'de novo' UMP biosynthetic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the formation of UMP, uridine monophosphate, starting with the synthesis of (S)-dihydroorotate from bicarbonate; UMP biosynthesis may either occur via reduction by quinone, NAD+ or oxygen. [GOC:ecd, GOC:jl]

De novo UMP biosynthesis is a fundamental metabolic pathway responsible for synthesizing uridine monophosphate (UMP), a crucial precursor for RNA, DNA, and other essential biomolecules. The process occurs in the cytoplasm and involves a series of enzymatic reactions that convert aspartate and carbamoyl phosphate to UMP.

**1. Carbamoyl Phosphate Synthesis:** The pathway begins with the synthesis of carbamoyl phosphate from bicarbonate, ammonia, and ATP by the enzyme carbamoyl phosphate synthetase II (CPSII). This reaction is tightly regulated and requires the presence of the allosteric activator, N-acetylglutamate.

**2. Formation of Carbamoyl Aspartate:** Carbamoyl phosphate reacts with aspartate, catalyzed by aspartate transcarbamoylase (ATCase), forming carbamoyl aspartate.

**3. Dihydroorotate Synthesis:** Carbamoyl aspartate undergoes a ring closure reaction, catalyzed by dihydroorotase, to form dihydroorotate.

**4. Orotate Synthesis:** Dihydroorotate is oxidized to orotate by the enzyme dihydroorotate dehydrogenase. This step involves the transfer of electrons to the electron transport chain, generating NADH.

**5. OMP Synthesis:** Orotate is then converted to orotidylate (OMP) by the enzyme orotate phosphoribosyltransferase (OPRT), which utilizes phosphoribosyl pyrophosphate (PRPP) as a substrate.

**6. UMP Synthesis:** Finally, OMP is decarboxylated by the enzyme OMP decarboxylase to form UMP.

**Regulation of de novo UMP Biosynthesis:**

The de novo UMP biosynthetic pathway is tightly regulated at multiple levels, including:

* **Allosteric regulation of ATCase:** ATCase is inhibited by CTP, the end product of pyrimidine biosynthesis, and activated by ATP, indicating a feedback loop that regulates pyrimidine nucleotide levels.
* **Regulation of CPSII:** CPSII is activated by N-acetylglutamate, a product of the glutamate metabolism pathway, which ensures that the pathway is active only when glutamate is available.
* **Regulation of OPRT:** OPRT is inhibited by UMP, ensuring that the pathway is not overactive when UMP levels are high.

**Importance of De novo UMP Biosynthesis:**

De novo UMP biosynthesis is essential for:

* **RNA and DNA synthesis:** UMP is a precursor for all four RNA and DNA nucleotides.
* **Production of other essential biomolecules:** UMP is also a precursor for UDP-glucose, a key molecule involved in carbohydrate metabolism, and for CDP-choline, a precursor for phospholipids.
* **Cellular growth and proliferation:** De novo UMP biosynthesis is crucial for the rapid synthesis of nucleotides required for cell division and growth.

**Clinical Significance:**

Deficiencies in enzymes involved in de novo UMP biosynthesis can lead to various genetic disorders, including orotic aciduria and mitochondrial DNA depletion syndrome. These disorders are characterized by defects in pyrimidine metabolism and can result in severe neurological, hematological, and developmental abnormalities.'
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Proteins (3)

Compounds (35)