The mechanism of the degradation of DNA by streptonigrin

Cone, Richard L.; Hasan, Syed Kazim; Lown, J. W.; Morgan, A R

doi:10.1139/o76-034

Cited by 187 publications

(101 citation statements)

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“…Streptonigrin (SNG) is an iron-activated antimicrobial compound which kills cells through accumulation of toxic oxygen intermediates that require iron for lethality (11,25,70,71). SNG has previously been used as an indirect proxy for the level of uncomplexed iron in the cell, with SNG resistance interpreted to reflect a low cellular iron content.…”

Section: Resultsmentioning

confidence: 99%

“…This suggests that in A. tumefaciens, SNG sensitivity cannot be used to approximate the cellular uncomplexed-iron concentration. It is worth noting that the cytotoxic activity of SNG functions via oxygen radical generation (11,14). It is plausible that Irr represses a toxic oxygen defense mechanism, and in the absence of this repression, A. tumefaciens can exhibit increased radical resistance even in the presence of elevated levels of iron.…”

Section: Discussionmentioning

confidence: 99%

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Antiparallel and Interlinked Control of Cellular Iron Levels by the Irr and RirA Regulators of Agrobacterium tumefaciens

Hibbing

Fuqua

2011

J Bacteriol

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The plant pathogen Agrobacterium tumefaciens encodes predicted iron-responsive regulators, Irr and RirA, that function in several other bacteria to control the response to environmental iron levels. Deletion mutations of irr and rirA, alone and in combination, were evaluated for their impact on cellular iron response. Growth was severely diminished in the ⌬irr mutant under iron-limiting conditions, but reversed to wild-type levels in an ⌬irr ⌬rirA mutant. The level of uncomplexed iron in the ⌬irr mutant was decreased, whereas the ⌬rirA mutant exhibited elevated iron levels. Sensitivity of the ⌬irr and ⌬rirA mutants to iron-activated antimicrobial compounds generally reflected their uncomplexed-iron levels. Expression of genes that encode iron uptake systems was decreased in the ⌬irr mutant, whereas that of iron utilization genes was increased. Irr function required a trihistidine repeat likely to mediate interactions with heme. Iron uptake genes were derepressed in the ⌬rirA mutant. In the ⌬irr ⌬rirA mutant, iron uptake and utilization genes were derepressed, roughly combining the phenotypes of the single mutants. Siderophore production was elevated in the rirA mutant, but most strongly regulated by an RirA-controlled sigma factor. Expression of rirA itself was regulated by Irr, RirA, and iron availability, in contrast to irr expression, which was relatively stable in the different mutants. These studies suggest that in A. tumefaciens, the Irr protein is most active under low-iron conditions, inhibiting iron utilization and activating iron acquisition, while the RirA protein is active under high-iron conditions, repressing iron uptake.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antiparallel and Interlinked Control of Cellular Iron Levels by the Irr and RirA Regulators of Agrobacterium tumefaciens

Hibbing

Fuqua

2011

J Bacteriol

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“…Some provoke strand breakage of DNA as one aspect of their mechanism of action. These include bleomycin [3,41, streptonigrin [5], mitomycin C [6], neocarzinostatin [7] and the anthracyclines [S, 91. Although there are several differcnces in structure and the exact mechanism of action, all appear to form radical species.…”

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confidence: 99%

Experimental and modelling studies on the DNA cleavage by elsamicin A

Parraga¹,

Orozco²,

Portugal³

1992

European Journal of Biochemistry

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The ability of elsamicin A, an antitumour antibiotic, to cleave DNA in the presence of ferrous iron and reducing agents, has been analysed using experimental and theoretical approaches. Experimentally, the antibiotic causes DNA breakage in the presence of ferrous ions and a reducing agent. The DNA-cleaving activity appears to be partially blocked by the action of superoxide dismutase and catalase. These results indicate that the elsamicin aglycone moiety (chartarin) can be involved in the production of free radicals. We have performed a broad theoretical study based in the quantummechanical framework, which allow us to determine the redox properties of elsamicin that lead to the generation of radical species. Our results clearly show that elsamicin acts as a true catalyst in the production of superoxide radicals. Moreover, it is suggested that the oxidation/reduction mechanism of the aglycone moiety of elsamicin (a lactone), leading to DNA breakage, is different from the mechanism followed by other well-known anti-cancer drugs, whose chromophore is a quinone. [12]. Fig. 1 shows the chemical structure of chartreusin. At first glance, this molecule resembles the anthracycline group of antibiotics: it also contains a chromophore and a sugar moiety. However, different from anthracyclines, the chromophore moiety (chartarin) is not a quinone, but contains a 5,12-dione portion, and bears a peculiar disaccharide bound to position 10 (Fig. 1). Since reduction and auto-oxidation occur in the quinone moiety of anthracyclines [S], it has been proposed that the 5,12-dione portion of chartreusin might be involved in the formation of free radicals [12]. Due to several drawbacks, chartreusin was not selected as an antitumour drug for clinical trials [13], and, until recently, there were no reports of chartreusin derivatives with improved activity [13, 141. Among them, the related antibiotic elsamicin A (Fig. 1) has been isolated from natural sources [13]. Elsamicin A is structurally related to chartreusin, but contains an amino sugar which makes it more water soluble than chartreusin, since at physiological pH this amino group will be positively charged. Elsamicin is about 30 times more potent than Correspondence to J.

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“…Streptonigrin and many of these naturally produced compounds promote ROS within a target cell (38). NADH may serve to continue redox cycling of streptonigrin (37,57), and the reduction in steady-state intracellular NADH may contribute to the toxicity of streptonigrin. Indeed, current work in our lab demonstrates that strains of B. burgdorferi are sensitive to another redox cycling compound, phenazine methosulfate (data not shown), which can be reduced by NADH.…”

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confidence: 99%