Voices of chemical biology

Davis, Benjamin G.; Backus, Keri; Ciulli, Alessio; Chica, Roberto A.; Li, Dan; Lee, Sang Yup; He, Chunyan; Weeks, Amy M.; Overall, Christopher C.; Hagihara, Shinya; Thuronyi, Ben; Kamat, Siddhesh S.; Guerrero, Ramon Hurtado; Yao, Shao Q.; Mahal, Lara K.; Voigt, Christopher A.; Woo, Christina M.; Strauss, Erick; Kikuchi, Kazuya; Dore, Timothy M.; Radford, Sheena E.; Li, Xiang; Heo, Won Do; Superti‐Furga, Giulio; Deans, Tara L.; Belousov, Vsevolod; Matthews, Megan L.; Jackson, C.J.; Malek, Shiva; Waldmann, Herbert; Rising, Anna; Jewett, Michael C.; Parker, Emily Anne; Murakami, Mário Tyago; Polizzi, Karen M.; Hamachi, Itaru; Erb, Tobias J.; Joo, Chirlmin; Uesugi, Motonari; Prinjha, Rab K.; Rechavi, Gidi; Solano, Roberto; Schulman, Brenda A.; David, Yael; Oslund, Rob C.

doi:10.1038/nchembio.1820

Cited by 11 publications

(5 citation statements)

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“…This intimate link between polyketide stereochemistry and biological activity makes the control of stereochemistry an attractive research area for attempts to generate new polyketide structures by synthetic biology [ 6 ]. The aim of this review is to trace how our understanding of these feature of the biosynthesis has developed, and more specifically, the critical role that an array of chemical biology approaches [ 7 ] has played in furnishing the underlying data. These include, but are not limited to, the synthesis of isotopically-labeled precursors and the analysis of the resulting labeling patterns, characterization by assays in vitro of wild type and mutant recombinant enzymes in the presence of synthetic substrates, and genetic engineering of model systems coupled with analysis of product structures by gas-chromatography/mass spectrometry (GC–MS) and liquid chromatography (LC)–MS.…”

Section: Introductionmentioning

confidence: 99%

Polyketide stereocontrol: a study in chemical biology

Weissman¹

2017

Beilstein J. Org. Chem.

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The biosynthesis of reduced polyketides in bacteria by modular polyketide synthases (PKSs) proceeds with exquisite stereocontrol. As the stereochemistry is intimately linked to the strong bioactivity of these molecules, the origins of stereochemical control are of significant interest in attempts to create derivatives of these compounds by genetic engineering. In this review, we discuss the current state of knowledge regarding this key aspect of the biosynthetic pathways. Given that much of this information has been obtained using chemical biology tools, work in this area serves as a showcase for the power of this approach to provide answers to fundamental biological questions.

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Section: Introductionmentioning

confidence: 99%

Polyketide stereocontrol: a study in chemical biology

Weissman¹

2017

Beilstein J. Org. Chem.

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“…T he last two decades have been exciting times in seeing a new science take shape and develop-chemical biology. Continuously defining itself (Bertozzi et al 2015), the scope of chemical biology is broad and highly multidisciplinary. We will discuss here one approach of chemical biology, wherein chemicals are "mutated" to obtain knowledge on a protein or a cellular state in a manner akin to how proteins are mutated in structural biology or cells are en-gineered in cell biology.…”

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confidence: 99%

A Chemical Biology Approach to the Chaperome in Cancer—HSP90 and Beyond

Taldone

Wang

Rodina

et al. 2019

Cold Spring Harb Perspect Biol

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Cancer is often associated with alterations in the chaperome, a collection of chaperones, cochaperones, and other cofactors. Changes in the expression levels of components of the chaperome, in the interaction strength among chaperome components, alterations in chaperome constituency, and in the cellular location of chaperome members, are all hallmarks of cancer. Here we aim to provide an overview on how chemical biology has played a role in deciphering such complexity in the biology of the chaperome in cancer and in other diseases. The focus here is narrow and on pathologic changes in the chaperome executed by enhancing the interaction strength between components of distinct chaperome pathways, specifically between those of HSP90 and HSP70 pathways. We will review chemical tools and chemical probe-based assays, with a focus on HSP90. We will discuss how kinetic binding, not classical equilibrium binding, is most appropriate in the development of drugs and probes for the chaperome in disease. We will then present our view on how chaperome inhibitors may become potential drugs and diagnostics in cancer.

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“…Through the advent of chemical biology tools, the study of the chaperome in native, endogenous cellular states was enabled. In the discipline of chemical biology, chemicals rather than biological systems are "mutated" to interrogate a protein or a cellular state similar to how proteins are mutated in structural biology or cells are engineered in cell biology (Bertozzi et al, 2015). These chemicals are referred to as 'probes', and can be soluble ligands used to inhibit or activate a target, solid-support attached ligands used for affinity capture of the target and its interactors, fluorescently labeled or radiolabeled ligands for target detection and quantification in biological samples and/or whole organisms, among others (Workman & Collins, 2010).…”

Section: Epichaperome Discoverymentioning

confidence: 99%

The penalty of stress ‐ Epichaperomes negatively reshaping the brain in neurodegenerative disorders

Ginsberg

Joshi

Sharma

et al. 2021

Journal of Neurochemistry

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Adaptation to acute and chronic stress and/or persistent stressors is a subject of wide interest in central nervous system disorders. In this context, stress is an effector of change in organismal homeostasis and the response is generated when the brain perceives a potential threat. Herein, we discuss a nuanced and granular view whereby a wide variety of genotoxic and environmental stressors, including aging, genetic risk factors, environmental exposures, and age-and lifestyle-related changes, act as direct insults to cellular, as opposed to organismal, homeostasis. These two concepts of how stressors impact the central nervous system are not mutually exclusive. We discuss how maladaptive stressor-induced changes in protein connectivity through epichaperomes, disease-associated pathologic scaffolds composed of tightly bound chaperones, co-chaperones, and other factors, impact intracellular protein functionality altering phenotypes, that in turn disrupt and remodel brain networks ranging from intercellular to brain connectome levels. We provide an evidence-based view on how these maladaptive changes ranging from stressor to phenotype provide unique precision medicine opportunities for diagnostic and therapeutic development, especially in the context of neurodegenerative disorders including Alzheimer's disease where treatment options are currently limited.

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Voices of chemical biology

Abstract: Agreeing on a precise definition of chemical biology has been a persistent challenge for the field. We asked a diverse group of scientists to “define chemical biology” and present a selection of responses.

Cited by 11 publications

References 0 publications

Polyketide stereocontrol: a study in chemical biology

Polyketide stereocontrol: a study in chemical biology

A Chemical Biology Approach to the Chaperome in Cancer—HSP90 and Beyond

The penalty of stress ‐ Epichaperomes negatively reshaping the brain in neurodegenerative disorders

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