Incell biology, actinomycin D is shown to have the ability to inhibittranscription. Actinomycin D does this by bindingDNA at the transcription initiation complex and preventing elongation ofRNA chain byRNA polymerase.[13]
Because actinomycin can bind DNA duplexes, it can also interfere withDNA replication, although other chemicals such ashydroxyurea are better suited for use in the laboratory as inhibitors of DNA synthesis.
Actinomycin D and itsfluorescent derivative,7-aminoactinomycin D (7-AAD), are used as stains inmicroscopy andflow cytometry applications. The affinity of these stains/compounds for GC-rich regions of DNA strands makes them excellent markers for DNA. 7-AAD binds to single stranded DNA; therefore it is a useful tool in determining apoptosis and distinguishing between dead cells and live ones.[18]
Actinomycin D is composed of a centralphenoxazinonechromophore tethered to two identical cyclic peptides and was first structurally characterized by Nuclear Magnetic Resonance (NMR) analysis in 1982.[19] The biosynthesis of Actinomycin D has been under investigation since its discovery; early fermentation feeding experiments revealed the roles of bothtryptophan andD-glutamate as precursor substrates,[20][19] and strain mutagenesis experiments demonstrated that a phenoxazinone synthase enzyme might be responsible for coupling of two moieties of4-methyl-3-hydroxyanthranilic acid (4-MHA) into the final phenoxazinone structure.[21] The 4-MHA substrate was shown to be produced from tryptophan through the action of enzymes such astryptophan dioxygenase,kynurenine formamidase,kynurenine hydroxylase,hydroxykynurenase, andmethyltransferase.[22][23]
Early experiments elucidated the presence of non-ribosomal peptide synthetases,[24][25][26][27] and subsequent purification and heterologous expression experiments[24][25][28][29] showed theacmD andacmA genes to be responsible for activation of the 4-MHA, which then undergoes chain elongation through the action of theacmB andacmC genes. In total, the NRPS assembly line is composed of twenty-two modules, including two each ofepimerase andmethylase domains.[30][23] Recent sequencing of the actinomycin D gene cluster inStreptomyces chrysomallus showed that the four NRPS genes were surrounded on both sides by the two clusters of the genes involved in the well-studiedkynurenine pathway and responsible for the production of 4-MHA from tryptophan, with nineparalogs identified between the two clusters.[23]
Biosynthetic scheme of actinomycin D demonstrating the conversion of tryptophan to 4-MHA and the subsequent elongation by nonribosomal peptide synthetase assembly line genes. Figure modified from Keller et al., 2010.[23]
^abcdefghi"Dactinomycin". The American Society of Health-System Pharmacists.Archived from the original on 11 September 2017. Retrieved8 December 2016.
^British national formulary: BNF 69 (69 ed.). British Medical Association. 2015. p. 582.ISBN978-0-85711-156-2.
^The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva:World Health Organization. 2023.hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^Turan T, Karacay O, Tulunay G, Boran N, Koc S, Bozok S, Kose MF (2006). "Results with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) chemotherapy in gestational trophoblastic neoplasia".International Journal of Gynecological Cancer.16 (3):1432–1438.doi:10.1111/j.1525-1438.2006.00606.x.PMID16803542.S2CID32560653.
^Khatua S, Nair CN, Ghosh K (November 2004). "Immune-mediated thrombocytopenia following dactinomycin therapy in a child with alveolar rhabdomyosarcoma: the unresolved issues".Journal of Pediatric Hematology/Oncology.26 (11):777–779.doi:10.1097/00043426-200411000-00020.PMID15543019.
^Uberti EM, Fajardo M, Ferreira SV, Pereira MV, Seger RC, Moreira MA, et al. (December 2009). "Reproductive outcome after discharge of patients with high-risk hydatidiform mole with or without use of one bolus dose of actinomycin D, as prophylactic chemotherapy, during the uterine evacuation of molar pregnancy".Gynecologic Oncology.115 (3):476–481.doi:10.1016/j.ygyno.2009.09.012.PMID19818481.
^Hagemann RF, Concannon JP (April 1973). "Mechanism of intestinal radiosensitization by actinomycin D".The British Journal of Radiology.46 (544):302–308.doi:10.1259/0007-1285-46-544-302.PMID4720744.
^Hollstein U (1974). "Actinomycin. Chemistry and mechanism of action".Chemical Reviews.74 (6):625–652.doi:10.1021/cr60292a002.
^Waksman SA, Woodruff HB (1940). "Bacteriostatic and bacteriocidal substances produced by soil actinomycetes".Proceedings of the Society for Experimental Biology and Medicine.45:609–614.doi:10.3181/00379727-45-11768.S2CID84774334.
^"Dactinomycin".LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases. 2012.PMID31644085.
^Toba K, Koike T, Watanabe K, Fuse I, Takahashi M, Hashimoto S, et al. (January 2000). "Cell kinetic study of normal human bone marrow hematopoiesis and acute leukemia using 7AAD/PY".European Journal of Haematology.64 (1):10–21.doi:10.1034/j.1600-0609.2000.09005.x.PMID10680701.S2CID41065740.
^abShafer RH, Formica JV, Delfini C, Brown SC, Mirau PA (December 1982). "Biosynthesis and characterization of [15N]actinomycin D and conformational analysis by nitrogen-15 nuclear magnetic resonance".Biochemistry.21 (25):6496–6503.doi:10.1021/bi00268a027.PMID6129895.
^Sivak A, Katz E (July 1962). "Biosynthesis of the actinomycin chromophore. Influence of alpha-, 4-, 5-, and 6-methyl-DL-tryptophan on actinomycin synthesis".Biochimica et Biophysica Acta.62 (1):80–90.doi:10.1016/0006-3002(62)90493-6.PMID13913519.
^Stindl A, Keller U (August 1994). "Epimerization of the D-valine portion in the biosynthesis of actinomycin D".Biochemistry.33 (31):9358–9364.doi:10.1021/bi00197a041.PMID8049237.
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