Emissive synthetic cofactors: A highly responsive NAD+ analogue reveals biomolecular recognition features.

Emissive synthetic cofactors: A highly responsive NAD+ analogue reveals biomolecular recognition features. Chemistry. 2019 Jan 15;: Authors: Feldmann J, Li Y, Tor Y Abstract Apart from its function as a redox cofactor, nicotinamide adenine dinucleotide (NAD+) is a crucial substrate for NAD+-consuming enzymes, including PARPs. Their association with severe diseases necessitates the development of new discovery and analytical tools based on traceable NAD+ surrogates. Here we describe the synthesis, photophysics and biochemical utilization of an emissive, thieno[3,4-d]pyrimidine-based, NAD+ surrogate, termed NthAD+. It is enzymatically prepared from synthetic thATP via nicotinamide mononucleotide adenylyltransferase 1. NthAD+ displays useful photophysical features including red-shifted absorption and emission maxima as well as a relatively high quantum yield. NthAD+ is reduced by alcohol dehydrogenase to NthADH and affords thADP-ribose (thADPr) upon hydrolysis by NAD+-nucleosidase. Furthermore, NthAD+ can be engaged in Cholera toxin A-catalyzed mono(thADP-ribosyl)ation but cannot promote PARP1-mediated poly(thADP-ribosyl)ation. Its high photophysical responsiveness facilitates spectroscopic real-time monitoring. As an N7-lacking NAD+ surrogate, the thieno-based cofactor shows reduced biocompatibility (i.e. functional similarity compared to native NAD+) relative to its isothiazolo-based analogue. The distinct tolerance displayed by diver...
Source: Chemistry - Category: Chemistry Authors: Tags: Chemistry Source Type: research