α-Lactalbumin:Oleic Acid Complex Spontaneously Delivers Oleic Acid to Artificial and Erythrocyte Membranes

Wen, Hanzhen; Strømland, Øyvind; Halskau, Øyvind

doi:10.1016/j.jmb.2015.08.009

Cited by 10 publications

(12 citation statements)

References 39 publications

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“…The α-LA component of the cytotoxic complexes confers specificity for tumor cell membranes through protein interactions that are maintained even in the lipid complex, in the presence of oleic acid [ 313 ]. Wen et al monitored the membrane, oleic acid, and protein components of bovine α-LA complexed with oleic acid (BLAOA; a HAMLET-like complex prepared at alkaline pH [ 17 ]) and how they associate with each other [ 314 ]. Using ultracentrifugation, they found that the oleic acid and lipid components follow each other closely.…”

Section: Anti-tumorigenic Activities Of α-Lactalbuminmentioning

confidence: 99%

α-Lactalbumin, Amazing Calcium-Binding Protein

Permyakov

2020

Biomolecules

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α-Lactalbumin (α-LA) is a small (Mr 14,200), acidic (pI 4–5), Ca2+-binding protein. α-LA is a regulatory component of lactose synthase enzyme system functioning in the lactating mammary gland. The protein possesses a single strong Ca2+-binding site, which can also bind Mg2+, Mn2+, Na+, K+, and some other metal cations. It contains several distinct Zn2+-binding sites. Physical properties of α-LA strongly depend on the occupation of its metal binding sites by metal ions. In the absence of bound metal ions, α-LA is in the molten globule-like state. The binding of metal ions, and especially of Ca2+, increases stability of α-LA against the action of heat, various denaturing agents and proteases, while the binding of Zn2+ to the Ca2+-loaded protein decreases its stability and causes its aggregation. At pH 2, the protein is in the classical molten globule state. α-LA can associate with membranes at neutral or slightly acidic pH at physiological temperatures. Depending on external conditions, α-LA can form amyloid fibrils, amorphous aggregates, nanoparticles, and nanotubes. Some of these aggregated states of α-LA can be used in practical applications such as drug delivery to tissues and organs. α-LA and some of its fragments possess bactericidal and antiviral activities. Complexes of partially unfolded α-LA with oleic acid are cytotoxic to various tumor and bacterial cells. α-LA in the cytotoxic complexes plays a role of a delivery carrier of cytotoxic fatty acid molecules into tumor and bacterial cells across the cell membrane. Perhaps in the future the complexes of α-LA with oleic acid will be used for development of new anti-cancer drugs.

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Section: Anti-tumorigenic Activities Of α-Lactalbuminmentioning

confidence: 99%

α-Lactalbumin, Amazing Calcium-Binding Protein

Permyakov

2020

Biomolecules

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“…It may be that the unusual membrane effects exerted by this compound's display could explain its broad efficacy, as both lowering the membrane CSA and inducing isotropic or inverse phase components would be detrimental to cell membrane integrity. Indeed, there are many studies that link cytotoxicity or drug action to such mechanisms, including the alkylphosplipids [5], protein-fatty acid complexes delivering cytotoxic oleic acid to the membrane [54,55], and numerous membrane-active proteins and peptides [31,33,52,56]. Environmental toxicity of pollutants has also been ascribed to membrane effects in some cases [41].…”

Section: Discussionmentioning

confidence: 99%

Bioactive Metabolites of Marine Origin Have Unusual Effects on Model Membrane Systems

et al. 2020

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Marine sponges and soft corals have yielded novel compounds with antineoplastic and antimicrobial activities. Their mechanisms of action are poorly understood, and in most cases, little relevant experimental evidence is available on this topic. In the present study, we investigated whether agelasine D (compound 1) and three agelasine analogs (compound 2–4) as well as malonganenone J (compound 5), affect the physical properties of a simple lipid model system, consisting of dioleoylphospahtidylcholine and dioleoylphosphatidylethanolamine. The data indicated that all the tested compounds increased stored curvature elastic stress, and therefore, tend to deform the bilayer which occurs without a reduction in the packing stress of the hexagonal phase. Furthermore, lower concentrations (1%) appear to have a more pronounced effect than higher ones (5–10%). For compounds 4 and 5, this effect is also reflected in phospholipid headgroup mobility assessed using 31P chemical shift anisotropy (CSA) values of the lamellar phases. Among the compounds tested, compound 4 stands out with respect to its effects on the membrane model systems, which matches its efficacy against a broad spectrum of pathogens. Future work that aims to increase the pharmacological usefulness of these compounds could benefit from taking into account the compound effects on the fluid lamellar phase at low concentrations.

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“…These results indicate that BAMLET treatment leads to a decrease in cancer cell energy production capacity and metabolic activities. Multiple lines of investigation by others indicate that the cellular target of BAMLET is the plasma membrane [ 30 , 43 , 59 – 65 ]. Our bioinformatics analysis of bacterial membrane proteins revealed ATP synthase as the only membrane protein to have a structural difference in HAMLET-sensitive bacteria compared to HAMLET-resistant bacteria, the difference being the lack of subunit I in sensitive bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…The many proposed cellular targets include membrane ion channels [ 29 , 47 – 50 ], histones [ 51 – 53 ], mitochondria [ 54 – 56 ], proteasomes [ 19 ], α-actinin [ 57 ], annexin [ 30 ], and ATP synthase [ 58 ]. Multiple lines of evidence indicate that the initial BAMLET target is the cellular membrane of cancer cells [ 30 , 43 , 59 – 65 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is generally accepted that the cytotoxicity of BAMLET-like anti-cancer complexes is due to a structural balance of its components, the protein and the oleic acid that can be accommodated by the protein, resulting in release of the oleic acid component to the cell membrane, termed “cargo off-loading” [ 66 – 68 ]. The novel protein-lipid structure of BAMLET-like complexes, in an aqueous environment will hold a nanoscale droplet of oleic acid oil in a cytotoxic “solubilised” state [ 68 ], so called because when the complex comes into contact with lipid membranes, the oleic acid dissociates from the protein complex and associates with the cell membrane [ 65 ]. This behaviour is in contrast to the unreactive behaviour of oleic acid in the bulk phase of a macroscale droplet of oil.…”

Section: Introductionmentioning

confidence: 99%

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BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state

et al. 2018

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Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.

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α-Lactalbumin:Oleic Acid Complex Spontaneously Delivers Oleic Acid to Artificial and Erythrocyte Membranes

Cited by 10 publications

References 39 publications

α-Lactalbumin, Amazing Calcium-Binding Protein

α-Lactalbumin, Amazing Calcium-Binding Protein

Bioactive Metabolites of Marine Origin Have Unusual Effects on Model Membrane Systems

BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state

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