Structural basis of omega-3 fatty acid transport across the blood–brain barrier

Cater, Rosemary J.; Chua, Geok Lin; Erramilli, Satchal K.; Keener, James E.; Choy, Brendon C.; Tokarz, Piotr; Chin, Cheen Fei; Quek, Debra Q Y; Kloss, Brian; Pepe, Joseph G.; Parisi, Giacomo; Wong, Bernice H.; Clarke, Oliver; Marty, Michael T.; Kossiakoff, Anthony A.; Khelashvili, George; Silver, David L.; Mancia, Filippo

doi:10.1038/s41586-021-03650-9

Cited by 87 publications

(158 citation statements)

References 79 publications

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“…However, multiple reports have attributed alternative functions to MFS transporters, such as the translocation of lipids associated with fundamental biological pathways. Some examples include the bacterial lysophospholipid transporter LplT, involved in lipids recycling in Gram-negative bacteria 7 , 18 ; the human transporter MFSD2A, expressed at the blood–brain and blood–retinal barrier, contributing to major uptake of docosahexaenoic acid (DHA) 5 , 6 , 19 – 22 ; the human transporters Spns2 23 , 24 , and MFSD2B 25 , which contribute to transport of sphingosine 1-phosphate (S1P) in endothelial cells and erythrocytes; and the gentiobiosyl-diacylglycerol transporter LtaA, involved in cell wall synthesis in Staphylococcus aureus 26 , 27 . However, despite their well-described cellular roles, the mechanisms of MFS lipid transporters remain insufficiently understood.…”

Section: Introductionmentioning

confidence: 99%

“…Until now, a high-resolution structure of outward-facing LtaA, and inward- and outward-facing structures of MFSD2A have been elucidated 21 , 22 , 27 . Both transporters display the canonical MFS fold of 12 transmembranes (TM) helices and an amphipathic central cavity that has not been observed in any MFS transporter of water-soluble molecules.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter

et al. 2022

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Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters take part in lipid translocation, but their mechanisms remain largely unknown. Major facilitator superfamily (MFS) lipid transporters play central roles in cell wall synthesis, brain development and function, lipids recycling, and cell signaling. Recent structures of MFS lipid transporters revealed overlapping architectural features pointing towards a common mechanism. Here we used cysteine disulfide trapping, molecular dynamics simulations, mutagenesis analysis, and transport assays in vitro and in vivo, to investigate the mechanism of LtaA, a proton-dependent MFS lipid transporter essential for lipoteichoic acid synthesis in the pathogen Staphylococcus aureus. We reveal that LtaA displays asymmetric lateral openings with distinct functional relevance and that cycling through outward- and inward-facing conformations is essential for transport activity. We demonstrate that while the entire amphipathic central cavity of LtaA contributes to lipid binding, its hydrophilic pocket dictates substrate specificity. We propose that LtaA catalyzes lipid translocation by a ‘trap-and-flip’ mechanism that might be shared among MFS lipid transporters.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter

et al. 2022

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“…Recent studies have found that omega-3 PUFAs have the property of crossing the blood-brain barrier through specific receptors. 20 We speculated that ALA, which is easily transmembrane mediated by receptors, was the reason for the high uptake of ALA-modified chemotherapeutic drugs and their NPs in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] The latest research claimed that omega-3 PUFA may be the key to opening the blood-brain barrier. 20 Omega-3 PUFA could be recognized by specialized transporters MFSD2A and promoted their crossing the blood-brain barrier. 20 This ability to easily transmembrane may enable omega-3 PUFA modified drugs have higher uptake, which is helpful for the design of new drugs.…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles: In vitro and in vivo

Xu¹,

Hao²,

Wang³

et al. 2021

IJN

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Purpose: Small molecule modified antitumor drug conjugate nanoparticles have the advantages of high drug loading, simple synthesis and preparation, and better biocompatibility. Due to the large demand for exogenous α-linolenic acid (ALA) by tumor cells, we synthesized α-linolenic acid-paclitaxel conjugate (ALA-PTX) and prepared α-linolenic acidpaclitaxel conjugate nanoparticles (ALA-PTX NPs), in order to obtain better tumor cellular uptake and antitumor activity in vitro and in vivo. Methods: We synthesized and characterized ALA-PTX, and then prepared and characterized ALA-PTX NPs. The cellular uptake, uptake pathways, intracellular behavior, in vitro and in vivo antitumor activity of ALA-PTX NPs were evaluated. Results:The size of ALA-PTX NPs was approximately 110.7±1.7 nm. The drug loading was approximately 90% (w/w) with CrEL-free and organic solvent-free characteristics. The cellular uptake of ALA-PTX NPs was significantly higher than that of PTX injection by MCF-7, MCF-7/ADR and HepG2 cells. In these three cell lines, the cellular uptake of ALA-PTX NPs at 6h was approximately 1.5-2.6 times higher than that of PTX injection. ALA-PTX NPs were ingested through clathrin-mediated endocytosis, then transferred to lysosomes, and could dissolve in cells to play an antitumor activity. The in vitro and in vivo antitumor activity of ALA-PTX NPs was confirmed in MCF-7/ADR and HepG2 cell models and tumor-bearing nude mouse models. Conclusion: ALA-PTX NPs developed in our study could provide a new method for the preparation of nano-delivery systems suitable for antitumor therapy that could increase tumor cellular uptake and enhance antitumor activity.

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“…This transporter is also present in different mammalian species. A cryo-electron microscopic study reveals 12 transmembrane helices and an amphipathic cavity containing the Na + and lysolipid binding site [ 105 ]. The important role of this transporter in brain pathology is demonstrated by a recent study showing a genetic variant of this protein to cause congenital microcephaly and hypomyelination [ 106 , 107 ].…”

Section: Pla2 and Lysophospholipidsmentioning

confidence: 99%

Dynamic Role of Phospholipases A2 in Health and Diseases in the Central Nervous System

Sun

Geng

Teng

et al. 2021

Cells

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Phospholipids are major components in the lipid bilayer of cell membranes. These molecules are comprised of two acyl or alkyl groups and different phospho-base groups linked to the glycerol backbone. Over the years, substantial interest has focused on metabolism of phospholipids by phospholipases and the role of their metabolic products in mediating cell functions. The high levels of polyunsaturated fatty acids (PUFA) in the central nervous system (CNS) have led to studies centered on phospholipases A2 (PLA2s), enzymes responsible for cleaving the acyl groups at the sn-2 position of the phospholipids and resulting in production of PUFA and lysophospholipids. Among the many subtypes of PLA2s, studies have centered on three major types of PLA2s, namely, the calcium-dependent cytosolic cPLA2, the calcium-independent iPLA2 and the secretory sPLA2. These PLA2s are different in their molecular structures, cellular localization and, thus, production of lipid mediators with diverse functions. In the past, studies on specific role of PLA2 on cells in the CNS are limited, partly because of the complex cellular make-up of the nervous tissue. However, understanding of the molecular actions of these PLA2s have improved with recent advances in techniques for separation and isolation of specific cell types in the brain tissue as well as development of sensitive molecular tools for analyses of proteins and lipids. A major goal here is to summarize recent studies on the characteristics and dynamic roles of the three major types of PLA2s and their oxidative products towards brain health and neurological disorders.

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Structural basis of omega-3 fatty acid transport across the blood–brain barrier

Cited by 87 publications

References 79 publications

Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter

Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter

Antitumor Activity of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles: In vitro and in vivo

Dynamic Role of Phospholipases A2 in Health and Diseases in the Central Nervous System

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