Chemical Pyrophosphorylation of Functionally Diverse Peptides

Marmelstein, Alan M.; Yates, Lauren; Conway, John H.; Fiedler, Dorothea

doi:10.1021/ja411737c

Cited by 41 publications

(55 citation statements)

References 31 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent advances by the Fiedler, Jessen and Potter laboratories are likely to help in surmounting these challenges. 78,79,[126][127][128][129] Highly pure PP-IPs with β-phosphate moieties at specific carbon atoms have been synthesized by these groups, including non-hydrolysable analogues that are stable in cells and can bind target proteins but not pyrophosphorylate them. 47,78,130 A system for intracellular delivery and photouncaging of chemically synthesized PP-IPs has recently been developed, 79 which promises to open up new methods to study the functions of these molecules in different subcellular compartments.…”

Section: Perspective On the Futurementioning

confidence: 99%

Inositol Pyrophosphates: Energetic, Omnipresent and Versatile Signalling Molecules

et al. 2017

View full text Add to dashboard Cite

| Inositol pyrophosphates (PP-IPs) are a class of energy-rich signalling molecules found in all eukaryotic cells. These are derivatives of inositol that contain one or more diphosphate (or pyrophosphate) groups in addition to monophosphates. The more abundant and best studied PP-IPs are diphosphoinositol pentakisphosphate (IP 7 ) and bis-diphosphoinositol tetrakisphosphate (IP 8 ). These molecules can influence protein function by two mechanisms: binding and pyrophosphorylation. The former involves the specific interaction of a particular inositol pyrophosphate with a binding site on a protein, while the latter is a unique attribute of inositol pyrophosphates, wherein the β-phosphate moiety is transferred from a PP-IP to a pre-phosphorylated serine residue in a protein to generate pyrophosphoserine. Both these events can result in changes in the target protein's activity, localisation or its interaction with other partners. As a consequence of their ubiquitous presence in all eukaryotic organisms and all cell types examined till date, and their ability to modify protein function, PP-IPs have been found to participate in a wide range of metabolic, developmental, and signalling pathways.This review highlights many of the known functions of PP-IPs in the context of their temporal and spatial distribution in eukaryotic cells. The pathway of synthesis of inositol polyphosphates has been characterized in yeast, slime moulds, plants and animals. The simplest anabolic pathway, characterized in the yeast Saccharomyces cerevisiae (Fig. 1) (Fig. 1). Interestingly, the PPIP5Ks also possess a phosphatase domain which selectively cleaves the 1-position β-phosphate of 1-IP 7 and IP 8 , thus targeting the products of the kinase domain.35, 36 A recent study identified another yeast phosphatase, Siw14, that specifically targets the 5-position β-phosphate of PP-IPs 37 (Fig. 1). As PP-IPs are found in all eukaryotic organisms, they display many conserved and divergent 2, 131 Siw14, an inositol pyrophosphate phosphatase in yeast, preferentially cleaves the C5 β-phosphate on PP-IPs. 37 The yeast enzymes are depicted in purple, and mammalian enzymes are depicted in green and are bracketed. The undetermined inositol pyrophosphate structure is represented with an interrogation mark. Myoinositol contains five equatorial (parallel to the axis) and one axial (perpendicular to the axis) hydroxyl groups. Carbon atoms on the myo-inositol ring are numbered on the structures of PI(4,5)P 2 and IP 6 .

show abstract

Section: Perspective On the Futurementioning

confidence: 99%

Inositol Pyrophosphates: Energetic, Omnipresent and Versatile Signalling Molecules

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Another recent utilization of this reaction in the area of intrinsically labile PTMs allowed us to obtain and characterize the properties of site-specifically phosphorylated lysine-peptides for the first time (Figure 2b) [30]. Reports describing access to other forms of phosphorylated peptides and proteins included the synthesis of phospho-Hismimetics by Muir and coworkers using Ru-catalyzed cycloaddition reactions (Figure 2b) [31] and the use of phosphorimidazolide reagents to generate pyrophosphorylated peptides by Fiedler et al, which represents the first example of synthetic pyrophosphorylation and facilitated the in vitro characterization of this recently described PTM (Figure 2b) [32].…”

Section: Current Opinion In Chemical Biologymentioning

confidence: 98%

“…Staudinger reaction of azides with phosphites followed by light initiated hydrolysis gave phosphorylated tyrosine analogues and naturally occurring phosphorylated lysine peptides in 1 and 2 [28 ,30]. High yielding and selective synthesis of pyrophosphopeptides in 3 [32]. attachment for PEG, since its rare occurrence in proteins and its low pK a value and high nucleophilicity allows for a rapid and selective conjugation reaction under physiologic conditions.…”

Section: Protein-peg Conjugatesmentioning

confidence: 99%

More than add-on: chemoselective reactions for the synthesis of functional peptides and proteins

Schumacher

Hackenberger

2014

Current Opinion in Chemical Biology

View full text Add to dashboard Cite

“…However, it has been noted that there is no direct evidence this covalent modification occurs in vivo [1,2]. There are as yet no antibody-based or proteomic methods that can address this issue [27]. An indirect, ‘back-phosphorylation’ assay for protein pyrophosphorylation has been developed [28], although such methodology may instead act as a bioassay for the degree of endogenous CK2-mediated protein phosphorylation [29].…”

Section: Introduction – the Multifunctionality Of Pp-inspsmentioning

confidence: 99%

Towards pharmacological intervention in inositol pyrophosphate signalling

Shears

2016

Biochemical Society Transactions

View full text Add to dashboard Cite

To help define the molecular basis of cellular signalling cascades, and their biological functions, there is considerable value in utilizing a high-quality chemical ‘probe’ that has a well-defined interaction with a specific cellular protein. Such reagents include inhibitors of protein kinases and small molecule kinases, as well as mimics or antagonists of intracellular signals. The purpose of this review is to consider recent progress and promising future directions for the development of novel molecules that can interrogate and manipulate the cellular actions of inositol pyrophosphates (PP-IPs) – a specialized, ‘energetic’ group of cell-signalling molecules in which multiple phosphate and diphosphate groups are crammed around a cyclohexane polyol scaffold.

show abstract

Chemical Pyrophosphorylation of Functionally Diverse Peptides

Cited by 41 publications

References 31 publications

Inositol Pyrophosphates: Energetic, Omnipresent and Versatile Signalling Molecules

Inositol Pyrophosphates: Energetic, Omnipresent and Versatile Signalling Molecules

More than add-on: chemoselective reactions for the synthesis of functional peptides and proteins

Towards pharmacological intervention in inositol pyrophosphate signalling

Contact Info

Product

Resources

About