Connecting chemical worlds for a sustainable future.

Chemistry plays a central role in science and is the basis of one of the major, more impactful, and diverse industries. However, to address the most pressing global challenges, we must learn to create connections in an effective and meaningful way, with other disciplines, industries, and society at large. Here, we present the IUPAC Top Ten Emerging Technologies in Chemistry as an example of an initiative that highlights the value of the most promising advances in chemistry and contributes to creating connections to accelerate sustainable solutions for our society and our planet.

Chemical Solutions to the Current Polycrisis.

In the past 15 years, we've experienced an unprecedented series of crises, including financial (2008), health (2020), and most recently the supply chain disruptions and the energy emergency in Europe, caused by the war in Ukraine (2022). On top of that, climate change still poses a serious threat to our lives and our planet. These interconnected challenges create tremendous societal problems and compromise the viability of the chemical industry in an environment of price volatility and high inflation. Thus, the International Union of Pure and Applied Chemistry (IUPAC) has launched a series of actions to tackle this and raise awareness of the role of chemistry in solving our major threats. Since 2019, IUPAC has identified the "Top Ten Emerging Technologies in Chemistry" to connect chemical researchers with industry, bridging the gap between science and innovation, maintaining the current competitiveness of the chemical industry, as well as tackling our most pressing global challenges.

Inhibitors against Fungal Cell Wall Remodeling Enzymes.

Fungal ß-1,3-glucan glucanosyltransferases are glucan-remodeling enzymes that play important roles in cell wall integrity, and are essential for the viability of pathogenic fungi and yeasts. As such, they are considered possible drug targets, although inhibitors of this class of enzymes have not yet been reported. Herein we report a multidisciplinary approach based on a structure-guided design using a highly conserved transglycosylase from Sacharomyces cerevisiae, that leads to carbohydrate derivatives with high affinity for Aspergillus fumigatus Gel4. We demonstrate by X-ray crystallography that the compounds bind in the active site of Gas2/Gel4 and interact with the catalytic machinery. The topological analysis of noncovalent interactions demonstrates that the combination of a triazole with positively charged aromatic moieties are important for optimal interactions with Gas2/Gel4 through unusual pyridinium cation-π and face-to-face π-π interactions. The lead compound is capable of inhibiting AfGel4 with an IC50 value of 42 µm.

A Native Ternary Complex Trapped in a Crystal Reveals the Catalytic Mechanism of a Retaining Glycosyltransferase.

Glycosyltransferases (GTs) comprise a prominent family of enzymes that play critical roles in a variety of cellular processes, including cell signaling, cell development, and host-pathogen interactions. Glycosyl transfer can proceed with either inversion or retention of the anomeric configuration with respect to the reaction substrates and products. The elucidation of the catalytic mechanism of retaining GTs remains a major challenge. A native ternary complex of a GT in a productive mode for catalysis is reported, that of the retaining glucosyl-3-phosphoglycerate synthase GpgS from M. tuberculosis in the presence of the sugar donor UDP-Glc, the acceptor substrate phosphoglycerate, and the divalent cation cofactor. Through a combination of structural, chemical, enzymatic, molecular dynamics, and quantum-mechanics/molecular-mechanics (QM/MM) calculations, the catalytic mechanism was unraveled, thereby providing a strong experimental support for a front-side substrate-assisted SN i-type reaction.