An Analog of the Human Albumin N-Terminus (Asp-Ala-His-Lys) Prevents Formation of Copper-Induced Reactive Oxygen Species

Bar‐Or, David; Rael, Leonard T.; Lau, Edward; Rao, Nagaraja K.R.; Thomas, Gregory W.; Winkler, James V.; Yukl, Richard L.; Kingston, R. G.; Curtis, C. G.

doi:10.1006/bbrc.2001.5042

Cited by 143 publications

(89 citation statements)

References 52 publications

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“…[65] We observed that addition of either HSA or DAHK abolished HOC production from Cu-Ab ( Figure 5, upper panel). Cu-DAHK did not produce significant amount of HOC in line with the literature, [23,66] and neither did Cu-HSA (< 2 %). In order to increase the assay sensitivity, measurements were repeated by using higher concentrations of Cu-protein/peptide and ascorbate ( Figure 5, lower panel).…”

Section: Measurement Of Hydroxyl Radical Productionsupporting

confidence: 88%

Copper Transfer from Cu–Aβ to Human Serum Albumin Inhibits Aggregation, Radical Production and Reduces Aβ Toxicity

Perrone¹,

Mothes²,

Vignes³

et al. 2009

ChemBioChem

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Amyloid-beta peptides (Abeta) and the protein human serum albumin (HSA) interact in vivo. They are both localised in the blood plasma and in the cerebrospinal fluid. Among other functions, HSA is involved in the transport of the essential metal copper. Complexes between Abeta and copper ions have been proposed to be an aberrant interaction implicated in the development of Alzheimer's disease, where Cu is involved in Abeta aggregation and production of reactive oxygen species (ROS). In the present work, we studied copper-exchange reaction between Abeta and HSA or the tetrapeptide DAHK (N-terminal Cu-binding domain of HSA) and the consequence of this exchange on Abeta-induced ROS production and cell toxicity. The following results were obtained: 1) HSA and DAHK removed Cu(II) from Abeta rapidly and stoichiometrically, 2) HSA and DAHK were able to decrease Cu-induced aggregation of Abeta, 3) HSA and DAHK suppressed the catalytic HO(.) production in vitro and ROS production in neuroblastoma cells generated by Cu-Abeta and ascorbate, 4) HSA and DAHK were able to rescue these cells from the toxicity of Cu-Abeta with ascorbate, 5) DAHK was more potent in ROS suppression and restoration of neuroblastoma cell viability than HSA, in correlation with an easier reduction of Cu(II)-HSA than Cu-DAHK by ascorbate, in vitro. Our data suggest that HSA is able to decrease aberrant Cu(II)-Abeta interaction. The repercussion of the competition between HSA and Abeta to bind Cu in the blood and brain and its relation to Alzheimer's disease are discussed.

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Section: Measurement Of Hydroxyl Radical Productionsupporting

confidence: 88%

Copper Transfer from Cu–Aβ to Human Serum Albumin Inhibits Aggregation, Radical Production and Reduces Aβ Toxicity

Perrone¹,

Mothes²,

Vignes³

et al. 2009

ChemBioChem

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“…It was also determined that DAHK prevents lipid oxidation in a copper-catalyzed oxidant system [14]. The DAHK peptide as well as HSA was shown to be able to remove copper rapidly and stoichiometrically from Aβ, to restrict Aβ aggregation, to suppress the catalytic ROS production and to reduce neurotoxicity [15].…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic study of Cu2+ binding to the DAHK and GHK peptides by isothermal titration calorimetry (ITC) with the weaker competitor glycine

et al. 2011

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The peptides Asp-Ala-His-Lys (DAHK) and Gly-His-Lys (GHK) are naturally occurring copper(II)-chelating motives in human serum and cerebrospinal fluid. Here the sensitive thermodynamic technique isothermal titration calorimetry (ITC) has been used to study the energetics of copper(II) binding to DAHK and GHK peptides in the presence of the weaker ligand glycine as a competitor. DAHK and GHK bind Cu(II) predominantly in a 1:1 stoichiometry with conditional dissociation constants (i.e. at pH 7.4, in the absence of the competing chelators glycine and HEPES buffer) of 2.6 +/-0.4 x 10 -14 M and of 7.0 +/-1.0 x 10 -14 M, respectively. Furthermore, the apparent ΔH values were measured and the number of protons released upon Cu(II) binding was determined by performing experiments in different buffers. This allowed us to determine the conditional ΔG, ΔH, and ΔS, i.e. corrected for the contributions of the weaker ligand glycine and the buffer at pH 7.4. We found that the entropic and enthalpic contributions to the Cu(II)-binding to GHK and DAHK are distinct, with a higher enthalpic contribution for GHK. The obtained thermodynamic parameters correspond well to those in the literature obtained by other techniques, suggesting that the use of the weaker ligand glycine as a competitor in ITC provides accurate data for Cu(II)-binding to high affinity peptides, which cannot be accurately determined without the use of a competitor ligand.3

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“…12 It was also determined that DAHK prevented lipid oxidation in a copper-catalyzed oxidant system. 13 The protective effects of DAHK may also be due in part to the fact that, in addition to acting as a copper chelator, the copper-DAHK complex is a potent superoxide dismutase mimetic, thereby increasing the antioxidant potential of the We hypothesized that the antioxidant properties of this 4 -amino acid terminus of HSA might explain, in part, its neuroprotective effects after ischemia/reperfusion injury in brain. To test this hypothesis, we utilized HSA and DAHK in a neuronal cell culture model of oxidative injury.…”

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confidence: 99%

“…10 A metal binding site on HSA, the 4 -amino acid terminal sequence of the molecule, is unique to human albumin and may play a prominent role in its neuroprotective effects. [11][12][13][14][15] The 4 amino acids occupying the N-terminus of HSAaspartate, alanine, histidine, and lysine (DAHK)-constitute a relatively high-affinity binding site for a number of cations, specifically nickel, cobalt, and copper. 11 In recent series of reports, it was demonstrated that a synthetic peptide composed of these 4 amino acids could inhibit copper-induced oxidative DNA double-strand breaks and telomere shortening in cell cultures.…”

mentioning

confidence: 99%

“…12 It was also determined that DAHK prevented lipid oxidation in a copper-catalyzed oxidant system. 13 The protective effects of DAHK may also be due in part to the fact that, in addition to acting as a copper chelator, the copper-DAHK complex is a potent superoxide dismutase mimetic, thereby increasing the antioxidant potential of the tetrapeptide or HSA itself. 13 It was recently demonstrated that a novel synthetic analogue of DAHK could improve recovery of rat hearts from an ischemia/reperfusion insult, 16 suggesting that this approach may similarly be useful in the treatment of stroke.…”

mentioning

confidence: 99%

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Human Serum Albumin and its N-Terminal Tetrapeptide (DAHK) Block Oxidant-Induced Neuronal Death

Gum

Swanson

Alano

et al. 2004

Stroke

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Background and Purpose-Studies using animal models of stroke have shown that human serum albumin (HSA) significantly ameliorates cerebral ischemic injury after both transient and permanent ischemia, even when administered after the onset of ischemia or reperfusion. The mechanism of this effect remains uncertain, and prior studies suggest both indirect hemodynamic and direct cytoprotective effects. HSA is a potent antioxidant, in part because of its strong copper-binding capacity. Here we examined the effect of HSA on oxidant-induced neuronal death in a cortical cell culture system. Methods-Murine cortical cultures were exposed to oxidative stress generated by hydrogen peroxide and by a mixture of copper plus ascorbic acid. We examined the ability of HSA and a tetrapeptide occupying its N-terminus (DAHK) to prevent neuronal death after these challenges. Results-H 2 O 2 and CuCl 2 /ascorbic acid were used at concentrations that, in the absence of HSA, killed Ͼ90% of the neurons. HSA provided complete protection at a concentration of 37.5 mol/L and 50% protection at 3.75 mol/L. The copper-binding tetrapeptide DAHK had nearly identical potency and efficacy. HSA and DAHK were also equally effective in preventing neuronal death induced by CuCl 2 /ascorbic acid. Conclusions-HSA has potent antioxidant properties, probably due to binding of copper and other transition metals. HSA extravasation into ischemic brain may provide neuroprotection by limiting metal-catalyzed oxidant stress. The tetrapeptide DAHK may be an effective, small-molecular-weight alternative to HSA as a therapeutic agent for stroke. Key Words: albumins Ⅲ antioxidants Ⅲ copper Ⅲ ischemia Ⅲ neurons A recent series of studies has explored the efficacy of human serum albumin (HSA) as a therapeutic agent in experimental models of stroke. 1-7 HSA was administered intravenously to treat permanent or transient cerebral ischemia and was more effective in transient ischemia. HSA significantly reduced infarct size, edema, and sodium accumulation and improved neurological outcome, even when administered up to 2 hours after onset of ischemia. While these studies demonstrated significant efficacy for HSA in the treatment of stroke, the mechanism for this robust neuroprotection remains undetermined. A number of possible mechanisms have been examined, including the effect of HSA on local cerebral perfusion, blood-brain barrier disruption, systemic fatty acid responses, and microvascular patency. While many of these mechanisms probably contribute, none appear robust enough to account for the large neuroprotective effect of HSA. [2][3][4][5]8,9 HSA is a unique molecule. It maintains colloidal osmotic pressure in the vasculature and has a number of important functional properties. 10 It strongly binds fatty acids, some drugs, and drug metabolites, and it has a number of cation and anion binding sites. 8,10 HSA is also a potent antioxidant, acting both as a free radical scavenger and as a chelator of transition metals and heme. 10 A metal binding site on HSA, the 4 -ami...

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An Analog of the Human Albumin N-Terminus (Asp-Ala-His-Lys) Prevents Formation of Copper-Induced Reactive Oxygen Species

Cited by 143 publications

References 52 publications

Copper Transfer from Cu–Aβ to Human Serum Albumin Inhibits Aggregation, Radical Production and Reduces Aβ Toxicity

Copper Transfer from Cu–Aβ to Human Serum Albumin Inhibits Aggregation, Radical Production and Reduces Aβ Toxicity

Thermodynamic study of Cu2+ binding to the DAHK and GHK peptides by isothermal titration calorimetry (ITC) with the weaker competitor glycine

Human Serum Albumin and its N-Terminal Tetrapeptide (DAHK) Block Oxidant-Induced Neuronal Death

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