CAD, A Multienzymatic Protein at the Head of de Novo Pyrimidine Biosynthesis

Caño-Ochoa, Francisco Del; Moreno-Morcillo, María; Ramón‐Maiques, Santiago

doi:10.1007/978-3-030-28151-9_17

Cited by 35 publications

(42 citation statements)

References 128 publications

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“…The dihydroorotase domain, a Zn metalloenzyme locating between CPS and ATC domains, hydrolyzes carbamoyl aspartate to dihydroorotate (DHO) (8). CAD, governing the initiation of pyrimidine de novo synthesis pathway (9)(10)(11), is under precise control in cells (12,13).…”

Section: Pyrimidine Biosynthesis Through De Novo Pathwaysmentioning

confidence: 99%

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Wang

Cui

et al. 2021

Front. Oncol.

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Metabolic rewiring is considered as a primary feature of cancer. Malignant cells reprogram metabolism pathway in response to various intrinsic and extrinsic drawback to fuel cell survival and growth. Among the complex metabolic pathways, pyrimidine biosynthesis is conserved in all living organism and is necessary to maintain cellular fundamental function (i.e. DNA and RNA biosynthesis). A wealth of evidence has demonstrated that dysfunction of pyrimidine metabolism is closely related to cancer progression and numerous drugs targeting pyrimidine metabolism have been approved for multiple types of cancer. However, the non-negligible side effects and limited efficacy warrants a better strategy for negating pyrimidine metabolism in cancer. In recent years, increased studies have evidenced the interplay of oncogenic signaling and pyrimidine synthesis in tumorigenesis. Here, we review the recent conceptual advances on pyrimidine metabolism, especially dihydroorotate dehydrogenase (DHODH), in the framework of precision oncology medicine and prospect how this would guide the development of new drug precisely targeting the pyrimidine metabolism in cancer.

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Section: Pyrimidine Biosynthesis Through De Novo Pathwaysmentioning

confidence: 99%

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Wang

Cui

et al. 2021

Front. Oncol.

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“…CAD encodes a multienzymatic cytoplasmic protein harboring four functional domains, each catalyzing one of the initial reactions for de novo biosynthesis of pyrimidine nucleotides: glutamine amidotransferase (GLN), carbamoyl phosphate synthetase (SYN), aspartate transcarbamoylase (ATC), and dihydroorotase (DHO) 1 – 3 (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy

Caño-Ochoa

Abedalthagafi

et al. 2020

Genetics in Medicine

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Purpose Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy. Methods Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype. Results We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype. Conclusions We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.

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“…CAD encodes a multienzymatic cytoplasmic protein harboring four functional domains, each catalyzing one of the initial reactions for de novo biosynthesis of pyrimidine nucleotides: glutamine amidotransferase (GLN), carbamoyl-phosphate synthetase (SYN), aspartate transcarbamoylase (ATC) and dihydroorotase (DHO) [1][2][3] (Figure 1). This metabolic pathway is essential for nucleotide homeostasis, cell growth and proliferation 4 .…”

Section: Introductionmentioning

confidence: 99%

Cell-based analysis ofCADvariants identifies individuals likely to benefit from uridine therapy

Caño-Ochoa

Abedalthagafi

et al. 2020

Preprint

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Purpose: Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the non-specific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy.Methods: Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype. Results:We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype. Conclusions:We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD deficient individuals, who could benefit from uridine therapy. KeywordsCongenital disorder of glycosylation; de novo pyrimidine biosynthesis; carbamoyl phosphate synthetase; aspartate transcarbamoylase; dihydroorotase

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CAD, A Multienzymatic Protein at the Head of de Novo Pyrimidine Biosynthesis

Cited by 35 publications

References 128 publications

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine

Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy

Cell-based analysis ofCADvariants identifies individuals likely to benefit from uridine therapy

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