Synthesis of Stable NAD+  Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitinating Enzyme SdeC.

Synthesis of Stable NAD+ Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitinating Enzyme SdeC. Chembiochem. 2020 May 18;: Authors: van der Heden van Noort G, Madern JM, Kim RQ, Misra M, Dikic I, Zhang Y, Ovaa H, Codee JDC, Filippov DV Abstract Stable NAD +  analogues carrying single atom substitutions in either the furanose ring or the nicotinamide part have proven their value as inhibitors for NAD +  consuming enzymes. To investigate the potential of such compounds to inhibit the adenosine diphosphate ribosyl (ADPr) transferase activity of the Legionella SdeC-enzyme, we prepared three NAD +  analogues, namely carba-nicotinamide adenosine dinucleotide (c-NAD + ), thio-nicotinamide adenosine dinucleotide (S-NAD + ) and benzamide adenosine dinucleotide (BAD). We optimized the chemical synthesis of thio-nicotinamide riboside and for the first time used an enzymatic approach to convert all three  ribosides into the corresponding NAD +  mimics. We thus expanded the known scope of substrates for the NRK1/NMNAT1 enzyme combination by turning all three modified ribosides into NAD +  analogues in a scalable manner. We then compared all three of the NAD + -mimics side-by-side in a single assay for enzyme inhibition on Legionella effector enzyme SdeC. The class of SidE enzymes to which SdeC belongs, was recently identified to be important in bacterial virulence and we found SdeC to be inhibited by S-NAD +  an...
Source: Chembiochem - Category: Biochemistry Authors: Tags: Chembiochem Source Type: research