5VJN

Crystal Structure of Adenine Phosphoribosyltransferase from Saccharomyces cerevisiae Complexed with D-2,5-Dideoxy-2,5-Imino-Altritol 1,6-Bisphosphate (D-DIAB) and Adenine

Summary for 5VJN

• Entry DOI: 10.2210/pdb5vjn/pdb
• Related: 5VJP
• Descriptor: Adenine phosphoribosyltransferase 1, [(2R,3S,4R,5R)-3,4-dihydroxypyrrolidine-2,5-diyl]bis(methylene) bis[dihydrogen (phosphate)], 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: adenine phosphoribosyltransferase, transition state analogue, d-2, 5-dideoxy-2, 5-imino-altritol-1, 6-bisphosphate, d-diab, transferase-transferase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Saccharomyces cerevisiae (Baker's yeast)
• Total number of polymer chains: 2
• Total formula weight: 42325.36

Authors

Harijan, R.K.,Ducati, R.G.,Bonanno, J.B.,Almo, S.C.,Schramm, V.L. (deposition date: 2017-04-19, release date: 2017-12-27, Last modification date: 2023-10-04)

Primary citation

Harris, L.D.,Harijan, R.K.,Ducati, R.G.,Evans, G.B.,Hirsch, B.M.,Schramm, V.L.
Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase.
ACS Chem. Biol., 13:152-160, 2018

PubMed Abstract: Phosphoribosyl transferases (PRTs) are essential in nucleotide synthesis and salvage, amino acid, and vitamin synthesis. Transition state analysis of several PRTs has demonstrated ribocation-like transition states with a partial positive charge residing on the pentose ring. Core chemistry for synthesis of transition state analogues related to the 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) reactant of these enzymes could be developed by stereospecific placement of bis-phosphate groups on an iminoaltritol ring. Cationic character is provided by the imino group and the bis-phosphates anchor both the 1- and 5-phosphate binding sites. We provide a facile synthetic path to these molecules. Cyclic-nitrone redox methodology was applied to the stereocontrolled synthesis of three stereoisomers of a selectively monoprotected diol relevant to the synthesis of transition-state analogue inhibitors. These polyhydroxylated pyrrolidine natural product analogues were bis-phosphorylated to generate analogues of the ribocationic form of 5-phosphoribosyl 1-phosphate. A safe, high yielding synthesis of the key intermediate represents a new route to these transition state mimics. An enantiomeric pair of iminoaltritol bis-phosphates (L-DIAB and D-DIAB) was prepared and shown to display inhibition of Plasmodium falciparum orotate phosphoribosyltransferase and Saccharomyces cerevisiae adenine phosphoribosyltransferase (ScAPRT). Crystallographic inhibitor binding analysis of L- and D-DIAB bound to the catalytic sites of ScAPRT demonstrates accommodation of both enantiomers by altered ring geometry and bis-phosphate catalytic site contacts.

PubMed: 29178779
DOI: 10.1021/acschembio.7b00601

Experimental method

X-RAY DIFFRACTION (1.78 Å)