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ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.

Human C-reactive protein (CRP) is a pentameric complex involved in immune defense and regulation of autoimmunity. CRP is also a therapeutic target, with both administration and depletion of serum CRP being pursued as a possible treatment for autoimmune and cardiovascular diseases, among others. CRP binds to phosphocholine (PC) moieties on membranes to activate the complement system via the C1 complex, but it is unknown how CRP, or any pentraxin, binds to C1. Here, we present a cryoelectron tomography (cryoET)-derived structure of CRP bound to PC ligands and the C1 complex. To gain control of CRP binding, a synthetic mimotope of PC was synthesized and used to decorate cell-mimetic liposome surfaces. Structure-guided mutagenesis of CRP yielded a fully active complex able to bind PC-coated liposomes that was ideal for cryoET and subtomogram averaging. In contrast to antibodies, which form Fc-mediated hexameric platforms to bind and activate the C1 complex, CRP formed rectangular platforms assembled from four laterally associated CRP pentamers that bind only four of the six available globular C1 head groups. Potential residues mediating lateral association of CRP were identified from interactions between unit cells in existing crystal structures, which rationalized previously unexplained mutagenesis data regarding CRP-mediated complement activation. The structure also enabled interpretation of existing biochemical data regarding interactions mediating C1 binding and identified additional residues for further mutagenesis studies. These structural data therefore provide a possible mechanism for regulation of complement by CRP, which limits complement progression and has consequences for how the innate immune system influences autoimmunity. [ABSTRACT FROM AUTHOR]

Nucleophilic substitution reactions are elementary reactions in organic chemistry that are used in many synthetic routes. By quantum chemical methods, we have investigated the intrinsic competition between the backside SN2 (SN2‐b) and frontside SN2 (SN2‐f) pathways using a set of simple alkyl triflates as the electrophile in combination with a systematic series of phenols and partially fluorinated ethanol nucleophiles. It is revealed how and why the well‐established mechanistic preference for the SN2‐b pathway slowly erodes and can even be overruled by the unusual SN2‐f substitution mechanism going from strong to weak alcohol nucleophiles. Activation strain analyses disclose that the SN2‐b pathway is favored for strong alcohol nucleophiles because of the well‐known intrinsically more efficient approach to the electrophile resulting in a more stabilizing nucleophile–electrophile interaction. In contrast, the preference of weaker alcohol nucleophiles shifts to the SN2‐f pathway, benefiting from a stabilizing hydrogen bond interaction between the incoming alcohol and the leaving group. This hydrogen bond interaction is strengthened by the increased acidity of the weaker alcohol nucleophiles, thereby steering the mechanistic preference toward the frontside SN2 pathway. [ABSTRACT FROM AUTHOR]

The transfer of an adenosine diphosphate (ADP) ribose moiety to a nucleophilic side chain by consumption of nicotinamide adenine dinucleotide is referred to as ADP‐ribosylation, which allows for the spatiotemporal regulation of vital processes such as apoptosis and DNA repair. Recent mass‐spectrometry based analyses of the "ADP‐ribosylome" have identified histidine as ADP‐ribose acceptor site. In order to study this modification, a fully synthetic strategy towards α‐configured N(τ)‐ and N(π)‐ADP‐ribosylated histidine‐containing peptides has been developed. Ribofuranosylated histidine building blocks were obtained via Mukaiyama‐type glycosylation and the building blocks were integrated into an ADP‐ribosylome derived peptide sequence using fluorenylmethyloxycarbonyl (Fmoc)‐based solid‐phase peptide synthesis. On‐resin installation of the ADP moiety was achieved using phosphoramidite chemistry, and global deprotection provided the desired ADP‐ribosylated oligopeptides. The stability under various chemical conditions and resistance against (ADP‐ribosyl) hydrolase‐mediated degradation has been investigated to reveal that the constructs are stable under various chemical conditions and non‐degradable by any of the known ADP‐ribosylhydrolases. [ABSTRACT FROM AUTHOR]