Dihydroorotase: Difference between revisions

Revision as of 12:35, 31 December 2024

Dihydroorotase

  [[File:Dihydroorotase|200px|alt=]]

Crystal structure of 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.

External Links

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

Template:Pyrimidine metabolism

@@ Line 1: / Line 1: @@
-Dihydroorotase is an enzyme that plays a crucial role in the biosynthesis of pyrimidine nucleotides, which are essential building blocks of DNA and RNA. It catalyzes the conversion of carbamoyl aspartate to dihydroorotate in the fourth step of the de novo pyrimidine biosynthesis pathway. This enzyme is found in all living organisms, from bacteria to humans, highlighting its fundamental importance in cellular processes.
+Dihydroorotase
-== Structure and Function ==
+{{Infobox enzyme
-Dihydroorotase is a homodimeric enzyme, meaning it is composed of two identical subunits. Each subunit consists of two domains: an N-terminal domain and a C-terminal domain. The N-terminal domain contains the active site, where the catalytic reaction takes place, while the C-terminal domain is involved in stabilizing the overall structure of the enzyme.
+| name = Dihydroorotase
+| image = Dihydroorotase_structure.png
+| width = 250
+| caption = Crystal structure of dihydroorotase
+| EC_number = 3.5.2.3
+| CAS_number = 9025-60-9
+| GO_code = 0004151
+}}
-The catalytic mechanism of dihydroorotase involves the binding of carbamoyl aspartate to the active site. This substrate undergoes a series of chemical reactions, resulting in the formation of dihydroorotate. The enzyme utilizes a metal ion, typically zinc or iron, as a cofactor to facilitate these reactions.
+'''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]].
-== Role in Pyrimidine Biosynthesis ==
+==Structure==
-Pyrimidine nucleotides are essential for DNA and RNA synthesis, as well as other cellular processes such as energy metabolism and signal transduction. The de novo pyrimidine biosynthesis pathway is responsible for the production of these nucleotides from simple precursors.
+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.
-Dihydroorotase is a key enzyme in this pathway, as it converts carbamoyl aspartate, which is derived from carbamoyl phosphate and aspartate, into dihydroorotate. Dihydroorotate is subsequently converted into orotate by the enzyme dihydroorotate dehydrogenase, leading to the synthesis of uridine monophosphate (UMP), a precursor for all pyrimidine nucleotides.
+==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]].
-== Clinical Significance ==
+==Mechanism==
-Given its crucial role in pyrimidine biosynthesis, any dysfunction or deficiency in dihydroorotase can have significant consequences. In humans, defects in this enzyme have been associated with rare genetic disorders known as dihydroorotase deficiency and hereditary orotic aciduria.
+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.
-Dihydroorotase deficiency is characterized by impaired pyrimidine biosynthesis, leading to a decrease in the production of pyrimidine nucleotides. This can result in severe developmental abnormalities, intellectual disability, and growth retardation. Hereditary orotic aciduria, on the other hand, is characterized by the accumulation of orotic acid, a precursor of pyrimidine nucleotides, in the urine. This condition can lead to anemia, failure to thrive, and developmental delays.
+==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.
-== References ==
+==Clinical Significance==
-<references>
+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]].
-<ref>Example Reference 1</ref>
-<ref>Example Reference 2</ref>
-</references>
-== See Also ==
+==Related Enzymes==
-* [[Pyrimidine Biosynthesis]]
+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.
-* [[Dihydroorotate Dehydrogenase]]
-* [[Carbamoyl Phosphate Synthetase]]
-* [[Aspartate Transcarbamoylase]]
+==See Also==
+* [[Pyrimidine metabolism]]
+* [[Nucleotide synthesis]]
+* [[Enzyme catalysis]]
+==External Links==
+* [Dihydroorotase at the US National Library of Medicine Medical Subject Headings (MeSH)]
+{{Enzymes}}
+{{Pyrimidine metabolism}}
+[[Category:EC 3.5.2]]
+[[Category:Metalloenzymes]]
+[[Category:Pyrimidine metabolism]]
 [[Category:Enzymes]]
-[[Category:Metabolic Pathways]]
-[[Category:Genetic Disorders]]