https://www.cell.com/molecular-cell/pdf/S1097-2765(15)00358-5.pdf

SIRT5 Regulates both Cytosolic and Mitochondrial Protein Malonylation with Glycolysis as a Major Target

Functional tools are needed to understand complex biological systems. Here we review how chemical reporters in conjunction with bioorthogonal labeling methods can be used to image and retrieve nucleic acids, proteins, glycans, lipids and other metabolites in vitro, in cells as well as in whole organisms. By tagging these biomolecules, researchers can now monitor their dynamics in living systems and discover specific substrates of cellular pathways. These advances in chemical biology are thus providing important tools to characterize biological pathways and are poised to facilitate our understanding of human diseases.

/pdf/chemical-reporters-for-biological-discovery-3wsrfbsxxs.pdf

Chemical reporters for biological discovery

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.

/pdf/metallodrugs-are-unique-opportunities-and-challenges-of-370m076u4c.pdf

Metallodrugs are unique: opportunities and challenges of discovery and development

Proteins constitute the majority of nature’s worker biomolecules. Designed for specific functions, complex tertiary structures make proteins ideal candidates for analysing natural systems and creating novel biological tools. Owing to both their large size and the need for proper folding, de novo synthesis of proteins has been quite a challenge, leading scientists to focus on modifying protein templates already provided by nature. Recently developed methods for protein modification fall into two broad categories: those that can modify the natural protein template directly and those that require genetic manipulation of the amino acid sequence before modification. The goal of this Review is not only to provide a window through which to view the many opportunities created by novel protein modification techniques‚ but also to act as an initial guide to help scientists find direction and form ideas in an ever-growing field. In addition to highlighting methods reported in the past 5 years, we aim to provide a broader sense of the goals and outcomes of protein modification and bioconjugation in general. While the main body of this paper comprises reactions involving the direct modification of expressed proteins, some further functionalization strategies as well as biological applications are also acknowledged. The discussion concludes by speculating which trends and discoveries will most likely come next in the field. Over the past 5 years, many novel site-selective protein modification techniques have been reported. Key features of these various strategies as well as prominent examples are discussed in this Review.

/pdf/contemporary-approaches-to-site-selective-protein-44jsa6i2gc.pdf

Contemporary approaches to site-selective protein modification

This tutorial review covers the recent advances made in the study of gold complexes containing N-heterocyclic carbene ligands with biological properties. The great stability, ease of modulation of the electronic properties and excellent σ-donating capacity displayed by NHCs allow gold-NHC derivatives to reach high stability in biological media and relatively good internalization into cells and for that they have emerged as excellent potential chemotherapeutics. The new gold-NHC derivatives show superior anticancer activity compared to other standards such as Cisplatin or Auranofin. In addition, the application of gold-NHC complexes in the treatment of other human diseases as antibacterial, antioxidant and antiparasitic agents is reviewed for the first time.

/pdf/recent-advances-in-gold-nhc-complexes-with-biological-2vvnz8v42t.pdf

Recent advances in gold-NHC complexes with biological properties

Metal N-heterocyclic carbene (NHC) complexes are a promising class of anti-cancer agents displaying potent in vitro and in vivo activities. Taking a multi-faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti-cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti-tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB-1, accompanied by expected downstream mechanisms of action. Additionally, PtII and PdII analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal–NHC scaffold in the design of anti-cancer metal medicines with multiple molecular targets.

Cyclometalated Gold(III) Complexes Containing N‐Heterocyclic Carbene Ligands Engage Multiple Anti‐Cancer Molecular Targets

https://www.cell.com/molecular-cell/pdf/S1097-2765(19)30657-4.pdf

Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics

Post-translational modifications (PTMs) have key roles in regulating protein-protein interactions in living cells. However, it remains a challenge to identify these PTM-mediated interactions. Here we develop a new lysine-based photo-reactive amino acid, termed photo-lysine. We demonstrate that photo-lysine, which is readily incorporated into proteins by native mammalian translation machinery, can be used to capture and identify proteins that recognize lysine PTMs, including 'readers' and 'erasers' of histone modifications.

Photo-lysine captures proteins that bind lysine post-translational modifications.

Protein posttranslational modifications (PTMs) play fundamental roles in regulating normal cell physiology and disease pathogenesis. Extensive studies on their cellular functions and mechanisms have advanced our understanding on some well-known PTMs such as phosphorylation, methylation, and acetylation. However, the biological roles played by many newly identified PTMs still remain poorly understood. Lysine malonylation, a covalent modification of the side chain of lysine, with a malonyl group incorporated at the eamine (Figure 1a), was recently identified as a novel PTM using two different approaches. One involved an antibody-

A chemical probe for lysine malonylation.

Cysteine thiols of many cancer-associated proteins are attractive targets of anticancer agents. Herein, we unequivocally demonstrate a distinct thiol-targeting property of gold(III) mesoporphyrin IX dimethyl ester (AuMesoIX) and its anticancer activities. While the binding of cysteine thiols with metal complexes usually occurs via M–S bond formation, AuMesoIX is unique in that the meso-carbon atom of the porphyrin ring is activated by the gold(III) ion to undergo nucleophilic aromatic substitution with thiols. AuMesoIX was shown to modify reactive cysteine residues and inhibit the activities of anticancer protein targets including thioredoxin, peroxiredoxin, and deubiquitinases. Treatment of cancer cells with AuMesoIX resulted in the formation of gold-bound sulfur-rich protein aggregates, oxidative stress-mediated cytotoxicity, and accumulation of ubiquitinated proteins. Importantly, AuMesoIX exhibited effective antitumor activity in mice. Our study has uncovered a gold(III)-induced ligand scaffold reactivity for thiol targeting that can be exploited for anticancer applications.

https://www.pnas.org/content/pnas/117/3/1321.full.pdf

Yi Man Eva Fung

Papers

Cyclometalated Gold(III) Complexes Containing N‐Heterocyclic Carbene Ligands Engage Multiple Anti‐Cancer Molecular Targets

Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics

Photo-lysine captures proteins that bind lysine post-translational modifications.

A chemical probe for lysine malonylation.

An anticancer gold(III)-activated porphyrin scaffold that covalently modifies protein cysteine thiols