69205-79-4Relevant articles and documents
Synthesis of azide congeners of preQ1 as potential substrates for tRNA guanine transglycosylase
Brooks, Allen F.,Garcia, George A.,Showalter, Hollis D.
, p. 1192 - 1198 (2021)
PreQ1 (2) is a precursor of queuine (1) that in eubacteria is incorporated into transfer RNA (tRNA) by tRNA guanine transglycosylase (TGT) before being further elaborated into queuine. The queuine modification is unusual and occurs across all eukaryotes and eubacteria with few exceptions, but its function remains unclear. As the modified nucleotide occurs through incorporation of a specially synthesized nucleotide instead of via modification of a genetically encoded base, a study of the sites of modification by prepared probes is possible. We report the synthesis of two novel azide congeners (3,4) of preQ1 for this purpose. The evaluation of their interaction with TGT shows that both probes act as weak competitive inhibitors of guanine exchange of guanine(34) tRNATyr with a Ki of ~70 μM. However, we could not show that these are substrates for TGT-catalyzed incorporation into tRNA. We believe the reason for this is a marked loss of binding due to the azide functionality of 3 and 4 abrogating the possibility of two hydrogen bonds to the carbonyl group of Leu231 and Met260 of TGT, previously observed for the terminal methylene amine of preQ1 by x-ray crystallography.
COMPOUNDS
-
Page/Page column 27-28, (2022/02/09)
The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is selected from C or N; X is selected from O or S; R1 is selected from hydrogen or methyl; Z is CR2R3, wherein R2 and R3 are each independently selected from hydrogen and (1-5C)alkyl, or R2 and R3 are taken together with the carbon atom to which they are attached to form a cyclopropyl or cyclobutyl ring; Z1 is selected from CR4R5, O, S, C(O) or NR6, wherein R4 and R5 are each independently selected from hydrogen, OH, (1-5C)alkyl and phenyl, or R4 and R5 are taken together with the carbon atom to which they are attached to form a cyclopropyl ring, and R6 is selected from hydrogen and (1-5C)alkyl, provided that one, but not both, of Z and Z1 is CH2.
Creation of an Engineered Amide Synthetase Biocatalyst by the Rational Separation of a Two-Step Nitrile Synthetase
Hennessy, Alexis J. A.,Huang, Wenli,Savary, Chloé,Campopiano, Dominic J.
, (2022/01/06)
The synthesis of amides through acid and amine coupling is one of the most commonly used reactions in medicinal chemistry, yet still requires atom-inefficient coupling reagents. There is a current demand to develop greener, biocatalytic approaches to amide bond formation. The nitrile synthetase (NS) enzymes are a small family of ATP-dependent enzymes which catalyse the transformation of a carboxylic acid into the corresponding nitrile via an amide intermediate. The Bacillus subtilis QueC (BsQueC) is an NS involved in the synthesis of 7-cyano-7-deazaguanine (CDG) natural products. Through sequence homology and structural analysis of BsQueC we identified three highly conserved residues, which could potentially play important roles in NS substrate binding and catalysis. Rational engineering led to the creation of a NS K163A/R204A biocatalyst that converts the CDG acid into the primary amide, but does not proceed to the nitrile. This study suggests that NSs could be further developed for coupling agent-free, amide-forming biocatalysts.
