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Photoaffinity-Based Chemical Proteomics Reveals 7-Oxocallitrisic Acid Targets CPT1A to Trigger Lipogenesis Inhibition.

ABSTRACT: One of the natural terpenoids isolated from Resina Commiphora, 7-oxocallitrisic acid (7-OCA), has lipid metabolism regulatory activity. To uncover its lipogenesis inhibition mechanism, we developed a photoaffinity and clickable probe based on the 7-OCA scaffold and performed chemical proteomics to profile its potential cellular targets. It was found that 7-OCA could directly interact with carnitine palmitoyl transferase 1A (CPT1A) to promote its activity to reduce lipid accumulation. The present work reveals our understanding of the mode of lipid mebabolism regulation by abietic acids and provides new clues for antiobesity drug development with CPT1A as a main target.

SUBMITTER: Jiang J

PROVIDER: S-EPMC8667300 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Photoaffinity-Based Chemical Proteomics Reveals 7-Oxocallitrisic Acid Targets CPT1A to Trigger Lipogenesis Inhibition.

Jiang Jianbing J Liu Ying Y Yang Shuxin S Peng Huipai H Liu Jiawang J Cheng Yong-Xian YX Li Nan N

ACS medicinal chemistry letters 20211102 12

One of the natural terpenoids isolated from <i>Resina Commiphora</i>, 7-oxocallitrisic acid (7-OCA), has lipid metabolism regulatory activity. To uncover its lipogenesis inhibition mechanism, we developed a photoaffinity and clickable probe based on the 7-OCA scaffold and performed chemical proteomics to profile its potential cellular targets. It was found that 7-OCA could directly interact with carnitine palmitoyl transferase 1A (CPT1A) to promote its activity to reduce lipid accumulation. The ...[more]

PMID: 34917253

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Project description:Celastrol, a natural substance isolated from plant extracts used in traditional Chinese medicine, has been extensively investigated as a possible drug for treatment of cancer, autoimmune diseases, and protein misfolding disorders. Although studies focusing on celastrol's effects in specific cellular pathways have revealed a considerable number of targets in a diverse array of in vitro models there is an essential need for investigations that can provide a global view of its effects. To assess cellular effects of celastrol and to identify target proteins as biomarkers for monitoring treatment regimes, we performed large-scale quantitative proteomics in cultured human lymphoblastoid cells, a cell type that can be readily prepared from human blood samples. Celastrol substantially modified the proteome composition and 158 of the close to 1800 proteins with robust quantitation showed at least a 1.5 fold change in protein levels. Up-regulated proteins play key roles in cytoprotection with a prominent group involved in quality control and processing of proteins traversing the endoplasmic reticulum. Increased levels of proteins essential for the cellular protection against oxidative stress including heme oxygenase 1, several peroxiredoxins and thioredoxins as well as proteins involved in the control of iron homeostasis were also observed. Specific analysis of the mitochondrial proteome strongly indicated that the mitochondrial association of certain antioxidant defense and apoptosis-regulating proteins increased in cells exposed to celastrol. Analysis of selected mRNA transcripts showed that celastrol activated several different stress response pathways and dose response studies furthermore showed that continuous exposure to sub-micromolar concentrations of celastrol is associated with reduced cellular viability and proliferation. The extensive catalog of regulated proteins presented here identifies numerous cellular effects of celastrol and constitutes a valuable biomarker tool for the development and monitoration of disease treatment strategies.

Dataset Information

Photoaffinity-Based Chemical Proteomics Reveals 7-Oxocallitrisic Acid Targets CPT1A to Trigger Lipogenesis Inhibition.

Publications

Photoaffinity-Based Chemical Proteomics Reveals 7-Oxocallitrisic Acid Targets CPT1A to Trigger Lipogenesis Inhibition.

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