Spectroscopy and photochemistry of thiouracils: implications for the mechanism of photocrosslinking in tRNA

Milder, Steven J.; Kliger, David S.

doi:10.1021/ja00311a025

Cited by 45 publications

(81 citation statements)

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“…S 1 (nπ*) electronic transitions, respectively [10,18,19,34,200,201]. These assignments are supported by quantum chemical calculations [11,17,18,196,[202][203][204]. Additional absorption bands are observed closer to 200 nm (see, for example, Fig.…”

Section: Steady-state and Time-resolved Photochemistry Of The 4-thiousupporting

confidence: 64%

“…Calculations [17,18,196,203] and experimental results agree that the T 1 state has primarily ππ* character and can decay by radiative (minor pathway; Φ Ph~1 0 À2 to 10 À4 ) and nonradiative (major pathway; Φ NR ! 0.99) processes (Table 11).…”

Section: Triplet State Dynamicsmentioning

confidence: 57%

“…The absorption spectra shift from the UVC region in the nucleic acid monomers out to the UVA region in the thiobases. Furthermore, sulfur substitution inhibits ultrafast internal conversion to the ground state and dramatically increases the rate of intersystem crossing to the triplet manifold by enhanced spin-orbit coupling [11,17,18,27,33], which leads to near-unity triplet yields in these nucleic acid base analogues [11,16,18,22,31,144,195,196].…”

Section: Thiobasesmentioning

confidence: 99%

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Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Pollum

Martínez‐Fernández

Crespo‐Hernández

2014

Topics in Current Chemistry

111

200

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The steady-state and time-resolved photochemistry of the natural nucleic acid bases and their sulfur- and nitrogen-substituted analogues in solution is reviewed. Emphasis is given to the experimental studies performed over the last 3-5 years that showcase topical areas of scientific inquiry and those that require further scrutiny. Significant progress has been made toward mapping the radiative and nonradiative decay pathways of nucleic acid bases. There is a consensus that ultrafast internal conversion to the ground state is the primary relaxation pathway in the nucleic acid bases, whereas the mechanism of this relaxation and the level of participation of the (1)πσ*, (1) nπ*, and (3)ππ* states are still matters of debate. Although impressive research has been performed in recent years, the microscopic mechanism(s) by which the nucleic acid bases dissipate excess vibrational energy to their environment, and the role of the N-glycosidic group in this and in other nonradiative decay pathways, are still poorly understood. The simple replacement of a single atom in a nucleobase with a sulfur or nitrogen atom severely restricts access to the conical intersections responsible for the intrinsic internal conversion pathways to the ground state in the nucleic acid bases. It also enhances access to ultrafast and efficient inter-system crossing pathways that populate the triplet manifold in yields close to unity. Determining the coupled nuclear and electronic pathways responsible for the significantly different photochemistry in these nucleic acid base analogues serves as a convenient platform to examine the current state of knowledge regarding the photodynamic properties of the DNA and RNA bases from both experimental and computational perspectives. Further investigations should also aid in forecasting the prospective use of sulfur- and nitrogen-substituted base analogues in photochemotherapeutic applications.

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Section: Steady-state and Time-resolved Photochemistry Of The 4-thiousupporting

confidence: 64%

Section: Triplet State Dynamicsmentioning

confidence: 57%

Section: Thiobasesmentioning

confidence: 99%

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Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Pollum

Martínez‐Fernández

Crespo‐Hernández

2014

Topics in Current Chemistry

111

200

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“…This base is unusual in that it has an absorption maximum in the near-UV region (334 nm). After exposure to near-UV, S4U participates in a photochemical reaction which generates intramolecular cross-linking between S4U and a specific cytosine (13,14,29). These cross-linked tRNAs have been shown to be poor substrates for aminoacylation (51).…”

mentioning

confidence: 99%

Near-UV stress in Salmonella typhimurium: 4-thiouridine in tRNA, ppGpp, and ApppGpp as components of an adaptive response

1988

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We have examined the role of 4-thiouridine in the responses of Salmonella typhimurium to near-UV irradiation. Mutants lacking 4-thiouridine (nuv) and mutants defective in the synthesis of ppGpp (guanosine 5'-diphosphate-3'-diphosphate) (relA) were found to be sensitive to killing by near-UV. Near-UV induced the synthesis of a set of proteins that were not induced in the nuv mutant. Some of these proteins were identified as oxidative defense proteins, and others were identified as ppGpp-inducible proteins. Over 100-fold increases in ApppGpp (adenosine 5', 5"'-triphosphoguanosine-3"'-diphosphate, the adenylylated form of ppGpp) were observed in wild-type cells after near-UV irradiation but not in the 4-thiouridine-deficient mutant. These data support a model in which ppGpp and ApppGpp, a dinucleotide proposed to be synthesized by tRNA-aminoacyl synthetases as a response to the cross-linking of 4-thiouridine in tRNA by near-UV, induce the synthesis of proteins necessary for resistance to near-UV irradiation.One of the most common stresses confronted by organisms is solar radiation. The most energetic part of the solar spectrum which penetrates the atmosphere is the near-UV region (300 to 400 nm) (22). Studies on the environment mortality of bacteria have found that die-off is dependent on light exposure, especially the near-UV portion of the solar spectrum (10,16,17). Since enteric bacteria such as Escherichia coli must adapt to exposures of near-UV during transmission between hosts (8), they are an ideal system for characterizing mechanisms involved in protection from the toxic effects of near-UV.The irradiation of growing E. coli cells with near-UV results in the cessation of growth long before lethal effects are observed (21,22). This growth lag is dependent on the tRNA-modified base 4-thiouridine (s4U), which is found in 65% of tRNA species (22,40,45). This base is unusual in that it has an absorption maximum in the near-UV region (334 nm). After exposure to near-UV, S4U participates in a photochemical reaction which generates intramolecular cross-linking between S4U and a specific cytosine (13,14,29). These cross-linked tRNAs have been shown to be poor substrates for aminoacylation (51). The accumulation of nonaminoacylated tRNA serves to trigger the stringent response via the relA gene product, which is involved in the synthesis of ppGpp (guanosine 5'-diphosphate-3'-diphosphate) (9, 15), which then acts to inhibit stable RNA synthesis while inducing amino acid biosynthesis (15, 43). Inhibition of protein synthesis after near-UV exposure in E. coli is a result of both the stringent response and decreased aminoacylation of tRNA (44).Near-UV exerts toxic effects on E. coli and Salmonella typhimurium at higher fluences, primarily through oxidative mechanisms (22, 23). Macromolecules which absorb in the near-UV region (i.e., heme and flavins) may act as endogenous photosensitizers, transferring the absorbed energy to 02 and forming toxic oxygen species (10,22,23,48). The response of bacteria to oxidative stress (s...

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“…To some extent the formation yield of the triplet state can be a measure of 1 O 2 production. In general, the formation yields of the triplet state in thiocarbonyl compounds was found to be very efficient, e.g., 0.9 for thiouracils in H 2 O[56], 0.99 for 6-thiopurine in THF,[57] 0.7[58] and 0.6[59] for 4-thiouridine in CH 3 CN, an unity for 4-thiothymidine in an ionic liquid,[60] and 0.8 for thioguanosine in aqueous solution[61], and was quenched by 3 O 2 at a diffusing rate constant of 6.8×10 9 M −1 s −1 . [62] These measurements are in line with our Φ Δ value of 0.58 for 6-TG.…”

Section: Discussionmentioning

confidence: 99%

Quantification of thiopurine/UVA-induced singlet oxygen production

Zhang

Barnes

Zhu

et al. 2011

Journal of Photochemistry and Photobiology A: Chemistry

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Thiopurines were examined for their ability to produce singlet oxygen (1O2) with UVA light. The target compounds were three thiopurine prodrugs, azathioprine (Aza), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), and their S-methylated derivatives of 6-methylmercaptopurine (me6-MP) and 6-methylthioguanine (me6-TG). Our results showed that these thiopurines were efficient 1O2 sensitizers under UVA irradiation but rapidly lost their photoactivities for 1O2 production over time by a self-sensitized photooxidation of sulfur atoms in the presence of oxygen and UVA light. The initial quantum yields of 1O2 production were determined to be in the range of 0.30–0.6 in aqueous solutions. Substitution of a hydrogen atom with a nitroimidazole or methyl group at S decreased the efficacy of photosensitized 1O2 production as found for Aza, me6-MP and me6-TG. 1O2-induced formation of 8-oxo-7,8-dihydro-2’-dexyguanosine (8-oxodGuo) was assessed by incubation of 6-methylthiopurine/UVA-treated calf thymus DNA with human repair enzyme 8-oxodGuo DNA glycosylase (hOGG1), followed by apurinic (AP) site determination. Because more 8-oxodGuo was formed in Tris D2O than in Tris H2O, 1O2 is implicated as a key species in the reaction. These findings provided quantitative information on the photosensitization efficacy of thiopurines and to some extent revealed the correlations between photoactivity and phototoxicity.

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Spectroscopy and photochemistry of thiouracils: implications for the mechanism of photocrosslinking in tRNA

Cited by 45 publications

References 0 publications

Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Photochemistry of Nucleic Acid Bases and Their Thio- and Aza-Analogues in Solution

Near-UV stress in Salmonella typhimurium: 4-thiouridine in tRNA, ppGpp, and ApppGpp as components of an adaptive response

Quantification of thiopurine/UVA-induced singlet oxygen production

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