Pyrimidine Biosynthesis

• Pyrimidine nucleotide biosynthesis follows a unique strategy compared to purine synthesis.
• The pyrimidine ring is assembled before being attached to ribose-phosphate.
• Carbamoyl phosphate synthetase II (CPS II) starts pyrimidine synthesis in the cytosol.
• In contrast to CPS I in the urea cycle, which uses ammonia, CPS II uses glutamine as its nitrogen source.
• Aspartate transcarbamoylase (ATCase) is responsible for catalyzing the committed step in pyrimidine biosynthesis.
• ATCase combines carbamoyl phosphate and aspartate, leading to carbamoyl aspartate.
• Cytidine triphosphate (CTP), the pathway's final product, inhibits ATCase through feedback inhibition.
• Dihydroorotase facilitates the cyclization of carbamoyl aspartate, resulting in dihydroorotate.
• Dihydroorotate dehydrogenase (DHODH) oxidizes dihydroorotate to create orotate.
• DHODH is located on the outer surface of the inner mitochondrial membrane.
• Orotate is linked to PRPP (phosphoribosyl pyrophosphate) through the action of orotate phosphoribosyltransferase.
• This process leads to the formation of orotidine monophosphate (OMP).
• OMP decarboxylase mediates the conversion of OMP to uridine monophosphate (UMP).
• UMP undergoes phosphorylation, resulting in both UDP and UTP.
• CTP synthetase converts UTP to CTP.
• CTP synthetase depends on glutamine as a nitrogen donor.
• Ribonucleotide reductase is responsible for converting ribonucleotides into deoxyribonucleotides.
• Thymidylate synthase converts dUMP to dTMP.
• Tetrahydrofolate is required as a cofactor in the conversion of dUMP to dTMP.
• Dihydrofolate reductase (DHFR) is responsible for regenerating tetrahydrofolate from dihydrofolate.
• Several drugs are designed to target pyrimidine biosynthesis as a cancer therapy.
• 5-Fluorouracil acts as a suicide inhibitor of thymidylate synthase.
• Methotrexate functions by inhibiting dihydrofolate reductase (DHFR).
• Mycophenolic acid inhibits IMP dehydrogenase, which is involved in guanine nucleotide synthesis, indirectly affecting pyrimidine synthesis.
• Genetic defects in pyrimidine biosynthetic enzymes can lead to different disorders.
• Orotic aciduria arises from a deficiency in either orotate phosphoribosyltransferase or OMP decarboxylase.
• A key indicator of orotic aciduria is the accumulation of orotic acid in the urine.
• Treatment for orotic aciduria involves administering uridine, which bypasses the blocked step and reduces orotic acid production.

Explore the unique pyrimidine nucleotide biosynthesis strategy. Learn about the key enzymes involved, including CPS II, ATCase, and DHODH, and their roles in the synthesis. Understand the regulation of pyrimidine synthesis through feedback inhibition.