Glossary of Terms Used in Molecular Toxicology

Douglas M Templeton, Michael Schwenk, John Duffus

IUPAC 2020, published by the Royal Society of Chemistry, www.rsc.org, ISBN: 978-1-78801-771-8; https://doi.org/10.1039/9781839160714

Chemists need to understand the mechanisms of toxicity of the substances with which they deal. Both industrial and academic research chemists are faced with an ever-increasing burden in ensuring a safe environment in the laboratory and the workplace. Chemists must use both chemical and toxicological principles in formulating and enforcing current legislation introduced to ensure safe handling of substances throughout their life cycle. The goal of the Glossary of Terms Used in Molecular Toxicology is to assist chemists in approaching the toxicological literature with a critical eye, as chemical toxicology becomes more integrated into chemical curricula, chemical safety, and legislation.

In 2017, the authors collected a series of glossaries that were first published in Pure and Applied Chemistry, revised and updated many definitions, and added several hundred new ones. This was published as the Comprehensive Glossary of Terms Used in Toxicology. Upon completion of that work, it was realized that a number of molecular aspects of toxicology that relate to the biochemistry and cell biology of toxicity had been given short shrift, and the attempt to redress this in the Glossary of Terms Used in Molecular Toxicology has resulted in a companion volume with several thousand new terms, mostly derived from the literature of molecular biology, biochemistry, medicinal chemistry, and molecular pharmacology (see iupac.org/project/2017-012-1-700). As defined it in the Preface, Molecular Toxicology is considered to be “the science, studied at subcellular, cellular, and tissue levels, of the interactions of substances and other physicochemical stressors with the structural and functional molecules of the cell and its immediate surroundings, along with the defenses that the organism may mount against these adverse factors, as they affect the organism’s biological integrity and well-being.”

The choice of terms for the Glossary reveals the complexity of contemporary molecular biology that is relevant to toxicologists and informed chemists. We have necessarily included some terms of general cell metabolism, cell signaling, and biomolecular structure that do not obviously impact immediately upon toxicology, but that will be encountered by the reader of the literature covering molecular aspects of cell toxicity. Many of the biomolecules included are either established or emerging targets for medicinal chemists engaged in drug development. We have avoided compiling terms in molecular genetics, as that would seem to require a separate work of similar length.

It will be appreciated that the field of biomolecular and biomedical research is rapidly changing, as the tools of molecular science continue to facilitate an explosion of knowledge of the interactions of genes and proteins among themselves and with exogenous substances. Indeed, many terms included here were evolving as the glossary was in preparation, and each week new literature appears that reports new gene products and their interactions, and renders some definitions wanting. The complexion of molecular cell biology changed sufficiently during the three years that this Glossary was in preparation; leaving it, in some respects, egregiously incomplete. This is a reality that plagues any rapidly developing field. It should be viewed as a sampling of molecular players and concepts, and taken as a snapshot at the date of publication.

Although few people read glossaries, dictionaries, lexicons, or encyclopediae from cover to cover, we hope that this volume goes beyond a reference work for the practicing chemist, and may interest some who wish to browse through it to get a flavour of the subject. They may gain a better appreciation of complexities in molecular toxicology, and of some problems in terminology within IUPAC and in cognate disciplines. And, some entries may even entertain.

The entry term (or “headword” in the practice of lexicography) is often followed by one or more synonyms before a definition is presented. Sometimes, multiple synonyms arise because an entity was discovered more than once, with different functions in different contexts, or in different organisms, or in different laboratories, and only later were these entities recognized as homologous. When multiple synonyms are listed for a single term, we list them in the order we think represents preferred terms or decreasingly common usage. In some cases, terms that permeated the older literature but are no longer in preferred current use are indicated. For example, under the headword ATP7A are listed the synonyms P-type Cu²⁺ transporter, copper-transporting ATPase 1, copper pump 1, and Menkes disease protein (MNK); these refer to the same entity designated by the Enzyme Commission number EC 7.2.2.9. Or, we note the cyclin-dependent kinase p21 is also known as p21/Cip1/Waf1, cyclin-dependent kinase inhibitor 1, and CDK-interacting protein 1.

Another feature that may be noted by the casual browser of the Glossary is the complexity of acronyms used in molecular biology, e.g., NB-ARC [nucleotide-binding domain present in APAF-1 (apoptotic protease-activating factor-1), resistance (R) proteins and CED-4 (Caenorhabditis elegans death-4) protein]; or ADAMTS (a disintegrin and metalloproteinase with a thrombospondin domain). In some cases, the acronym gives a short history lesson on the discovery of the molecule, as for the caspase 8 inhibitor FLIP [also known by the synonyms cellular FLICE inhibitor protein (c-FLIP), caspase 8 and FADD-like apoptosis regulator (CFLAR), caspase 8-related protein (Casper), and Flice inhibitory protein (I-FLICE)]. FLIP can be broken down into its acronymic contributors and then reads as “FADD-like ICE inhibitor protein”, or in full “(factor for apoptotic signaling-associated protein with death domain)-like interleukin-1b-converting enzyme inhibitory protein.” A 22-page appendix collects all the acronyms used in the Glossary.

While IUPAC has a good handle on chemical nomenclature, this is not always the case in cognate fields that are in play in the Glossary. Whenever we refer to an enzyme activity, we try to give the current Enzyme Commission (EC) number to avoid ambiguity, but the assignment of these numbers is a fluid proposition as more is learned about components and true biological substrates. We try to mention earlier designations when they are still prominent in the literature. For instance, the E1 ubiquitin ligase is now designated EC 6.2.1.45, but was formerly included in EC 6.3.2.21, and before that EC 6.3.2.19; and all are still found in articles of interest.

More problematic are naming conventions for genes and proteins, where there is no central authority for denoting gene and protein names across species, and subsets of biologists use different conventions. A universal convention is to italicize a gene name, but human genes are given in roman uppercase, while mouse genes have only the first letter capitalized. For instance, the human sonic hedgehog gene and protein symbols are written as SHH and SHH, respectively, while for the mouse the corresponding terms are Shh and SHH. The Xenopus equivalents are shh and Shh. Other conventions are used in the yeast, bacterial, and zebra fish communities, for example, and we try to adhere to these conventions when referencing species-specific molecules. Full names of proteins are generally not capitalized (e.g., human apelin, which has the protein symbol APLN and gene symbol APLN), unless frequently done so by convention (e.g., Fas, Jagged, Smad, and Snail); and never for more common proteins such as actin, insulin, and tubulin; or enzymes such as catalase and ornithine decarboxylase. Even on this last point, though, some major textbooks disagree.

There is a recognized problem of multiple recommended definitions of some terms in various IUPAC sources, and issues with some definitions in the Gold Book. We do not wish to exacerbate this problem, which is being addressed in the Gold Book revision, and for the few previously defined terms that we have included, we have tried to stick as closely as possible to pre-existing Gold Book definitions. This has not always been possible. For example, a previous IUPAC definition of “antigenic determinant” gives “epitope” as a synonym. However, we define the terms separately, noting that an epitope is a structural feature of an antigen, whereas an antigenic determinant is a functional attribute. As another example, a previous IUPAC definition of an enzyme reads “Macromolecule, usually a protein that functions as a catalyst.” This is problematic, as the wording implies that any macromolecule is an enzyme, though usually a protein catalyst of any reaction. Our revised wording specifies a protein or nucleic acid catalyst of a biologic reaction, and recognizes that an apoprotein without its coenzyme conjugate does not qualify.

To end on a lighter note, there may be some entertainment value for the reader in examples of trivia, such as the derivation of “anandamide”, an endogenous cannabinoid receptor ligand, from a Sanskrit word for joy; or that the inhibitory membrane protein “klotho” is named for one of the Fates who was responsible for spinning the thread of human life. The reader will also learn that the G protein “SOS” is a name meaning “son of sevenless”, and the smad proteins derive their name in part from the Drosophila gene product “mad”, standing for “mothers against decapentaplegic”, perhaps demonstrating that not only chemists have a sense of humor.