Natural Products and Their Biological Targets: Proteomic and Metabolomic Labeling Strategies

Böttcher, Thomas; Pitscheider, Maximilian; Sieber, Stephan A.

doi:10.1002/anie.200905352

Cited by 189 publications

(124 citation statements)

References 142 publications

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“…The mining of these sequences (silent genes) sometimes leads to absolutely new metabolites. 35,36 Several strategies to increase the bacterial diversity include novel culturing methods, varying culturing environments (co-cultures or mixed cultures) and isolating rare or slowly growing microbes. Simple engineering of natural product biosynthesis using mutasynthesis (precursor-directed biosynthesis) has been proven to be very productive for obtaining unnatural natural products (hybrid molecules) in the area of macrolides, aminoglycosides, and glycopeptides.…”

Section: Genome Miningmentioning

confidence: 99%

Thoughts and facts about antibiotics: Where we are now and where we are heading

Bérdy¹

2012

J Antibiot

926

557

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The declining trends in microbial metabolite and natural products research and the refocusing of this research area are discussed. Renewing natural products research requires inexhaustible natural resources, as well as new genetic techniques and microbial sources, including endophytic microbes. The numbers of known bioactive metabolites are summarized according to their microbiological origin, biological activities and chemical structures. Synthetic and natural product-based libraries are also compared. Importantly, the wide range of microbial metabolite bioactivities, future trends and the importance of prioritizing natural products over synthetic compounds are emphasized.

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Section: Genome Miningmentioning

confidence: 99%

Thoughts and facts about antibiotics: Where we are now and where we are heading

Bérdy¹

2012

J Antibiot

926

557

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“…37 Therefore, future studies will be needed to clarify a more integrated targeting profile by 1 and the network relating protein modification and gene expression changes induced by this compound using systems biology strategies. 38,39 Collectively, the present results provide at least a plausible molecular basis of ROS toxicity and for the downstream electrophilic cellular responses stimulated by gambogic acid (1) in cancer cells. Mounting evidence indicates that cancer cells are generally more vulnerable to further oxidative insults induced by compounds that abrogate the antioxidant systems in cells 40 and that a potential synergetic effect for inactivating cancer cells can be achieved by combining different chemical agents that may induce ROS production or alter redox conditions.…”

mentioning

confidence: 65%

Gambogic Acid Deactivates Cytosolic and Mitochondrial Thioredoxins by Covalent Binding to the Functional Domain

Yang

Ding

et al. 2012

J. Nat. Prod.

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Gambogic acid (1) is a cytotoxic caged xanthone derived from the resin of Garcinia hanburyi. Compound 1 selectively induces apoptosis in cancer cells, at least partially, by targeting the stress response to reactive oxygen species (ROS). However, the molecular mechanism of ROS toxicity stimulated by 1 remains poorly understood. In this study, mass spectrometric and biochemical pharmacological approaches were used that resulted in the identification of both cytosolic thioredoxin (TRX-1) and mitochondrial thioredoxin (TRX-2) as the molecular targets of 1. The results obtained showed that 1 deactivates TRX-1/2 proteins by covalent binding to the active cysteine residues in the functional domain via Michael addition reactions. Since both TRX-1 and TRX-2 play key roles in regulating the redox signaling of cancer cells, the present findings may shed light on the relationship between protein binding and cellular ROS accumulation induced by 1. This provides support for the current clinical trials of gambogic acid (1) being conducted alone or in combination with other agents that appear to increase ROS generation in order to selectively kill cancer cells.

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“…To overcome this limitation, several groups have used activity-based protein profiling (ABPP) combined with bio-orthogonal click chemistry to identify drug targets both in vitro and in vivo (supplemental Fig. S1) (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). ABPP probes exert their functions via covalent reactions with the target proteins or photoaffinity-based labeling via the incorporation of photoreactive groups.…”

mentioning

confidence: 99%

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

Wang

Tan

Nguyễn

et al. 2014

Molecular & Cellular Proteomics

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Drug target identification is a critical step toward understanding the mechanism of action of a drug, which can help one improve the drug's current therapeutic regime and expand the drug's therapeutic potential. However, current in vitro affinity-chromatography-based and in vivo activity-based protein profiling approaches generally face difficulties in discriminating specific drug targets from nonspecific ones. Here we describe a novel approach combining isobaric tags for relative and absolute quantitation with clickable activity-based protein profiling to specifically and comprehensively identify the protein targets of andrographolide (Andro), a natural product with known anti-inflammation and anti-cancer effects, in live cancer cells. We identified a spectrum of specific targets of Andro, which furthered our understanding of the mechanism of action of the drug. Our findings, validated through cell migration and invasion assays, showed that Andro has a potential novel application as a tumor metastasis inhibitor. Moreover, we have unveiled the target binding mechanism of Andro with a combination of drug analog synthesis, protein engineering, and mass-spectrometry-based approaches and determined the drugbinding sites of two protein targets, NF-B and actin. Molecular & Cellular Proteomics 13: 10.1074/mcp. M113.029793, 876-886, 2014.As most drugs exert pharmacological effects by interacting with their target proteins, the identification of these target proteins is a critical step in unraveling the mechanisms of drug action. It is also imperative for our understanding of the pharmacodynamics of a known drug, suggesting potentially unrevealed actions and thus refining future clinical applications of the substance. Traditional approaches used to identify protein targets of a drug typically utilize immobilized drug affinity chromatography coupled with mass spectrometry (MS) 1 (1, 2). These methods can be applied to cell lysates, but not in an in vivo setting, because of the requirement of a solid support. In vitro target profiling might not accurately reflect the drug's actions in the in vivo physiological environment. To overcome this limitation, several groups have used activity-based protein profiling (ABPP) combined with bio-orthogonal click chemistry to identify drug targets both in vitro and in vivo (supplemental Fig. S1) (3-15). ABPP probes exert their functions via covalent reactions with the target proteins or photoaffinity-based labeling via the incorporation of photoreactive groups. With the increasing sensitivity of modern MS platforms, low-abundance protein targets can be successfully identified. Although both conventional affinity chromatography and recent ABPP-based methods allow us to detect a set of candidate protein targets for a drug, it remains difficult to 1 The abbreviations used are: MS, mass spectrometry; ABPP, activity-based protein profiling; ICABPP, clickable activity-based protein profiling; iTRAQ, isobaric tags for relative and absolute quantitation; DMSO, dimethyl sulfoxide; Andro, androgr...

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Natural Products and Their Biological Targets: Proteomic and Metabolomic Labeling Strategies

Cited by 189 publications

References 142 publications

Thoughts and facts about antibiotics: Where we are now and where we are heading

Thoughts and facts about antibiotics: Where we are now and where we are heading

Gambogic Acid Deactivates Cytosolic and Mitochondrial Thioredoxins by Covalent Binding to the Functional Domain

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

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