Disease relevance of Cda

• Based on the crystal structure of the distantly related Escherichia coli cytidine deaminase, we propose that this amino acid is positioned on a solvent-exposed loop of APOBEC3G on the same face of the protein as the catalytic site [1].
• This suggests an approach to the treatment of human tumors possessing elevated levels of cytidine deaminase such as certain leukemias, bronchogenic carcinoma of the lung, adenocarcinomas of the colon and rectum, astrocytomas, and certain tumors which are refractory to chemotherapy with 1-beta-D-arabinofuranosylcytosine [2].
• Methotrexate and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene [3].
• Bioactive cytidine deaminase, an inhibitor of granulocyte-macrophage colony-forming cells, is massively released in fulminant meningococcal sepsis [4].
• Mutations in the two aromatic residues of CD1 but not CD2, which are conserved in cytidine deaminase core domains and are required for RNA binding, prevented encapsidation into HIV-1, HTLV-I and MLV [5].

High impact information on Cda

• It has been suggested that AID may function as an RNA-editing enzyme or as a cytidine deaminase on DNA [6].
• Activation-induced cytidine deaminase (AID), a putative RNA-editing cytidine deaminase, is expressed strictly in activated B cells and is indispensable in both CSR and somatic hypermutation [7].
• RNA-editing cytidine deaminase Apobec-1 is unable to induce somatic hypermutation in mammalian cells [8].
• The cytidine deaminase catalytic subunit [apo-B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1)] of the multiprotein editing complex has been identified [9].
• We have shown that metabolism of FdCyd can be directed through the former pathway by inhibition of cytidine deaminase with tetrahydrouridine [10].

Chemical compound and disease context of Cda

• A recent report showing induction of DNA mutations in Escherichia coli by overexpression of AID, Apobec-1, and related members of the RNA-editing cytidine deaminase family suggested that they may directly modify deoxycytidine in DNA in mammalian cells (DNA-editing model) [8].
• The ability to confer drug resistance to Ara-C through gene transfer of cytidine deaminase may have the potential as a selectable marker and for the protection of the bone marrow from the toxicity produced by this analog so as to increase its effectiveness in cancer chemotherapy [11].

Biological context of Cda

• In addition, cytidine deaminase (cytidine aminohydrolase, EC 3.5.4.5) activity increased with erythropoietic maturation, as it does during murine erythropoiesis in vivo [12].
• In contrast, ara-U or ara-C alone had a negligible therapeutic effect. ara-U-induced alterations in the systemic pharmacokinetics of ara-C are the result of inhibition of cytidine deaminase activity by HiCAU in liver and kidneys [13].
• The amino acid sequence encoded by AID cDNA is homologous to that of apolipoprotein B (apoB) mRNA-editing enzyme, catalytic polypeptide 1 (APOBEC-1), a type of cytidine deaminase that constitutes a catalytic subunit for the apoB mRNA-editing complex [14].
• CD catalyzes the deamination and pharmacological inactivation of cytosine nucleoside analogues, such as cytosine arabinoside (Ara-C) [15].
• These results demonstrate the potential of the MFG-DHFR-IRES/CD vector to confer drug resistance to both MTX and ARA-C and may have future application in chemoprotection of normal hematopoietic cells in patients with cancer [16].

Anatomical context of Cda

• Infection of mouse bone marrow cells with the dmDHFR-CD construct also showed high levels of resistance to MTX and ara-C in a CFU-GM assay [17].
• Retrovirus-mediated expression of dmDHFR-CD in NIH 3T3 cells conferred significant resistance (10- to 12-fold) against MTX and ara-C, compared with mock- and single gene-infected cells and the level of resistance obtained was similar to that of cells expressing both CD and dmDHFR from a retroviral bicistronic vector [17].
• CDD is found in serum and different tissues, with particularly high concentrations in polymorphonuclear neutrophils (PMN) [4].
• The new compounds failed to show significant activity against tumor cell lines in culture, L1210 cells in vivo, virus cytotoxicity in cell culture, or cytidine deaminase [18].
• The growth-regulating property of CDD could be explained by depletion of deoxycytidine nucleotides necessary for DNA synthesis or by a direct effect of CDD binding to specific receptors on progenitor cells [19].

Associations of Cda with chemical compounds

• As a substrate for mouse kidney cytidine deaminase, the apparent Km value for 5,6-dihydro-5-azacytidine (33 micronM) is of the same order of magnitude as that for cytidine (37 micronM) but less than that for 5-azacytidine (2.1 X 10(3) micronM) [20].
• Moreover, the high efficacy of this compound was long lasting in the host animal, regardless of the treatment schedules or the presence of the 1-beta-D-arabinofuranosylcytosine-inactivating enzyme, cytidine deaminase [21].
• Furthermore, the elevated levels of cytidine deaminase in these mouse tumors may result in selective conversion of F3methyl-dCyd to 5-trifluorothymidine at the tumor site [2].
• Deoxycytidylate and cytidine deaminase enzyme assays have confirmed that H4Urd administration effectively inhibited normal cytidine deaminase activities, while only weakly inhibiting the elevated levels found in tumor tissue [22].
• In vitro experiments using a glutathione S-transferase AID fusion protein revealed significant cytidine deaminase activity that is blocked by tetrahydrouridine and by zinc chelation [14].

Other interactions of Cda

• Our observations suggest that BQR may not only affect dihydroorotate dehydrogenase activity, but may also inhibit the enzyme cytidine deaminase, which converts cytidine to uridine [23].
• Cytidine deaminase from mouse kidney converted CDC into CDU; thymidine phosphorylase converted CDU into 5-chlorouracil (5-CU) [24].
• Toxoplasma gondii appear to have a single non-specific uridine phosphorylase enzyme which can catalyze the reversible phosphorolysis of uridine, deoxyuridine and thymidine, and a single cytidine deaminase activity which can deaminate both cytidine and deoxycytidine [25].
• A novel affinity chromatography method for the co-purification of deoxycytidine kinase and cytidine deaminase [26].

Analytical, diagnostic and therapeutic context of Cda

• Retroviral transfer and long-term expression of human cytidine deaminase cDNA in hematopoietic cells following transplantation in mice [15].
• Blood, marrow and spleen samples were obtained and analyzed for CD proviral DNA by PCR, CD activity by enzyme assay, and drug resistance to Ara-C by clonogenic assay [15].
• This conclusion was further substantiated by gel filtration experiments demonstrating a molecular weight (MW) of approximately 50 kd, which corresponds to the MW previously published for CDD activity [19].
• After administration of FdCyd plus GMP, the plasma levels of FdCyd, 5-fluoro-2'-deoxyuridine, which is converted from FdCyd by cytidine deaminase, and FUra were 2-, 6-, and 7-fold higher, respectively, than those after FdCyd alone 30 min after treatment [27].
• Comparative study of a novel nucleoside analogue (Troxatyl, troxacitabine, BCH-4556) and AraC against leukemic human tumor xenografts expressing high or low cytidine deaminase activity [28].

References