Uridine monophosphate synthase: Difference between revisions

Revision as of 16:18, 9 February 2025

Uridine Monophosphate Synthase

Uridine monophosphate synthase (UMPS) is a bifunctional enzyme that plays a crucial role in the de novo synthesis of pyrimidine nucleotides. It catalyzes the final two steps in the conversion of orotate to uridine monophosphate (UMP), a precursor for all pyrimidine nucleotides.

Structure and Function

UMPS is a multifunctional enzyme composed of two distinct domains: orotate phosphoribosyltransferase (OPRTase) and orotidine-5'-phosphate decarboxylase (OMP decarboxylase). These domains are responsible for the sequential conversion of orotate to UMP.

Orotate Phosphoribosyltransferase (OPRTase)

The OPRTase domain catalyzes the reaction between orotate and phosphoribosyl pyrophosphate (PRPP) to form orotidine-5'-monophosphate (OMP). This reaction is the first committed step in the pyrimidine biosynthetic pathway.

Orotidine-5'-Phosphate Decarboxylase

The OMP decarboxylase domain subsequently decarboxylates OMP to produce UMP. This reaction is highly efficient and is considered one of the most proficient enzyme-catalyzed reactions known.

Biological Significance

UMPS is essential for the synthesis of pyrimidine nucleotides, which are necessary for the synthesis of RNA and DNA. Deficiencies in UMPS activity can lead to orotic aciduria, a rare metabolic disorder characterized by excessive excretion of orotic acid in the urine and associated with megaloblastic anemia.

Genetic and Clinical Aspects

The gene encoding UMPS is located on chromosome 3 in humans. Mutations in this gene can lead to hereditary orotic aciduria. Patients with this condition may present with growth retardation, developmental delay, and anemia. Treatment often involves supplementation with uridine, which bypasses the metabolic block.

Related Pages

References

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-'''Uridine monophosphate synthase''' ('''UMPS''') is a critical enzyme in the [[nucleotide synthesis]] pathway, playing a pivotal role in the [[pyrimidine metabolism]] that leads to the synthesis of [[uridine monophosphate]] (UMP). This enzyme is essential for the proper functioning of [[cellular metabolism]] and [[DNA synthesis]] and repair. UMPS is a bifunctional enzyme, combining two enzymatic activities, orotate phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (ODC), into a single polypeptide chain. This unique feature allows for a streamlined and efficient pathway for UMP production from orotic acid.
+== Uridine Monophosphate Synthase ==
-==Function==
+'''Uridine monophosphate synthase''' (UMPS) is a bifunctional enzyme that plays a crucial role in the [[de novo synthesis]] of [[pyrimidine]] nucleotides. It catalyzes the final two steps in the conversion of [[orotate]] to [[uridine monophosphate]] (UMP), a precursor for all pyrimidine nucleotides.
-UMPS catalyzes the last two steps of the de novo pyrimidine synthesis pathway. Initially, orotic acid, a pyrimidine base, is converted into orotidine monophosphate (OMP) by the OPRT activity. Subsequently, the ODC activity of UMPS decarboxylates OMP to produce UMP, a precursor for all other pyrimidine nucleotides. UMP is then further phosphorylated to uridine diphosphate (UDP) and uridine triphosphate (UTP), which are essential for RNA synthesis, and can be converted into cytidine triphosphate (CTP) for DNA synthesis and cell membrane biosynthesis.
-==Genetics==
+== Structure and Function ==
-The gene encoding UMPS is located on [[chromosome]] 3 in humans (3q13). Mutations in this gene can lead to a reduction or absence of UMPS enzyme activity, resulting in a rare genetic disorder known as [[hereditary orotic aciduria]]. This condition is characterized by the excretion of large amounts of orotic acid in urine and is associated with various symptoms, including growth retardation, megaloblastic anemia, and immunodeficiency.
+UMPS is a multifunctional enzyme composed of two distinct domains: orotate phosphoribosyltransferase (OPRTase) and orotidine-5'-phosphate decarboxylase (OMP decarboxylase). These domains are responsible for the sequential conversion of orotate to UMP.
-==Clinical Significance==
+=== Orotate Phosphoribosyltransferase (OPRTase) ===
-Hereditary orotic aciduria is the primary clinical condition associated with UMPS deficiency. Diagnosis is typically made through genetic testing and analysis of urine for elevated levels of orotic acid. Treatment often involves oral administration of uridine, which bypasses the enzymatic block caused by UMPS deficiency, leading to an improvement in symptoms.
+The OPRTase domain catalyzes the reaction between orotate and [[phosphoribosyl pyrophosphate]] (PRPP) to form orotidine-5'-monophosphate (OMP). This reaction is the first committed step in the pyrimidine biosynthetic pathway.
-In addition to its role in hereditary orotic aciduria, UMPS activity is also of interest in cancer research. Some cancer cells exhibit increased pyrimidine synthesis, and inhibiting UMPS can potentially disrupt their growth. Therefore, UMPS inhibitors are being explored as chemotherapeutic agents.
+=== Orotidine-5'-Phosphate Decarboxylase ===
+The OMP decarboxylase domain subsequently decarboxylates OMP to produce UMP. This reaction is highly efficient and is considered one of the most proficient enzyme-catalyzed reactions known.
-==Pharmacology==
+== Biological Significance ==
-Given its crucial role in nucleotide synthesis, UMPS is a target for certain chemotherapeutic agents. For example, [[5-fluorouracil]] (5-FU) and its prodrugs are metabolized into nucleotide analogs that can inhibit UMPS, leading to a depletion of UTP and subsequent inhibition of RNA and DNA synthesis in rapidly dividing cancer cells.
+UMPS is essential for the synthesis of pyrimidine nucleotides, which are necessary for the synthesis of [[RNA]] and [[DNA]]. Deficiencies in UMPS activity can lead to [[orotic aciduria]], a rare metabolic disorder characterized by excessive excretion of orotic acid in the urine and associated with megaloblastic anemia.
-==See Also==
+== Genetic and Clinical Aspects ==
+The gene encoding UMPS is located on chromosome 3 in humans. Mutations in this gene can lead to hereditary orotic aciduria. Patients with this condition may present with growth retardation, developmental delay, and anemia. Treatment often involves supplementation with uridine, which bypasses the metabolic block.
+== Related Pages ==
+* [[Pyrimidine metabolism]]
+* [[Orotic aciduria]]
 * [[Nucleotide synthesis]]
-* [[Pyrimidine metabolism]]
-* [[Hereditary orotic aciduria]]
+== References ==
-* [[5-Fluorouracil]]
+{{Reflist}}
+[[File:OPRTase_in_Complex_with_OMP.jpg|thumb|right|300px|Structure of OPRTase in complex with OMP.]]
 [[Category:Enzymes]]
-[[Category:Genetics]]
+[[Category:Pyrimidine metabolism]]
-[[Category:Metabolism]]
-[[Category:Pharmacology]]
-{{Medicine-stub}}