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Chemical Tools for Synthesis, Modification, and Analysis of Lipids

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Chemical Tools for Synthesis, Modification, and Analysis of Lipids Chemical Society Reviews Chemical tools for synthesis, modification, and analysis of lipids Journal: Chemical Society Reviews Manuscript ID CS-TRV-02-2020-000154.R1 Article Type: Tutorial Review Date Submitted by the 12-May-2020 Author: Complete List of Authors: Flores, Judith; University of California, San Diego, Chemistry & Biochemistry White, Brittany; Cornell University, Chemistry and Chemical Biology Brea, Roberto; University of California, San Diego, Chemistry & Biochemistry Baskin, Jeremy; Cornell University, Chemistry and Chemical Biology Devaraj, Neal; University of California, San Diego, Chemistry and Biochemistry Page 1 of 13 PleaseChemical do not Society adjust Reviews margins TUTORIAL REVIEW Lipids: chemical tools for their synthesis, modification, and analysis †a †b a b, a, Received 00th January 20xx, Judith Flores, Brittany M. White, Roberto J. Brea, Jeremy M. Baskin * and Neal K. Devaraj * Accepted 00th January 20xx Lipids remain one of the most enigmatic classes of biological molecules. Whereas lipids are well known to form basic units DOI: 10.1039/x0xx00000x of membrane structure and energy storage, deciphering the exact roles and biological interactions of distinct lipid species rsc.li/chem-soc-rev has proven elusive. How these building blocks are synthesized, trafficked, and stored are also questions that require closer inspection. This tutorial review covers recent advances on the preparation, derivatization, and analysis of lipids. In particular, we describe several chemical approaches that form part of a powerful toolbox for controlling and characterizing lipid structure. We believe these tools will be helpful in numerous applications, including the study of lipid-protein interactions and the development of novel drug delivery systems. Key learning points 1. Importance of chemical tools in the control of lipid properties. 2. Synthetic methodologies for the construction and modification of lipids. 3. Recent approaches to monitor and analyze lipids. 4. Study of interactions between lipids and other biomolecules. 5. Lipid tools for the development of novel applications. as powerful tools in chemical and synthetic biology and novel chemical techniques have been described for studying lipids 1. Introduction both in vitro and in vivo. Lipids are fundamental building blocks of cells that play key In this tutorial review, we cover recently developed roles in signaling, energy storage, and membrane formation. technologies employed for chemical synthesis and Lipid species are highly diverse in structure, and their modifications of lipids in vitro and in live cells, as well as explore distribution varies between organisms. This immense diversity their associated biological applications. These topics include arises from the biosynthesis of various combinations of these chemoselective strategies for in situ formation of lipids, the building blocks and results in a wide range of functional design of chemical probes for lipid imaging and mass implications. Despite their significant relevance and essential spectrometry analysis, the study of lipid-protein interactions, functions, lipids remain less studied than equally important and the construction of lipid-based drug delivery systems. biomolecules, such as proteins and nucleic acids. One reason Applications of the discussed topics include origin of life studies, why lipids have been difficult to study is the relative lack of developing cancer drug delivery systems, and understanding techniques to both interrogate their manipulation and visualize the fundamental cell biology of lipid biosynthesis, trafficking, them. Moreover, given the high structural diversity of lipid and signaling. Throughout, we highlight techniques that, families, it is not possible to accommodate all classes with collectively, constitute a toolbox to control lipid structure. common methods of extraction, purification, characterization, and analysis. Therefore, much of what we know about lipids has come from studying synthetic membranes with specific lipid 2. Synthesis of membrane-forming lipids compositions. These model membranes consist of very few lipid A major goal of biomimetic membrane chemistry is to develop species, which enables a better understanding of the specific methods to synthesize cell-like membranes in the absence of properties and functions of the constituted lipids. Over the last enzymes. The general strategy is to find synthetic routes to few decades, lipid-based probes have become more prevalent produce membrane-forming lipids from simple non-membrane forming precursors, all in the presence of water, which is the solvent in which lipid self-assembly takes place. Given the a. Department of Chemistry and Biochemistry, University of California, San Diego, La importance of mimicking biological systems, several research Jolla, CA 92093, United States. E-mail: [email protected] b. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY groups have recently explored chemoselective coupling 14853, United States. E-mail: [email protected] reactions for the de novo generation of synthetic membranes. † These authors contributed equally to this work. Please do not adjust margins PleaseChemical do not Society adjust Reviews margins Page 2 of 13 Tutorial Review Chem Soc Rev These robust methodologies have allowed for building a diverse azide were coupled using a copper(I) catalyst, which afforded a toolbox to synthesize lipids chemically. The evolution of bilayer biomimetic triazole-containing phospholipid. Remarkably, the membrane formation by in situ lipid synthesis has been set forth CuAAC approach has been utilized to design a self-reproducing through the efforts of several groups. For instance, pioneering system that can drive the repeated synthesis and growth of work by Zepik et al. demonstrated that chemical reactions that phospholipid membranes (Fig. 1).3 The regeneration of form a sulfur bridge between surfactant precursors led to membrane-bound autocatalysts continuously induces the vesicle-forming amphiphiles that resembled naturally occurring formation of triazole phospholipids, mimicking natural phospholipids.1 In this section, we highlight the most prominent membrane generation. Employing a similar biomimetic strategies that have been employed for in situ formation of approach, Enomoto et al. added spatiotemporal control to lipids capable of driving self-assembly of biomimetic phospholipid synthesis using an intramolecular photoinduced membranes. electron transfer to generate copper(I) from a photosensitizer 2.1. Copper-catalyzed click chemistry dyad, triggering the CuAAC reaction and the subsequent in situ 4 Budin and Devaraj demonstrated the use of a copper-catalyzed phospholipid membrane formation. azide-alkyne cycloaddition (CuAAC) reaction for the efficient 2.2. Native chemical ligation (NCL) synthesis of phospholipids,2 paving the way for further NCL is one of the most popular tools for the synthesis and bioorthogonal reactions to be employed for lipid synthesis. In derivatization of large peptides, small proteins, and nucleic this study, a simple alkyne-functionalized lysolipid and an oleyl acids. Recently, Brea et al. used NCL to couple long-chain Judith Flores received her B.S. in Brittany M. White received her Biochemistry from California PhD in Chemistry (2018) from State University, San Marcos in the University of Oregon under 2017. Under the supervision of the guidance of Prof. Ramesh Prof. Kambiz Hamadani, she Jasti, synthesizing functionalized conducted biophysical research cycloparaphenylenes as novel focusing on protein kinetics. She biocompatible fluorescent then began her doctoral studies probes and organic materials. at University of California, San Afterwards, she moved to Diego in Prof. Neal K. Devaraj’s Cornell University to carry out laboratory in 2017. She currently postdoctoral studies with Prof. focuses on studying membrane Jeremy M. Baskin as a NIH protein integration in postdoctoral fellow. Her current biomimetic lipid membranes. research focuses on developing metabolic and fluorescent probes to image the dynamics of de novo phospholipid biosynthesis. Roberto J. Brea received his PhD Jeremy M. Baskin received his in Chemistry (2013) from the PhD in Chemistry (2009) from University of Santiago de the University of California, Compostela (Spain), under the Berkeley under the guidance of supervision of Prof. Juan R. Prof. Carolyn R. Bertozzi. Then, Granja, working on the design, he moved to the Yale School of synthesis and potential Medicine, where he was a applications of supramolecular postdoctoral fellow in the group nanosystems based on ,-cyclic of Prof. Pietro De Camilli and peptides. Afterwards, he moved developed a passion for to the University of California, membrane biology and lipid San Diego (USA) to carry out metabolism. Afterwards, he postdoctoral studies with Prof. joined the Department of Neal K. Devaraj as a Human Frontier Science Program (Cross- Chemistry and Chemical Biology and Weill Institute for Cell and Disciplinary) fellow. Since 2018, he has worked as an Assistant Molecular Biology at Cornell University (2015). His research Project Scientist at University of California, San Diego (USA). His laboratory operates at the interface of chemical biology tool current research focuses on the design and preparation of self- development and mechanistic cell biology to understand assembled non-natural cellular systems. important roles of lipids in fundamental and disease-related cellular signaling. He
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