CDA (Cytidine Deaminase)
2009-09-01 Yoshiro Saito AffiliationDivision of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
DNA/RNA
Description
The human CDA spans approximately 30 kB and consists of 4 exons. No splice variant was reported.
Transcription
The full length CDA mRNA is 985 bp with an open reading frame of 441 bp.
Pseudogene
No pseudogene was reported.
Proteins
Note
X-ray crystal structures of CDA from Yeast (1R5T) and Bacillus Subtilis (1JTK, 1UX0, 1UX1 and 1UWZ) are publicized in the PDB.
Description
The human CDA protein consists of 146 amino acids and has a molecular weight of 16,184. This is a soluble cytoplasmic protein and it is involved in pyrimidine salvaging.
Expression
Although the protein expression profile in tissues has not been revealed, its mRNA expression determined by Nothern blotting was observed in high levels in liver and placenta, low in lung and kidney, but not in heart, brain and muscle (Laliberte and Momparler, 1994). High CDA activity was reported in liver and spleen, and moderate in lung, kidney, large intestine mucosa and colon mucosa (Ho, 1973).
Localisation
This protein is localized in cytoplasm.
Function
CDA catalyzes hydrolytic deamination of cytidine and deoxycytidine into uridine and deoxyuridine, respectively. This protein also inactivate chemotherapeutic nucleoside analogs 2,2-difluorodeoxycytidine (gemcitabine) and cytosine arabinoside (cytarabine, Ara-C).
Mutations
Germinal
Two nonsynonymous genetic varitions, 79A>C (Lys27Gln) and 208G>A (Ala70Thr), have been found in the human CDA gene (Yue et al., 2003). Ethnic differences in the minor allele frequencies of these variations have been reported. The 79A>C (Lys27Gln) was found at 0.30-0.36 frequencies in Caucasians, at 0.20-0.21 in Japanese and at 0.04-0.10 in Africans (Ueno et al., 2007). In contrast, the 208G>A (Ala70Thr) was found at 0.13 in Africans and 0.04 in Japanese, but not in Caucasians. Interestingly, the 208G>A (Ala70Thr) has not been detected in African-Americans. The mutant protein with 70Thr was reported to have remarkably reduced activities in vitro (Yue et al., 2003) and in vivo (Sugiyama et al., 2007). On the other hand, controvertial results on the effects of activities have been obtained for 79A>C (Lys27Gln). The recombinant enzyme with Gln27 retained its catalytic activities for cytidine and ara-C as substrates (Yue et al., 2003), while showing reduced activity with increased Km value in the case of gemcitabine (Gilbert et al., 2006). However, the minor allele of this SNP was reported to be associated with higher enzymatic activities for gemcitbine based on tests using lysates of red blood cells taken from Caucasian cancer patients (Giovannetti et al., 2008; Tibaldi et al., 2008). In line with this, the minor allele was associated with decreased response, shorter time to progression and overall survival, and lower frequencies of grade 3 and 4 neutropenia in Caucasian non-small cell lung cancer patients treated with gemcitabine and cisplatin (Tibaldi et al., 2008).
Implicated in
Entity name
Adverse reactions by anti-cancer drugs
Note
CDA is involved in the metabolic inactivation of anti-cancer drug gemcitabine and cytosine arabinoside (ara-C). CDA polymorphisms 208G>A (Ala70Thr) has been associated with adverse reactions including neutropenia by gemcitabine. Reduced clearance of gemcitabine and plasma CDA activities significantly depended on the number of minor allele 208A (70Thr) in 256 Japanese patients with cancer (Sugiyama et al., 2007). This polymorphism was also associated with increased incidences of grade 3/4 neutropenia in the patients coadministered with other anti-cancer drugs (Sugiyama et al., 2007). Notably, one patient with homozygous 208A (70Thr) showed severe hematologic and nonhematologic toxicities during chemotherapy with gemcitabine and cisplatin, and had 1/5 value of gemcitabine clearance and 12% of plasma CDA activity compared to those of the patients without CDA nonsynonymous polymorphisms (Yonemori et al., 2005, Sugiyama et al., 2007). Among the other panels of Japanese pancreatic cancer patients, three patients encountered life-threatening toxicities after chemotherapies including gemcitabine (Ueno et al., 2009). Two of them had homozygous CDA 208A (70Thr), and showed extremely low plasma CDA activity and gemcitabine clearance. Together with the previous one patient, homozygous 208A (70Thr) was suggested to be a key factor causing gemcitabine-induced severe adverse reactions in the Japanese (Ueno et al., 2009). With regard to another nonsynonymous polymorphism, the minor allele of CDA 79A>C (Lys27Gln) was associated with decreased response, shorter time to progression and overall survival, and lower frequencies of grade 3 and 4 neutropenia in Caucasian non-small cell lung cancer patients treated with gemcitabine and cisplatin (Tibaldi et al., 2008). Homozygous 79C (27Gln) was also associated with increased postinduction treatment-related motality with ara-C in patients with acute myeloid leukemia (Bhatla et al., 2008).
Entity name
Disease
CDA genetic polymorphisms (79A>C, Lys27Gln; 208G>A, Ala70Thr; 435T>C, silent) were not associated with susceptibility to acute myeloid leukemia in Chinese children (Yue et al., 2007).
Entity name
Colorectal cancer
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 19036079 | 2009 | Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia. | Bhatla D et al |
| 16551864 | 2006 | Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. | Gilbert JA et al |
| 18600531 | 2008 | Correlation between cytidine deaminase genotype and gemcitabine deamination in blood samples. | Giovannetti E et al |
| 18203981 | 2008 | Novel blood-based, five-gene biomarker set for the detection of colorectal cancer. | Han M et al |
| 4518302 | 1973 | Distribution of kinase and deaminase of 1-beta-D-arabinofuranosylcytosine in tissues of man and mouse. | Ho DH et al |
| 7923172 | 1994 | Human cytidine deaminase: purification of enzyme, cloning, and expression of its complementary DNA. | Laliberté J et al |
| 17194903 | 2007 | Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. | Sugiyama E et al |
| 18347182 | 2008 | Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. | Tibaldi C et al |
| 19293806 | 2009 | Homozygous CDA*3 is a major cause of life-threatening toxicities in gemcitabine-treated Japanese cancer patients. | Ueno H et al |
| 17595663 | 2007 | Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy? | Ueno H et al |
| 15814642 | 2005 | Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin. | Yonemori K et al |
| 12544510 | 2003 | A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. | Yue L et al |
| 18067088 | 2007 | [Single-nucleotide polymorphisms of the cytidine deaminase gene in childhood with acute leukemia and normal Chinese children]. | Yue LJ et al |
Other Information
Locus ID:
NCBI: 978
MIM: 123920
HGNC: 1712
Ensembl: ENSG00000158825
Variants:
dbSNP: 978
ClinVar: 978
TCGA: ENSG00000158825
COSMIC: CDA
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000158825 | ENST00000375071 | P32320 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA165966294 | Palmar-plantar erythrodysaesthesia syndrome | Disease | ClinicalAnnotation | associated | PD | 18473752, 21325291, 23736036 | |
| PA166131569 | difluorodeoxyuridine | Chemical | ClinicalAnnotation | associated | PK | 22838949 | |
| PA443622 | Carcinoma, Non-Small-Cell Lung | Disease | ClinicalAnnotation | associated | PK | PD | 16551864, 17194903, 17885621, 18347182, 18538445, 18600531, 20665488, 21325291, 21521023, 21590444, 21625252, 22134350, 22546611, 23651026 |
| PA443937 | Drug Toxicity | Disease | VariantAnnotation | associated | PD | 25850965 | |
| PA444511 | Hyperbilirubinemia | Disease | ClinicalAnnotation | associated | PD | 28347776 | |
| PA444750 | Leukemia | Disease | ClinicalAnnotation | associated | PK | PD | 19458626, 21325291, 21521023, 22304580, 22379997, 23651026, 25003625 |
| PA444760 | Leukemia, Myeloid, Acute | Disease | ClinicalAnnotation | associated | PK | PD | 21325291, 21521023, 22304580, 23651026 |
| PA444761 | Leukemia, Myeloid | Disease | ClinicalAnnotation | associated | PD | 19458626, 21325291, 21521023, 23651026 | |
| PA444840 | Lymphoma | Disease | ClinicalAnnotation | associated | PK | PD | 19458626, 21325291, 21521023, 22304580, 22379997, 23651026, 25003625 |
| PA444937 | Mesothelioma | Disease | ClinicalAnnotation | associated | PK | PD | 16551864, 17194903, 17885621, 18347182, 18538445, 18600531, 20665488, 21325291, 21521023, 21590444, 21625252, 22134350, 22546611, 23651026 |
| PA445062 | Neoplasms | Disease | ClinicalAnnotation | associated | PK | PD | 15814642, 17194903, 17885621, 18473752, 21325291, 21521023, 22304580, 22838949, 23651026, 23736036, 24167597, 24300978, 24361227, 28347776 |
| PA445113 | Neutropenia | Disease | ClinicalAnnotation, VariantAnnotation | associated | PK | PD | 15814642, 17194903, 24361227, 30889042 |
| PA445218 | Pancreatic Neoplasms | Disease | ClinicalAnnotation, VariantAnnotation | associated | PK | PD | 16551864, 17194903, 17885621, 18347182, 18538445, 18600531, 20665488, 21325291, 21521023, 21590444, 21625252, 22134350, 22546611, 23651026, 30889042 |
| PA448771 | capecitabine | Chemical | ClinicalAnnotation | associated | PD | 18473752, 21325291, 23736036, 24167597, 28347776 | |
| PA449177 | cytarabine | Chemical | ClinicalAnnotation | associated | PK | PD | 18473752, 19458626, 21325291, 21521023, 22304580, 22379997, 23230131, 23651026, 25003625 |
| PA449748 | gemcitabine | Chemical | ClinicalAnnotation, Literature, MultilinkAnnotation, Pathway, VariantAnnotation | ambiguous | PK | PD | 15814642, 16551864, 17194903, 17885621, 18347182, 18538445, 18600531, 20665488, 21325291, 21521023, 21590444, 21625252, 22134350, 22546611, 22838949, 23651026, 24300978, 24361227, 25162786, 30889042 |
| PA451996 | azacitidine | Chemical | VariantAnnotation | associated | PD | 25850965 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38294491 | 2024 | Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs. | 0 |
| 38294491 | 2024 | Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs. | 0 |
| 36329350 | 2023 | Upregulation of cytidine deaminase in NAT1 knockout breast cancer cells. | 1 |
| 37282621 | 2023 | Seven-membered ring nucleobases as inhibitors of human cytidine deaminase and APOBEC3A. | 3 |
| 36329350 | 2023 | Upregulation of cytidine deaminase in NAT1 knockout breast cancer cells. | 1 |
| 37282621 | 2023 | Seven-membered ring nucleobases as inhibitors of human cytidine deaminase and APOBEC3A. | 3 |
| 32103170 | 2020 | MUC1 oncoprotein mitigates ER stress via CDA-mediated reprogramming of pyrimidine metabolism. | 19 |
| 32807821 | 2020 | A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD(). | 4 |
| 32103170 | 2020 | MUC1 oncoprotein mitigates ER stress via CDA-mediated reprogramming of pyrimidine metabolism. | 19 |
| 32807821 | 2020 | A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD(). | 4 |
| 30889042 | 2019 | An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance). | 5 |
| 30889042 | 2019 | An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance). | 5 |
| 28827188 | 2018 | Single-nucleotide polymorphisms in the genes of CES2, CDA and enzymatic activity of CDA for prediction of the efficacy of capecitabine-containing chemotherapy in patients with metastatic breast cancer. | 5 |
| 28827188 | 2018 | Single-nucleotide polymorphisms in the genes of CES2, CDA and enzymatic activity of CDA for prediction of the efficacy of capecitabine-containing chemotherapy in patients with metastatic breast cancer. | 5 |
| 27979915 | 2017 | Neural Stem Cell-Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients. | 79 |
Citation
Yoshiro Saito
CDA (Cytidine Deaminase)
Atlas Genet Cytogenet Oncol Haematol. 2009-09-01
Online version: http://atlasgeneticsoncology.org/gene/998/cda
