Pyrimidine synthesis
Purines are synthesized by building the ring system on the ribose. In contrast, the pyrimidine ring is constructed first, followed by attachment of the pyrimidine base to ribose using a phosphoribosyltransferase similar to those used for purine salvage reactions. In both purine and pyrimidine synthesis, PRPP is used as the ribose donor, but the stage of the pathway is different. The first step of the pyrimidine synthesis pathway is the condensation of bicarbonate with nitrogen derived from glutamine to form carbamoyl phosphate. The enzyme involved is carbamoyl phosphate synthetase II and is different from the enzyme catalyzing the equivalent step in the urea cycle.
Carbamoyl phosphate synthetase II has three major differences:
1. It uses nitrogen from glutamine rather than from ammonium
2. It is a cytosolic rather than a mitochondrial enzyme
3. Its regulation is completely different.
In animals two separate pools of carbamoyl phosphate were noticed, they are
1. Mitochondrial pool, used for the urea cycle
2. Cytosolic pool, used for pyrimidine synthesis.
While in bacteria a single pool of carbamoyl phosphate was used for both purposes, and therefore their pathways are regulated slightly differently. The pyrimidine ring skeleton comes from two molecules, the carbamoyl phosphate from the first step, and the aspartate added in the second step. The ribose ring is not added until the synthesis of the pyrimidine orotic acid is complete. This orotic acid is then attached to PRPP with release of pyrophosphate.
UMP is the first “completed” product. UMP can then be phosphorylated to produce UDP. UDP acts as a branch point; it can be converted to UTP and used as a nucleotide, or it can serve as a substrate for the synthesis of the two other major pyrimidine nucleotides. Both CTP and TTP were synthesized as described in the following reaction.
Intext Questions
1. Nucleotide anabolism can be broadly characterized as ……………….
biosynthesis
2. Purine nucleotides are synthesized in ………………. of most of the tissues and
major site is ……………….
3. In salvage pathway purines both ………………. and ………………. can be
salvaged
4. The most common abnorbality of purine metabolism is ………………. in blood
5. In gout the ………………. accumulates in synovial fluid
