Copper-containing monooxygenases: enzymatic and biomimetic studies of the O-atom transfer catalysis

Blain, Ingrid; Slama, Patrick; Giorgi, Michel; Tron, Thierry; Réglier, Marius

doi:10.1016/s1389-0352(01)00068-x

Cited by 21 publications

(15 citation statements)

References 55 publications

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“…The broadening of the N—OH resonance indicated the complex formation between Ga(III) and the Leu–Ψ(CONOH)–Phe hydroxamate group. Of particular interest were the observed upfield shifts of Leu5, 9–α,β,δ in addition to the downfield shifts of (NOH)Phe6, 10–α and Leu5, 9–NH resonances (Figure 9). A Ga(III)– P1 complex may cause a cis ‐amide linkage between Leu and (NOH)Phe, as evidenced by the observed strong Leu‐α–Ψ(NOH)Phe‐α NOE cross peak (NOH)Phe‐α–Leu‐α in Figure 9(a).…”

Section: Resultsmentioning

confidence: 99%

“…Metal coordination plays essential roles in molecular recognition1 and assembly2–6 in the fields of biomedicine and chemistry. Both the three‐dimensional structures7, 8 and enzymatic functions9–11 of many biological systems depend on complexation of metals. Metal‐binding peptides are attractive targets for potential therapeutics via combinatorial chemistry due to the availability of a huge array of chiral synthons (amino acid derivatives), rapid assembly by automated solid‐phase procedures, and precedent in biological systems for metal complexation.…”

Section: Introductionmentioning

confidence: 99%

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Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

Liu

Kao

et al. 2006

Biopolymers

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Novel trihydroxamate-containing peptides were designed to mimic desferrioxamine (Desferal(R), DFO, a naturally occurring siderophore) but possess distinct conformational restrictions and varied lipophilicity to probe structure vs. metal coordination. The synthesis was performed via fragment condensation of hydroxamate-containing oligopeptides such as Fmoc-Leu- Psi[CON(OBz)]-Phe-Ala-Pro-OH and H-Leu-Psi[CON(OBz)]-Phe-Ala-Pro-OBu(t) (Fmoc: 9-fluor enylmethoxycarbonyl; OBz: benzyl; OBu(t): tert-butyl) either in solution or on a solid support. The metal-binding properties were studied by electrospray ionization-mass spectroscopy (ESI-MS), ultraviolet (UV)-visible spectroscopy, and (1)H nuclear magnetic resonance (NMR). Similar to the dihydroxamate analogs previously explored [Biopolymers (Peptide Science), 2003, Vol. 71, pp. 489-515], the compounds with three hydroxamates arrayed at 10-atom intervals, i.e., H-[Leu-Psi[CON(OH)]-Phe-Ala-Pro](3)-OH (P1), cyclo[Leu-Psi[CON(OH)]-Phe-Ala-Pro](3) (P2), and H-[Leu-Psi(CONOH)-Phe-Ala-Pro](2)-Leu-NHOH (P7), exhibited high affinities for intramolecular coordination with Fe(III) and Ga(III). As expected, both P1 and P2 showed higher relative Fe(III)-binding affinities than the corresponding dihydroxamate-containing peptide analogs (P11 and P12). Even though both P1 and P2 did not compete with DFO in the relative metal-binding affinity in both solution and gas phases, P1, P2, and DFO exhibited similar relative binding selectivities to 11 different metal ions including Fe(III), Fe(II), Al(III), Ga(III), In(III), Zn(II), Cu(II), Co(II), Ni(II), Gd(III), and Mn(II). Compared to the other metal ions, they had higher relative binding affinities with Fe(III), Fe(II), Al(III), Ga(III), and In(III). The decreased metal-binding affinities of P1 and P2 in comparison with DFO suggested the conformational restrictions of their backbones perturb their three hydroxamate groups from optimal hexadentate orientations for metal coordination. As detected by ESI-MS, P2 was distinguished from both P1 and DFO by solvation of its Ga(III) and Fe(III) complexes (such as acetonitrile or water), thereby stabilizing the resulting complexes in the gas phase. Noteworthy, P2 led to 69% death rate in Hela cells at a concentration of 50 microM, exhibiting higher cytotoxicity than DFO in vitro despite its much lower affinity for iron. This enhanced toxicity may simply reflect the increased lipophilicity of the cyclic trihydroxamate (P2) together with the improvements in its cell penetration, and/or subsequent intracellular molecular recognition of both side chains and hydroxamate groups. The cytotoxicity was significantly suppressed by precoordination with Ga(III) or Fe(III), suggesting a mechanism of toxicity via sequestration of essential metal ions as well as the importance of curbing the metal coordination before targeting. The potential of such siderophore-mimicking peptides in oncology needs further exploration.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

Liu

Kao

et al. 2006

Biopolymers

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“…Indeed, the free metals are promptly chelated by NM in neurons. The higher content of copper found in NM of LC compared to NM of SN is likely due to the occurrence of dopamine beta hydroxylase, a copper containing monooxygenase, responsible for the conversion of dopamine into norepinephrine (43).…”

Section: Copper Content In Lc Decreases With Aging Lc and Increases Imentioning

confidence: 97%

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

Zecca

Stroppolo

Gatti

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

440

469

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In this study, a comparative analysis of metal-related neuronal vulnerability was performed in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), known targets of the etiological noxae in Parkinson's disease and related disorders. LC and SN pars compacta neurons both degenerate in Parkinson's disease and other Parkinsonisms; however, LC neurons are comparatively less affected and with a variable degree of involvement. In this study, iron, copper, and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD), and copper͞zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN, and the ratio heavy-chain ferritin͞iron in LC was higher than in the SN. The NM concentration was similar in LC and SN, but the iron content in NM of LC was much lower than SN. In both regions, heavy-and light-chain ferritins were present only in glia and were not detectable in neurons. These data suggest that in LC neurons, the iron mobilization and toxicity is lower than that in SN and is efficiently buffered by NM. The bigger damage occurring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN, but copper was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper͞zinc-SOD had similar age trend in LC and SN. These results may explain at least one of the reasons underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes. L ocus coeruleus (LC) is the main brain region containing norepinephrine neurons. The rostral projections from these neurons seem to be involved in the modulation of neuronal activity, metabolism, and memory (1, 2), whereas the spinal cord projections are known to modulate spinal motoneuron function (3, 4).Neuronal loss in LC occurs in conditions such as Parkinson's disease (PD) and Alzheimer's disease and Down's syndrome (5, 6) with different cellular loss in rostral and caudal parts of LC. In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses. In idiopathic PD, most studies have documented a higher degree of neuronal loss in substantia nigra (SN) compared to LC (5-8). However, a recent study reported extensive impairment of LC neurons in PD (9). SN and LC share anatomical and biochemical similarities, being both pigmented because of neuromelanin (NM), and both composed of catecholaminergic neurons. Yet, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineintoxicated subjects, LC neurons are spared, whereas a large neuronal depletion occurs in SN (10, 11). Also, in other types of Parkinsonian syndromes caused by exposure to toxins, the LC neurons seem less damaged than those of...

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“…[45][46][47] Using al igand with an indane (Ind) substituent (IndPY2;P Y2 = bis[2-pyridyl(ethylamine)), we have shownt hat the reaction of the Cu I precursor (or alternatively Cu II in the presence of reductant)w ith dioxygeny ielded exclusively the cis-hydroxylated ligand (cis-(OH)-IndPY2) in am etalcontrolled reaction (Scheme 2A). [45][46][47] Using al igand with an indane (Ind) substituent (IndPY2;P Y2 = bis[2-pyridyl(ethylamine)), we have shownt hat the reaction of the Cu I precursor (or alternatively Cu II in the presence of reductant)w ith dioxygeny ielded exclusively the cis-hydroxylated ligand (cis-(OH)-IndPY2) in am etalcontrolled reaction (Scheme 2A).…”

Section: Introductionmentioning

confidence: 99%

Electrochemical Water Oxidation and Stereoselective Oxygen Atom Transfer Mediated by a Copper Complex

Kafentzi

Papadakis

Gennarini

et al. 2018

Chemistry A European J

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Water oxidation by copper-based complexes to form dioxygen has attracted attention in recent years, with the aim of developing efficient and cheap catalysts for chemical energy storage. In addition, high-valent metal-oxo species produced by the oxidation of metal complexes in the presence of water can be used to achieve substrate oxygenation with the use of H O as an oxygen source. To date, this strategy has not been reported for copper complexes. Herein, a copper(II) complex, [(RPY2)Cu(OTf) ] (RPY2=N-substituted bis[2-pyridyl(ethylamine)] ligands; R=indane; OTf=triflate), is used. This complex, which contains an oxidizable substrate moiety (indane), is used as a tool to monitor an intramolecular oxygen atom transfer reaction. Electrochemical properties were investigated and, upon electrolysis at 1.30 V versus a normal hydrogen electrode (NHE), both dioxygen production and oxygenation of the indane moiety were observed. The ligand was oxidized in a highly diastereoselective manner, which indicated that the observed reactivity was mediated by metal-centered reactive species. The pH dependence of the reactivity was monitored and correlated with speciation deduced from different techniques, ranging from potentiometric titrations to spectroscopic studies and DFT calculations. Water oxidation for dioxygen production occurs at neutral pH and is probably mediated by the oxidation of a mononuclear copper(II) precursor. It is achieved with a rather low overpotential (280 mV at pH 7), although with limited efficiency. On the other hand, oxygenation is maximum at pH 8-8.5 and is probably mediated by the electrochemical oxidation of an antiferromagnetically coupled dinuclear bis(μ-hydroxo) copper(II) precursor. This constitutes the first example of copper-centered oxidative water activation for a selective oxygenation reaction.

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Copper-containing monooxygenases: enzymatic and biomimetic studies of the O-atom transfer catalysis

Cited by 21 publications

References 55 publications

Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

Novel trihydroxamate‐containing peptides: Design, synthesis, and metal coordination

The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging

Electrochemical Water Oxidation and Stereoselective Oxygen Atom Transfer Mediated by a Copper Complex

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