Pharmacological Inhibition of Protein Lipidation

Ganesan, Lakshmi; Levental, Ilya

doi:10.1007/s00232-015-9835-4

Cited by 15 publications

(14 citation statements)

References 90 publications

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“…GPI and GIPC anchors modify proteins at the lumen side instead of in the cytosol as do the other three lipid modifications (Ganesan and Levental, 2015). Lipid modifications which are only found in specific proteins, such as cholesterol addition at the C-terminal glycine of proteins have also been reported (Buglino and Resh, 2012).…”

Section: Introductionmentioning

confidence: 99%

Progress toward Understanding Protein S-acylation: Prospective in Plants

2017

Front. Plant Sci.

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S-acylation, also known as S-palmitoylation or palmitoylation, is a reversible post-translational lipid modification in which long chain fatty acid, usually the 16-carbon palmitate, covalently attaches to a cysteine residue(s) throughout the protein via a thioester bond. It is involved in an array of important biological processes during growth and development, reproduction and stress responses in plant. S-acylation is a ubiquitous mechanism in eukaryotes catalyzed by a family of enzymes called Protein S-Acyl Transferases (PATs). Since the discovery of the first PAT in yeast in 2002 research in S-acylation has accelerated in the mammalian system and followed by in plant. However, it is still a difficult field to study due to the large number of PATs and even larger number of putative S-acylated substrate proteins they modify in each genome. This is coupled with drawbacks in the techniques used to study S-acylation, leading to the slower progress in this field compared to protein phosphorylation, for example. In this review we will summarize the discoveries made so far based on knowledge learnt from the characterization of protein S-acyltransferases and the S-acylated proteins, the interaction mechanisms between PAT and its specific substrate protein(s) in yeast and mammals. Research in protein S-acylation and PATs in plants will also be covered although this area is currently less well studied in yeast and mammalian systems.

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Section: Introductionmentioning

confidence: 99%

Progress toward Understanding Protein S-acylation: Prospective in Plants

2017

Front. Plant Sci.

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“…Unfortunately, these compounds ultimately failed in the clinic for two major reasons: (a) the prenylation enzymes are largely functionally redundant; (b) there are many prenylated proteins but few prenylating enzymes – thus broad inhibition of the prenylation machinery is achievable but untenably toxic due to off-target effects4047. We propose that targeting Ras palmitoylation will be less subject to these issues because the enzymes for palmitoylation are widely divergent and substrate specific338, and our target-based approach is designed to identify inhibitors of the process rather than a specific enzyme.…”

Section: Discussionmentioning

confidence: 99%

Click-Chemistry Based High Throughput Screening Platform for Modulators of Ras Palmitoylation

Ganesan

Shieh

Bertozzi

et al. 2017

Sci Rep

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Palmitoylation is a widespread, reversible lipid modification that has been implicated in regulating a variety of cellular processes. Approximately one thousand proteins are annotated as being palmitoylated, and for some of these, including several oncogenes of the Ras and Src families, palmitoylation is indispensable for protein function. Despite this wealth of disease-relevant targets, there are currently few effective pharmacological tools to interfere with protein palmitoylation. One reason for this lack of development is the dearth of assays to efficiently screen for small molecular inhibitors of palmitoylation. To address this shortcoming, we have developed a robust, high-throughput compatible, click chemistry-based approach to identify small molecules that interfere with the palmitoylation of Ras, a high value therapeutic target that is mutated in up to a third of human cancers. This assay design shows excellent performance in 384-well format and is sensitive to known, non-specific palmitoylation inhibitors. Further, we demonstrate an ideal counter-screening strategy, which relies on a target peptide from an unrelated protein, the Src-family kinase Fyn. The screening approach described here provides an integrated platform to identify specific modulators of palmitoylated proteins, demonstrated here for Ras and Fyn, but potentially applicable to pharmaceutical targets involved in a variety of human diseases.

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“…In addition, three main types of cytosolic lipid modifications take place: prenylation, the addition of an isoprenyl group such as 15‐carbon farnesyl or 20‐carbon geranylgeranyl to a cysteine through a thioether bond; N‐myristoylation, the addition of a myristoyl group to a glycine residue through an amide bond; and S‐acylation, the addition of long chain fatty acid, usually palmitate, to a cysteine through a thioester bond. There are some excellent general reviews on lipid modifications …”

Section: Introductionmentioning

confidence: 99%

“…There are some excellent general reviews on lipid modifications. [1][2][3][4][5][6] This review will focus mainly on S-acylation of peripheral and integral membrane proteins, with particular emphasis on how this chemical modification regulates the membrane affinity and intracellular trafficking of a few selected proteins (Figure 1). We first summarize below some general features of acylation and of the molecular machinery that carries it out.…”

Section: Introductionmentioning

confidence: 99%

The role of S‐acylation in protein trafficking

Daniotti

Pedro

Taubas

2017

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Protein S-acylation, also known as palmitoylation, consists of the addition of a lipid molecule to one or more cysteine residues through a thioester bond. This modification, which is widespread in eukaryotes, is thought to affect over 12% of the human proteome. S-acylation allows the reversible association of peripheral proteins with membranes or, in the case of integral membrane proteins, modulates their behavior within the plane of the membrane. This review focuses on the consequences of protein S-acylation on intracellular trafficking and membrane association. We summarize relevant information that illustrates how lipid modification of proteins plays an important role in dictating precise intracellular movements within cells by regulating membrane-cytosol exchange, through membrane microdomain segregation, or by modifying the flux of the proteins by means of vesicular or diffusional transport systems. Finally, we highlight some of the key open questions and major challenges in the field.

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Pharmacological Inhibition of Protein Lipidation

Cited by 15 publications

References 90 publications

Progress toward Understanding Protein S-acylation: Prospective in Plants

Progress toward Understanding Protein S-acylation: Prospective in Plants

Click-Chemistry Based High Throughput Screening Platform for Modulators of Ras Palmitoylation

The role of S‐acylation in protein trafficking

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