthesis and Metabolism.
Arabidopsis Book, 1(9), 1506―1519. https://doi.org/10.1199/tab.0018

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Figure 2. The carbamoyl phosphate synthetase II (CPS-II) reaction.

The de novo pyrimidine biosynthetic pathway (Figure 3):

Step 1: Carbamoyl-P synthesis.

Step 2: Condensation of carbamoyl phosphate and aspartate to yield carbamoyl-aspartate is catalyzed by

Step 3: An intramolecular condensation catalyzed by dihydroorotase gives the six-membered heterocyclic

Step 4: The oxidation of DHO by dihydroorotate dehydrogenase gives orotate.

Step 6: Decarboxylation of OMP by OMP decarboxylase yields UMP.

CliffsNotes. (n.d.). Pyrimidine Metabolism. Retrieved from https://www.cliffsnotes.com/study-guides/biology/

Garrett, R. H. & Grisham, C. M. (2011). Biochemistry (5th ed.). Cengage Learning.

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