Part 1: Formation of carbamoyl phosphate

de novo synthesis of a pyrimidine

Requires

2 ATP
Bicarbonate (HCO3-)
Ammonia (NH3) [which is derived from glutamine hydrolysis].

Again, this is why nucleotide production occurs in the liver, because it is the organ that can best handle nitrogen (ammonia) waste – so it makes sense that if nucleotide synthesis relies on ammonia formation, it ought to occur in a body organ that can best manage ammonia!

Forms

Carbamoyl phosphate

These molecules combine together with a phosphate as carbamoyl phosphate.
2 ADP and a phosphate are released in the reaction (remember that glutamine hydrolysis, itself, converts glutamine to glutamate).
And carbamoyl phosphate synthetase II catalyzes the reaction (in the cytosol).

(In comparison to CPS I, which acts within mitochondria)

Part 4

Formation of the uracil base of UMP, the thymine base of TMP, and the cytosine base of CTP

It's important that we skip to the end, now, and show where we want to end up in order to understand the biochemistry of the next steps in pyrimidine biosynthesis.

Uracil

The base of UMP

The decarboxylated monophosphate of OMP.

Forms the standard pyrimidine ring.
Include the oxygens that were found in orotate at carbons 2 and 4.
Leave off, for reasons we'll see, the carboxyl, at carbon 6 (it's decarboxylated).

Thymine

Thymine base of the monophosphate TMP.

Forms the standard pyrimidine ring.

Include the oxygens that were found in orotate at carbons 2 and 4.
Leave off, for reasons we'll see, the carboxyl, at carbon 6: it's decarboxylated.

If this looks exactly the same as uracil, you've drawn the structure correctly.
BUT there is a methyl at carbon 5 on the thymine
Thymine is a DNA base whereas uracil is an RNA base and is unmethylated at carbon 5.

Cytosine

The base of the triphosphate, CTP.
Forms the pyrimidine ring.
Include the oxygen that was found in orotate at carbon 2 but at carbon 4, add an amino group, instead.

Leave carbon 5 unmethylated.
Leave carbon 6 decarboxylated.

Orotidylate (OMP) to Uridylate (UMP)

OMP is decarboxylated via orotidylate decarboxylase to UMP (uridylate), which is the monophosphate of uracil.

Consider that without the enzyme orotidylate decarboxylase, it would take ~ 78 million years (a million life-times!) for the decarboxylation to occur.

UTP (Uracil) to CTP (Cytosine)

Uridylate (uridine monophosphate) is phosphorylated to UDP and UTP then that via glutamine hydrolysis ammonia is added to convert UTP to CTP (via CTP synthetase).

UMP to dUMP

Requires Ribonucleotide reductase

Let's address the catalytic action of ribonucleotide reductase, which is the enzyme that catalyzes the replacement of the 2' hydroxyl group on the ribose moiety with a hydrogen: in this instance, we need it to convert the uridylate (uridine monophosphate) to deoxyuridylate (deoxyuridine monophosphate).

Ribonucleotide reductase catalyzes the following reductions where the precursors are:

ADP, GDP, CDP, UDP

and the products are:

dADP, dGDP, dCDP, dUDP

Thus, in our reaction, omit the phosphorylation of UMP to UDP and subsequent dephosphorylation that will occur and simply show the role of ribonucleotide reductase in the conversion of uridylate to deoxyuridylate (dUMP), because that will lead us to the key knowledge point that we are converting uracil an RNA base to thymine a DNA (a deoxyribonucleic acid base).

dUMP to dTMP

N5, N10-Methylene-tetrahydrofolate adds a methyl group to deoxyuridylate.

Note that you'll see thymine indicated either as dTMP (to emphasize that the 2' hydroxyl is deoxygenated or, simply, as TMP.
Dihydrofolate is released.

Dihydrofolate reductase & Tetrahydrofolate reformation

For completion, dihydrofolate reductase uses NADPH as the reductant to reform tetrahydrofolate.

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Pyrimidine Biosynthesis

Pyrmidine biosynthesis occurs via two key pathways:

De novo synthesis

Involves ring synthesis followed by PRPP (activated ribose (phosphorylated ribose) attachment in the formation of the nucleotide.

Ring synthesis involves bicarbonate, ammonia, and 2 ATP.
These components undergo a reaction that is catalyzed by CPS 2 (cabamoyl phosphate synthetase 2).
The next set of necessary components are aspartate and NAD+.

Salvage pathway

Means the base is reincorporated into the nucleotide.

Nucleoside vs Nucleotide

A nucleoside is a BASE + a SUGAR.
A nucleotide is a BASE + a SUGAR + PHOSPHATE

Pyrimidine Biosynthesis

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