Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase

ACS Chem Biol. 2018 Jan 19;13(1):152-160. doi: 10.1021/acschembio.7b00601. Epub 2017 Dec 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / chemistry
  • Adenine / metabolism
  • Adenine Phosphoribosyltransferase / antagonists & inhibitors
  • Adenine Phosphoribosyltransferase / chemistry*
  • Adenine Phosphoribosyltransferase / metabolism*
  • Catalytic Domain
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Models, Molecular
  • Organophosphorus Compounds / chemical synthesis
  • Organophosphorus Compounds / chemistry*
  • Orotate Phosphoribosyltransferase / antagonists & inhibitors
  • Plasmodium falciparum / enzymology
  • Protein Conformation
  • Saccharomyces cerevisiae / enzymology
  • Stereoisomerism

Substances

  • Enzyme Inhibitors
  • Organophosphorus Compounds
  • Orotate Phosphoribosyltransferase
  • Adenine Phosphoribosyltransferase
  • Adenine