Two synthetic molecules developed to help elucidate cellular functions

CAPTION: Researchers at Gifu University’s Institute for Glyco-core Research have developed two synthetic approaches toproduce a fragment of a molecule called poly(ADP-ribose). By developing two ways to synthesize the fragment, researchers may
be able to better understand how it contributes to vital functions in the cell.

A sugar-based molecule naturally produced by the body can help cells grow, differentiate into
different types, self-destruct if need be and much more. It helps protect the cell’s genome, repair
DNA and regulate how genes are passed down. The molecule, called poly(adenosine diphosphateribose), or poly(ADP-ribose), holds the potential to inform disease prevention and treatments —if scientists can figure out exactly how it works.
To facilitate such scientific discovery, researchers at Gifu University’s Institute for Glyco-core
Research (iGCORE) in Japan developed two synthetic versions of an ADP-ribose fragment.
They published their approach on Sept. 23 in the European Journal of Organic Chemistry.

CAPTION: Although poly(ADP-ribose) occurs naturally, the molecular fragment — called ribosyl adenosine 5’,5”-diphosphate— varies too widely for researchers to infer broad functions.

When cells make new proteins, they translate the genetic instructions to machinery that can build
the proteins. During that process, some molecules or molecular fragments can bind to the protein
as a post-translational modification. The poly(ADP-ribose) fragment, known as ribosyl
adenosine 5′,5′′-diphosphate, could help reveal specific cellular functions, but naturally occurring
fragments are too varied for scientists to attribute broad functions.
“The problem is lack of the availability of homogeneous oligo- and poly(ADP-ribose) samples
which are necessary for molecular-level studies to elucidate their detailed functions,” said cocorresponding author Hide-Nori Tanaka, an assistant professor at iGCORE. Oligo- andpoly(ADP-ribose) refers to the number of components that bind together to make up the ADPribose molecule. “To address this bottleneck and accelerate ADP-ribose biology, we developed
two practical synthetic approaches to ribosyl adenosine 5',5"-diphosphate, a fragment ofpoly(ADP-ribose), for providing structurally well-defined ADP-ribose oligomer and polymer.”
The first method involved a stepwise assembly using a commercially available solution toproduce a framework to which the researchers then added carbohydrates. The second approach
was streamlined into a single step where researchers processed a known molecule that can bindto other molecules from a commercially available solution. Both methods produced a common
precursor that converts into a conjugation-ready building block that is primed for application in
ADP-ribose synthesis, according to Tanaka.

CAPTION: Researchers developed two synthetic approaches to produce the poly(ADP-ribose) fragment. Both approaches mayhelp researchers scale production of more uniform fragments for use in studies aimed at more precisely understanding their rolein cellular health.

“The next step is ADP-ribose oligomer synthesis using the building block we prepared in thispaper,” Tanaka said. “Our ultimate goal is to elucidate the detailed functions of oligo- andpoly(ADP-ribose) by chemical biology approach using synthetic molecules.”Collaborators, all from Gifu University, include co-corresponding author Hiromune Ando,Naoko Komura, Akihiro Imamura and Hideharu Ishida, iGCORE; Rui Hagino, the United
Graduate School of Agriculture Science; and Keita Mozaki, Department of Applied BioorganicChemistry. Tanaka, Ando, Imamura and Ishida are also affiliated with the United Graduate
School of Agricultural Science. Imamura and Ishida are also affiliated with the Department ofApplied Bioorganic Chemistry.
The Japan Society for the Promotion of Science, the Japan Science and Technology Agency, theUbe Industries Foundation and the Suntory Foundation for Life Sciences supported this work inpart.
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Suggested EurekAlert! Summary:A sugar-based molecule naturally produced by the body can help cells grow, differentiate into
different types, self-destruct if need be and much more. It helps protect the cell’s genome, repair
DNA and regulate how genes are passed down. The molecule, called poly(adenosinediphosphate ribose), or poly(ADP-ribose), holds the potential to inform disease prevention andtreatments—if scientists can figure out exactly how it works.