Dihydroorotase

Dihydroorotase is an enzyme that plays a crucial role in the de novo synthesis of pyrimidine nucleotides. It catalyzes the reversible cyclization of carbamoyl aspartate to dihydroorotate, an essential step in the pyrimidine biosynthesis pathway.

Structure

Dihydroorotase is a metalloenzyme that typically contains a zinc ion at its active site. The enzyme is composed of a single polypeptide chain that folds into a characteristic TIM barrel structure. The active site is located at the C-terminal end of the barrel, where the zinc ion is coordinated by histidine and aspartate residues.

Function

The primary function of dihydroorotase is to catalyze the conversion of N-carbamoyl-L-aspartate to L-dihydroorotate. This reaction is part of the pyrimidine biosynthesis pathway, which is essential for the production of nucleotides such as cytosine, thymine, and uracil. These nucleotides are critical components of DNA and RNA, making dihydroorotase vital for cellular replication and gene expression.

Mechanism

Dihydroorotase operates through a mechanism that involves the coordination of the substrate to the zinc ion, facilitating the cyclization reaction. The enzyme stabilizes the transition state and lowers the activation energy required for the reaction. The zinc ion plays a crucial role in polarizing the carbonyl group of the substrate, making it more susceptible to nucleophilic attack.

Regulation

The activity of dihydroorotase is regulated by the availability of its substrates and the presence of feedback inhibitors from downstream products in the pyrimidine biosynthesis pathway. Additionally, the enzyme can be regulated through post-translational modifications such as phosphorylation.

Clinical Significance

Deficiencies or malfunctions in dihydroorotase can lead to disruptions in pyrimidine metabolism, which may result in metabolic disorders. Understanding the function and regulation of dihydroorotase is important for developing therapeutic strategies for conditions related to nucleotide imbalance.

Related Enzymes

Dihydroorotase is part of a larger family of enzymes involved in pyrimidine metabolism, including carbamoyl phosphate synthetase, aspartate transcarbamoylase, and dihydroorotate dehydrogenase. These enzymes work in concert to ensure the proper synthesis and regulation of pyrimidine nucleotides.

See Also

• Pyrimidine metabolism
• Nucleotide synthesis
• Enzyme catalysis

External Links

• [Dihydroorotase at the US National Library of Medicine Medical Subject Headings (MeSH)]