Identification of a Molecular Target of a Novel Fungal Metabolite, Pyrrolizilactone, by Phenotypic Profiling Systems

Futamura, Yushi; Kawatani, Masahito; Muroi, Makoto; Aono, Harumi; Nogawa, Toshihiko; Osada, Hiroyuki

doi:10.1002/cbic.201300499

Cited by 26 publications

(20 citation statements)

References 46 publications

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“…These integrated profiling systems using MorphoBase and ChemProteoBase provide a powerful strategy to elucidate bioactive compound targets. [35][36][37][38] Recently, compounds synthesized by combinatorial chemistry have been viewed as more suitable than natural products for investigation using high-throughput screening that can process a large number of samples. However, microbial metabolites still represent an important resource for drug discovery because of their unique chemical structures and potent biological activities.…”

Section: Resultsmentioning

confidence: 99%

Chemical and biological studies of reveromycin A

Osada

2016

J Antibiot

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The research on antibiotics requires the integration of broad areas, such as microbiology, organic chemistry, biochemistry and pharmacology. It is similar to the field of chemical biology that is recently popular as an approach for drug discovery. When we isolate a new compound from a microorganism, we can pursue the interesting research on chemistry and biology. In this review, I would like to introduce our achievements in relation to reveromycin A.

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Section: Resultsmentioning

confidence: 99%

Chemical and biological studies of reveromycin A

Osada

2016

J Antibiot

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“…We previously established and utilized ChemProteoBase profiling method to predict the modes of action of bioactive compounds 26 27 28 29 30 31 . This method allows us to unravel the hidden target of the inhibitors reported as MTH1 inhibitors.…”

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confidence: 99%

Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Kawamura

Kawatani

Muroi

et al. 2016

Sci Rep

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108

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Since recent publications suggested that the survival of cancer cells depends on MTH1 to avoid incorporation of oxidized nucleotides into the cellular DNA, MTH1 has attracted attention as a potential cancer therapeutic target. In this study, we identified new purine-based MTH1 inhibitors by chemical array screening. However, although the MTH1 inhibitors identified in this study targeted cellular MTH1, they exhibited only weak cytotoxicity against cancer cells compared to recently reported first-in-class inhibitors. We performed proteomic profiling to investigate the modes of action by which chemically distinct MTH1 inhibitors induce cancer cell death, and found mechanistic differences among the first-in-class MTH1 inhibitors. In particular, we identified tubulin as the primary target of TH287 and TH588 responsible for the antitumor effects despite the nanomolar MTH1-inhibitory activity in vitro. Furthermore, overexpression of MTH1 did not rescue cells from MTH1 inhibitor–induced cell death, and siRNA-mediated knockdown of MTH1 did not suppress cancer cell growth. Taken together, we conclude that the cytotoxicity of MTH1 inhibitors is attributable to off-target effects and that MTH1 is not essential for cancer cell survival.

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“…CJ16264 ( 27 ) isolated from CL39457, an unidentified fungus likely an agonomycete strain, was shown to be a broad-spectrum Gram-positive antibiotic with limited activities against Gram-negative bacteria but have a relatively strong cytotoxicity with an IC 90 value of 8.0 µg/mL [ 81 ]. Similarly, pyrrolizilactone ( 28 ), which was also isolated from an uncharacterized fungus, was determined to be cytotoxic to various cancer cell lines with a proteasome inhibitor activity [ 82 , 83 ]. It is interesting to note from biosynthetic and bioactivity perspectives that 26 carries a trans -decalin moiety while 27 and 28 have a cis -configured decalin moiety (Fig.…”

Section: Diverse Structures and Biological Activities Of Tetramic Aci...mentioning

confidence: 99%

“…However, in some cases the stereochemistry of the decalin moiety does not appear to have a significant effect on the biological activities of the compounds as was the case for the antibiotic 8 and its similar cis counterparts 1 and 7 [ 49 ]. Also, the cis -decalin-containing pyrrolizidinone 28 is cytotoxic to various cancer cell lines with a proteasome inhibitor activity [ 82 , 83 ], but the trans relative 26 , while only moderately cytotoxic against human cancer cell lines [ 78 ], is a strong telomerase inhibitor [ 79 , 80 ]. Because there are only a handful of reports of cis -decalin type of pyrrolidine-2-one natural products, it is difficult to draw a clear conclusion on the structure–activity relationship on the stereochemistry of the decalin moieties.…”

Section: Decalin Ring Stereochemistry and Its Effect On The Biologica...mentioning

confidence: 99%

Recent advances in the chemo-biological characterization of decalin natural products and unraveling of the workings of Diels–Alderases

Watanabe

Sato

Osada

2022

Fungal Biol Biotechnol

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The Diels–Alder (DA) reaction refers to a [4 + 2] cycloaddition reaction that falls under the category of pericyclic reactions. It is a reaction that allows regio- and stereo-selective construction of two carbon–carbon bonds simultaneously in a concerted manner to generate a six-membered ring structure through a six-electron cyclic transition state. The DA reaction is one of the most widely applied reactions in organic synthesis, yet its role in biological systems has been debated intensely over the last four decades. A survey of secondary metabolites produced by microorganisms suggests strongly that many of the compounds possess features that are likely formed through DA reactions, and most of them are considered to be catalyzed by enzymes that are commonly referred to as Diels–Alderases (DAases). In recent years, especially over the past 10 years or so, we have seen an accumulation of a substantial body of work that substantiates the argument that DAases indeed exist and play a critical role in the biosynthesis of complex metabolites. This review will cover the DAases involved in the biosynthesis of decalin moieties, which are found in many of the medicinally important natural products, especially those produced by fungi. In particular, we will focus on a subset of secondary metabolites referred to as pyrrolidine-2-one-bearing decalin compounds and discuss the decalin ring stereochemistry and the biological activities of those compounds. We will also look into the genes and enzymes that drive the biosynthetic construction of those complex natural products, and highlight the recent progress made on the structural and mechanistic understanding of DAases, especially regarding how those enzymes exert stereochemical control over the [4 + 2] cycloaddition reactions they catalyze.

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Identification of a Molecular Target of a Novel Fungal Metabolite, Pyrrolizilactone, by Phenotypic Profiling Systems

Cited by 26 publications

References 46 publications

Chemical and biological studies of reveromycin A

Chemical and biological studies of reveromycin A

Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival

Recent advances in the chemo-biological characterization of decalin natural products and unraveling of the workings of Diels–Alderases

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