Citrate Complexes with Iron(II) and Iron(III)<sup>1</sup>

Hamm, Randall E.; Shull, Charles M.; Grant, David M.

doi:10.1021/ja01637a021

Cited by 116 publications

(54 citation statements)

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“…16 Metal ions are complexed by citrate generally via the C1 and C3 carboxylates and the C3 hydroxyl group. Hamm et al 17 concluded on the basis of titration data that the iron(III)−citric acid complex behaves as a tetrabasic acid, whereas the corresponding iron(II)−citrate exhibits tribasic behavior; similar findings were reported by Francis and Dodge. 14 Conductometric titration of ferric sulfate with excess trisodium citrate suggest complexes with stoichiometries of Fe 3+ 2 (cit) 3 and Fe 3+ 5 (cit) 4 , whereas titration with excess free citric acid indicates complexes of Fe 3+ 3 (cit) 2 ; thermometric titrations support the formation of both Fe 3+ 2 (cit) 3 and Fe 3+ 3 (cit) 2 .…”

Section: ■ Introductionsupporting

confidence: 62%

Redox Properties and Activity of Iron–Citrate Complexes: Evidence for Redox Cycling

Adam

Bounds

Kissner

et al. 2015

Chem. Res. Toxicol.

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Iron in iron overload disease is present as non-transferrin-bound iron, consisting of iron, citrate, and albumin. We investigated the redox properties of iron citrate by electrochemistry, by the kinetics of its reaction with ascorbate, by ESR, and by analyzing the products of reactions of ascorbate with iron citrate complexes in the presence of H2O2 with 4-hydroxybenzoic acid as a reporter molecule for hydroxylation. We report -0.03 V < E°' > +0.01 V for the (Fe(3+)-cit/Fe(2+)-cit) couple. The first step in the reaction of iron citrate with ascorbate is the rapid formation of mixed complexes of iron with citrate and ascorbate, followed by slow reduction to Fe(2+)-citrate with k = ca. 3 M(-1) s(-1). The ascorbyl radical is formed by iron citrate oxidation of Hasc(-) with k = ca. 0.02 M(-1) s(-1); the majority of the ascorbyl radical formed is sequestered by complexation with iron and remains EPR silent. The hydroxylation of 4-hydroxybenzoic acid driven by the Fenton reduction of iron citrate by ascorbate in the presence of H2O2 proceeds in three phases: the first phase, which is independent of the presence of O2, is revealed as a nonzero intercept that reflects the rapid reaction of accumulated Fe(2+) with H2O2; the intermediate oxygen-dependent phase fits a first-order accumulation of product with k = 5 M(-1) s(-1) under aerobic and k = 13 M(-1) s(-1) under anaerobic conditions; the slope of the final linear phase is ca. k = 5 × 10(-2) M(-1) s(-1) under both aerobic and anaerobic conditions. Product yields under aerobic conditions are greater than predicted from the initial concentration of iron, but they are less than predicted for continuous redox cycling in the presence of excess ascorbate. The ongoing formation of hydroxylated product supports slow redox cycling by iron citrate. Thus, when H2O2 is available, iron-citrate complexes may contribute to pathophysiological manifestations of iron overload diseases.

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Section: ■ Introductionsupporting

confidence: 62%

Redox Properties and Activity of Iron–Citrate Complexes: Evidence for Redox Cycling

Adam

Bounds

Kissner

et al. 2015

Chem. Res. Toxicol.

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“…Our studies showed that altering iron levels also had a marked effect on resistance to pentamidine. This is in agreement with the observation that citric and gluconic acids can act as iron-chelating agents [60,61] and respiration activity in the presence of these compounds at the pentamidine concentrations tested were significantly altered (S3 Fig). Many clinically relevant antimicrobials have shown to be affected by the presence of iron, including compounds belonging to tetracycline, aminoglycoside and quinolone classes [22]. Activity of these compounds can be altered by numerous factors, including the formation of stable complexes which can affect drug efficacy or have unfavourable effects on patient health.…”

Section: Discussionsupporting

confidence: 91%

Resistance to pentamidine is mediated by AdeAB, regulated by AdeRS, and influenced by growth conditions inAcinetobacter baumanniiATCC 17978

Adams

Stroeher

Hassan

et al. 2018

Preprint

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In recent years, effective treatment of infections caused by Acinetobacter baumannii has become challenging due to the ability of the bacterium to acquire or up-regulate antimicrobial resistance determinants. Two component signal transduction systems are known to regulate expression of virulence factors including multidrug efflux pumps. Here, we investigated the role of the AdeRS two component signal transduction system in regulating the AdeAB efflux system, determined whether AdeA and/or AdeB can individually confer antimicrobial resistance, and explored the interplay between pentamidine resistance and growth conditions in A. baumannii ATCC 17978. Results identified that deletion of adeRS affected resistance towards chlorhexidine and 4',6-diamidino-2-phenylindole dihydrochloride, two previously defined AdeABC substrates, and also identified an 8-fold decrease in resistance to pentamidine. Examination of ΔadeA, ΔadeB and ΔadeAB cells augmented results seen for ΔadeRS and identified a set of dicationic AdeAB substrates. RNA-sequencing of ΔadeRS revealed transcription of 290 genes were !2-fold altered compared to the wildtype. Pentamidine shock significantly increased adeA expression in the wildtype, but decreased it in ΔadeRS, implying that AdeRS activates adeAB transcription in ATCC 17978. Investigation under multiple growth conditions, including the use of Biolog phenotypic microarrays, revealed resistance to pentamidine in ATCC 17978 and mutants could be altered by bioavailability of iron or utilization of different carbon sources. In conclusion, the results of this study provide evidence that AdeAB in ATCC 17978 can confer intrinsic resistance to a subset of dicationic compounds and in particular, resistance to pentamidine can be significantly altered depending on the growth conditions. PLOS ONE | https://doi.org/10.1371/journal.pone

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“…The following formation constants were used: for Fe(III), log K ϭ 9. (16,22,32,33). Biodegradation of metal-citrate complexes.…”

Section: Methodsmentioning

confidence: 99%

“…Thermodynamic constants in the MINTEQA2 database were used in the calculations. The following formation constants were used: for Fe(III), log K ϭ 9.4 for [Fe(OH)Cit] Ϫ , where Cit is citrate, and log K ϭ 2.6 for [Fe(OH) 2 Cit] 2Ϫ ; for U-citrate, log K ϭ 7.4 for the mononuclear (UO 2 Cit) Ϫ and log K ϭ 18.9 for the binuclear [(UO 2 ) 2 (Cit) 2 ] 2Ϫ (16,22,32,33). Biodegradation of metal-citrate complexes.…”

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confidence: 99%

Mechanisms of biodegradation of metal-citrate complexes by Pseudomonas fluorescens

Joshi-Tope

Francis

1995

J Bacteriol

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Biodegradation of metal-citrate complexes by Pseudomonas fluorescens depends on the nature of the complex formed between the metal and citric acid. Bidentate Fe(III)-, Ni-, and Zn-citrate complexes were readily biodegraded, but the tridentate Cd-and Cu-citrate, and U-citrate complexes were not. The biodegradation of Ni-and Zn-citrate commenced after an initial lag period; the former showed only partial (70%) degradation, whereas the latter was completely degraded. Uptake studies with 14 C-labeled citric acid and metal-citrate complexes showed that cells grown in medium containing citric acid transported free citric acid at the rate of 28 nmol min ؊1 and Fe(III)-citrate at the rate of 12.6 nmol min ؊1 but not Cd-, Cu-, Ni-, U-, and Zn-citrate complexes. However, cells grown in medium containing Ni-or Zn-citrate transported both Ni-and Zn-citrate, suggesting the involvement of a common, inducible transport factor. Cell extracts degraded Fe(III)-, Ni-, U-, and Zn-citrate complexes in the following order: citric acid ‫؍‬ Fe(III)-citrate > Ni-citrate ‫؍‬ Zn-citrate > U-citrate. The cell extract did not degrade Cd-or Cu-citrate complexes. These results show that the biodegradation of the U-citrate complex was limited by the lack of transport inside the cell and that the tridentate Cd-and Cu-citrate complexes were neither transported inside the cell nor metabolized by the bacterium.Citric acid is a multidentate ligand and forms stable complexes with various metal ions (19). The rate and extent of biodegradation of several metal-citrate complexes by microorganisms vary. For example, Pseudomonas pseudoalcaligenes degraded Mg-citrate at a much lower rate than Ca-, Fe(III)-, and Al(III)-citrate (29). Studies with a Klebsiella sp. showed that citric acid and Mg-citrate were readily degraded, whereas Cd-, Cu-, and Zn-citrate were resistant to biodegradation (9). Both these studies also showed that metal toxicity was not responsible for the lack of or the lower rate of degradation of certain metal-citrate complexes but gave no other explanation. Biodegradation studies with Pseudomonas fluorescens showed that bidentate complexes of Fe(III)-, Ni-, and Zn-citrate were readily biodegraded, whereas complexes that involve the hydroxyl group of citric acid, the tridentate Cd-and Cu-citrate complexes, and U-citrate complex were not biodegraded (17). No relationship between biodegradability and stability of the complexes was observed. The tridentate Fe(II)-citrate complex, although recalcitrant, was readily biodegraded after oxidation and hydrolysis to the bidentate Fe(III)-citrate form, denoting a structure-function relationship in the metabolism of the complex (16).Microorganisms have selective transport systems for the uptake of metals of known biological function (11,23,28). Heavy metals are transported into cells by preexisting transport systems and are subsequently either chemically neutralized, sequestered, or removed from the cells by rapid efflux (6,35). Metals affect the transport of citric acid in bacteria. For example, the...

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Citrate Complexes with Iron(II) and Iron(III)¹

Cited by 116 publications

References 0 publications

Redox Properties and Activity of Iron–Citrate Complexes: Evidence for Redox Cycling

Redox Properties and Activity of Iron–Citrate Complexes: Evidence for Redox Cycling

Resistance to pentamidine is mediated by AdeAB, regulated by AdeRS, and influenced by growth conditions inAcinetobacter baumanniiATCC 17978

Mechanisms of biodegradation of metal-citrate complexes by Pseudomonas fluorescens

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Citrate Complexes with Iron(II) and Iron(III)1

Cited by 116 publications

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Redox Properties and Activity of Iron–Citrate Complexes: Evidence for Redox Cycling

Redox Properties and Activity of Iron–Citrate Complexes: Evidence for Redox Cycling

Resistance to pentamidine is mediated by AdeAB, regulated by AdeRS, and influenced by growth conditions inAcinetobacter baumanniiATCC 17978

Mechanisms of biodegradation of metal-citrate complexes by Pseudomonas fluorescens

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Citrate Complexes with Iron(II) and Iron(III)¹