Cytosine Deaminase: A Pyrimidine Base Salvage Enzyme Vital to the Effectiveness of a Substrate Mediated Enzyme Prodrug Chemotherapy
Received Date: Mar 31, 2018 / Accepted Date: Apr 02, 2018 / Published Date: Apr 09, 2018
The pyrimidine salvage enzyme cytosine deaminase occupies an important function in the effectiveness of substrate mediated enzyme prodrug chemotherapy. The basis of this chemotherapeutic approach is that cytosine deaminase can catalyze the deamination of 5-fluorocytosine to 5-fluorouracil.The resultant 5-fluorouracil formed is a radiosensitizer agent that enhances the radiological targetting of a variety of cancer cells in humans for elimination.
Keywords: Cytosine deaminase; Pyrimidine salvage; 5-Fluorocytosine; Prodrug; Cancer chemotherapy
The pyrimidine salvage pathway enzyme cytosine deaminase (EC 188.8.131.52) catalyzes the deamination of cytosine to uracil [1,2]. The resultant uracil is converted to the ribonucleotide uridine 5’- monophosphate by the enzyme uracil phosphoribosyltransferase. Cytosine deaminase has been detected in a variety of prokaryotic and eukaryotic organisms [1-7]. The importance of cytosine deaminase to chemotherapy is related to its ability to catalyze the deamination of the pyrimidine base analogue 5-fluorocytosine to 5-fluorouracil. The use of cytosine deaminase is one of the substrate mediated enzyme prodrug therapies that is used to treat various forms of cancer [8,9]. The pyrimidine analogue 5-fluorocytosine is considered a prodrug because it is non-toxic [8,9]. The 5-fluorouracil produced by cytosine deaminase has been shown to be a strong radiosensitizer that improves the efficacy of radiation treatment . The bacterial gene for cytosine deaminase has been placed in an adenoviral vector under the control of a viral promoter. In the presence of this viral vector, low dose irradiation of human colon cancer results in cytosine deaminase actively catalyzing the deamination of 5-fluorocytosine promoting cytotoxic cell effects . With cancer cells rapidly proliferating, the cancer cells require high levels of ribonucleotide triphosphates to sustain RNA synthesis. The 5-fluorouracil is eventually converted to 5- fluorouridine 5’-triphosphate which blocks RNA synthesis in organisms. The metabolism of 5-fluorouracil also results in the inhibition of the enzyme thymidylate synthetase causing a scarcity of thymidine nucleotides that blocks DNA synthesis. Essentially, this analogue specifically targets cancer cell growth by causing cessation of their nucleic acid synthesis leading to their cell death. Unfortunately, cytosine deaminase in organisms prefers cytosine as a substrate. The deamination of 5-fluorocytosine to 5-fluorouracil occurs at a slower rate making it less effectiveness in eventually producing 5- fluoronucleotides. One approach to overcome this problem is to alter the structure of cytosine deaminase by site-directed mutagenesis . By altering the active site of cytosine deaminase, its ability to catalyze the deamination of 5-fluorocytosine can be increased. Molecular chemotherapy involving the use of bacterial or yeast cytosine deaminase has been utilized to treat pancreatic cancer, prostate cancer, colon cancer, breast cancer and lung cancer [12-15]. This substrate mediated enzyme prodrug therapy clearly can target a wide range of cancer cells.
In conclusion, the enzyme cytosine deaminase and its ability to catalyze the deamination of the pyrimidine analogue 5-fluorocytosine has become a focus of cancer researchers. This pyrimidine salvage enzyme is being used in chemotherapeutic treatments to target certain types of cancer cells. Considering its potential importance to chemotherapy for cancer, additional research on cytosine deaminase needs to be undertaken to better understand how this enzyme functions and how its activity towards 5-fluorocytosine can be further enhanced using molecular methodologies as well as advanced delivery systems that will result in site-specific cancer cell treatments.
- West TP, Shanley MS, O'Donovan GA (1982) Purification and some properties of cytosine deaminase from Salmonella typhimurium. Biochim Biophys Acta 719: 251-258.
- Katsuragi T, Sakai T, Matsumoto K, Tonomura k (1986) Cytosine deaminase from Escherichia coli production, purification and some characteristics. Agric Biol Chem 50: 1721-1730.
- Chu C, West TP (1990) Pyrimidine ribonucleoside catabolism in Pseudomonas fluorescens biotype A. Antonie van Leeuwenhoek 57:253-257.
- West TP (1991) Pyrimidine base and ribonucleoside utilization by the Pseudomonas alcaligenes group. Antonie van Leeuwenhoek 59: 263-268.
- West TP (1996) Degradation of pyrimidine ribonucleosides by Pseudomonas aeruginosa. Antonie van Leeuwenhoek 69: 331-335.
- West TP (2000) Role of cytosine deaminase and ß-alanine-pyruvate transaminase in pyrimidine base catabolism by Burkholderia cepacia. Antonie van Leeuwenhoek 77: 1-5.
- Yao L, Li Y, Wu Y, Liu A, Yan H (2005) Product release is rate-limiting in the activation of the prodrug 5-fluorocytosine by yeast cytosine deaminase. Biochemistry 44: 5490-5497.
- Yata VK, Gopinath P, Ghosh SS (2012) Emerging implications of non-mammalian cytosine deaminases on cancer therapeutics. Appl Biochem Biotechnol 167: 2103-2116.
- Fejerskov B, Jarlstad Olesen MT, Zelikin AN (2017) Substrate mediated enzyme prodrug therapy. Adv Drug Deliv Rev 118: 24-34.
- Stackhouse MA, Pederson LC, Grizzle WE, Curiel DT, Gebert J, et al.(2000) Fractionated radiation therapy in combination with adenoviral delivery of the cytosine deaminase gene and 5-fluorocytosine enhances cytotoxic and antitumor effects in human colorectal and cholangiocarcinoma models. Gene Ther 7: 1019-1026.
- Fuchita M, Ardiani A, Zhao L, Serve K, Stoddard KL,et al. (2009) Bacterial cytosine deaminase mutants created by molecular engineering show improved 5-fluorocytosine-mediated cell killing in vitro and in vivo. Cancer Res 69: 4791-4799.
- Yi BR, Kim SU, Kim YB, Lee HJ, Cho MH, et al.(2012) Antitumor effects of genetically engineered stem cells expressing yeast cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties. Oncol Rep 27: 1823-1828.
- Nemani KV, Ennis RC, Griswold KE, Gimi B (2015) Magnetic nanoparticle hyperthermia induced cytosine deaminase expression in microencapsulated E. coli for enzyme-prodrug therapy. J Biotechnol 203: 32-40.
- Chen Z, Penet M-F, Krishnamachary B, Banerjee SR, Pomper MG, Bhujwalla ZM (2016) PSMA-specific theranostic nanoplex for combination of TRAIL gene and 5-FC prodrug therapy of prostate cancer. Biomaterials 80:57-67.
- Dore-Savard L, Chen Z, Winnard PT, Jr, Krisnamachary, Raman, V, Black ME, Bhujwalla ZM (2017) Delayed progression of lung metastases following delivery of a prodrug-activating enzyme. Anticancer Res 37: 2195-2200.
Citation: West TP (2018) Cytosine Deaminase: A Pyrimidine Base Salvage Enzyme Vital to the Effectiveness of a Substrate Mediated Enzyme Prodrug Chemotherapy. Biochem Physiol 7: e159. DOI: 10.4172/2168-9652.1000e159
Copyright: ©2018 West TP. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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