Christopher Thomas Walsh

Building upon the previous volumes, The Chemical Biology of Sulfur, The Chemical Biology of Phosphorus, and The Chemical Biology of Nitrogen, this book examines the organic chemistry of life, The Chemical Biology of Carbon. It examines chemical biology open to carbon-containing natural metabolites that allow both retrospective and predictive behaviours of both biosynthetic and degradative metabolism in primary and secondary pathways. This book also notes the centrality of a core set of heterocycles in metabolites and coenzyme forms of vitamins and how that chemistry enables life. The organic chemical fundamental considerations are always tied to specific metabolites and metabolic transformations. This context makes this volume not a classical organic or even bioorganic approach to organic chemistry in vivo but instead a unique analysis of how the rules and reactivities of organic chemistry underlie the organic chemistry of life. The Chemical Biology of Carbon is an ideal reference and guide for medicinal chemists, chemical biologists, organic chemists as well as postgraduate, graduate and advanced undergraduate students in these areas and related disciplines.

Covering: 2000 to 2022 Secondary metabolites are assembled by drawing off and committing some of the flux of primary metabolic building blocks to sets of enzymes that tailor the maturing scaffold to increase architectural and framework complexity, often balancing hydrophilic and hydrophobic surfaces. In this review we examine the small number of chemical strategies that tailoring enzymes employ in maturation of scaffolds. These strategies depend both on the organic functional groups present at each metabolic stage and one of two tailoring enzyme strategies. Nonoxidative tailoring enzymes typically transfer electrophilic fragments, acyl, alkyl and glycosyl groups, from a small set of thermodynamically activated but kinetically stable core metabolites. Oxidative tailoring enzymes can be oxygen-independent or oxygen-dependent. The oxygen independent oxidoreductases are often reversible nicotinamide …

The tripartite structures of the four 5′-nucleotide monophosphate (NMP) building blocks in all RNAs enable enzyme-catalyzed chemical modifications to three types of sites: the heterocyclic bases via N- and C-methylations and other alkylations, conversion of the N-glycoside linkages of the uridine moiety to the C–C glycoside link in pseudouridines, and the phosphodiester-mediated processes of 5′-capping, splicing, and 3′-tailing of premRNAs. We examine known cases for enzymatic covalent catalytic strategies that entail transient formation and breakdown of covalent enzyme–RNA adducts in each catalytic cycle. One case involves generation of the required carbon nucleophile during C5 methylation of cytosine residues in RNAs. A second examines the mechanism proposed for pseudouridine synthases and for replacement of a guanine residue in tRNAs by queuosine. The third category involves phosphoric …

The rising prevalence of multidrug-resistant bacteria is an urgent health crisis that can only be countered through renewed investment in the discovery and development of antibiotics. There is no panacea for the antibacterial resistance crisis; instead, a multifaceted approach is called for. In this Perspective we make the case that, in the face of evolving clinical needs and enabling technologies, numerous validated antibacterial targets and associated lead molecules deserve a second look. At the same time, many worthy targets lack good leads despite harboring druggable active sites. Creative and inspired techniques buoy discovery efforts; while soil screening efforts frequently lead to antibiotic rediscovery, researchers have found success searching for new antibiotic leads by studying underexplored ecological niches or by leveraging the abundance of available data from genome mining efforts. The judicious use of …

From DNA and RNA to proteins and vitamins the role of nitrogen is central in organismal metabolism. The Chemical Biology of Nitrogen comprehensively examines how the chemistry available to both inorganic and organic nitrogen compounds both enable and conditions the vast array of nitrogen biologies. This book provides a chemocentric approach to both the inorganic and organic chemical biology of nitrogen. Following an introduction to nitrogen trivalency the book progresses through the logic of inorganic nitrogen metabolism and organic nitrogen metabolites to nitrogen proteomics with an integrative approach to understanding the role of nitrogen in its many biologic roles. Authored by a renowned scientist and educator, this book is ideal for researchers in chemical biology and nitrogen metabolism and will be of particular interest to advanced students and postgraduates in biochemistry and chemical biology.

Alexander Todd, the 1957 Nobel laureate in chemistry is credited with the statement:" where there is life, there is phosphorus". Phosphorus chemical biology underlies most of life's reactions and processes, from the covalent bonds that hold RNA and DNA together, to the making and spending 75 kg of ATP every day, required to run almost all metabolic and mechanical events in cells. Authored by a renowned biochemist, The Chemical Biology of Phosphorus provides an in-depth, unifying chemical approach to the logic and reactivity of inorganic phosphate and its three major derivatives (anhydrides, mono-and diesters) throughout biology to examine why life depends on phosphorus. Covering the breadth of phosphorus chemistry in biology, this book is ideal for biochemistry students, postgraduates and researchers interested in the chemical logic of phosphate metabolites, energy generation, biopolymer accumulation and phosphoproteomics.

Peptide-based small molecule natural products can arise by two distinct biosynthetic strategies. One involves the normal ribosomal machinery to construct nascent proteins that, once released, undergo a series of posttranslational modifications, including selective proteolysis and then either side chain and/or backbone modifications to yield compact hydrolytically stable mature scaffolds. The second strategy is RNA-independent, utilizing nonribosomal peptide synthetase (NRPS) assembly lines to build short peptide frameworks that can also undergo extensive scaffold morphings by dedicated tailoring enzymes. The NRPS protein machinery is not limited by aminoacyl tRNA synthetase selectivities and allows insertion of many dozens of nonproteinogenic amino acid monomers.

A chemocentric view of the molecular structures of antibiotics, their origins, actions, and major categories of resistance Antibiotics: Challenges, Mechanisms, Opportunities focuses on antibiotics as small organic molecules, from both natural and synthetic sources. Understanding the chemical scaffold and functional group structures of the major classes of clinically useful antibiotics is critical to understanding how antibiotics interact selectively with bacterial targets. This textbook details how classes of antibiotics interact with five known robust bacterial targets: cell wall assembly and maintenance, membrane integrity, protein synthesis, DNA and RNA information transfer, and the folate pathway to deoxythymidylate. It also addresses the universe of bacterial resistance, from the concept of the resistome to the three major mechanisms of resistance: antibiotic destruction, antibiotic active efflux, and alteration of antibiotic targets. Antibiotics also covers the biosynthetic machinery for the major classes of natural product antibiotics. Authors Christopher Walsh and Timothy Wencewicz provide compelling answers to these questions: What are antibiotics? Where do antibiotics come from? How do antibiotics work? Why do antibiotics stop working? How should our limited inventory of effective antibiotics be addressed? Antibiotics is a textbook for graduate courses in chemical biology, pharmacology, medicinal chemistry, and microbiology and biochemistry courses. It is also a valuable reference for microbiologists, biological and natural product chemists, pharmacologists, and research and development scientists.