Efficient Ni Based Catalysts for Hydrotreatment of Lignin Dimer Model Compounds to Cycloalkanes/Cycloalkanols

Noble-metal catalytic cleavage of the ether bonds in lignin to obtain aromatic chemicals had achieved great success, and development of a low-cost and efficient catalyst was crucial. Herein, NixLay/CNT was...

Structure-function analysis of microRNA 3′-end trimming by Nibbler

Nibbler (Nbr) is a 3′-to-5′ exoribonuclease whose catalytic 3′-end trimming activity impacts microRNA (miRNA) and PIWI-interacting RNA (piRNA) biogenesis. Here, we report on structural and functional studies to decipher the contributions of Nbr’s N-terminal domain (NTD) and exonucleolytic domain (EXO) in miRNA 3′-end trimming. We have solved the crystal structures of the NTD core and EXO domains of Nbr, both in the apo-state. The NTD-core domain ofAedes aegyptiNbr adopts a HEAT-like repeat scaffold with basic patches constituting an RNA-binding surface exhibiting a preference for binding double-strand RNA (dsRNA) over single-strand RNA (ssRNA). Structure-guided functional assays inDrosophilaS2 cells confirmed a principal role of the NTD in exonucleolytic miRNA trimming, which depends on basic surface patches. Gain-of-function experiments revealed a potential role of the NTD in recruiting Nbr to Argonaute-bound small RNA substrates. The EXO domain ofA. aegyptiandDrosophila melanogasterNbr adopt a mixed α/β-scaffold with a deep pocket lined by a DEDDy catalytic cleavage motif. We demonstrate that Nbr’s EXO domain exhibits Mn2+-dependent ssRNA-specific 3′-to-5′ exoribonuclease activity. Modeling of a 3′ terminal Uridine into the catalytic pocket of Nbr EXO indicates that 2′-O-methylation of the 3′-U would result in a steric clash with a tryptophan side chain, suggesting that 2′-O-methylation protects small RNAs from Nbr-mediated trimming. Overall, our data establish that Nbr requires its NTD as a substrate recruitment platform to execute exonucleolytic miRNA maturation, catalyzed by the ribonuclease EXO domain.

Demystifying the catalytic pathway of Mycobacterium tuberculosis isocitrate lyase

Pulmonary tuberculosis, caused by Mycobacterium tuberculosis, is one of the most persistent diseases leading to death in humans. As one of the key targets during the latent/dormant stage of M. tuberculosis, isocitrate lyase (ICL) has been a subject of interest for new tuberculosis therapeutics. In this work, the cleavage of the isocitrate by M. tuberculosis ICL was studied using quantum mechanics/molecular mechanics method at M06-2X/6-31+G(d,p): AMBER level of theory. The electronic embedding approach was applied to provide a better depiction of electrostatic interactions between MM and QM regions. Two possible pathways (pathway I that involves Asp108 and pathway II that involves Glu182) that could lead to the metabolism of isocitrate was studied in this study. The results suggested that the core residues involved in isocitrate catalytic cleavage mechanism are Asp108, Cys191 and Arg228. A water molecule bonded to Mg2+ acts as the catalytic base for the deprotonation of isocitrate C(2)–OH group, while Cys191 acts as the catalytic acid. Our observation suggests that the shuttle proton from isocitrate hydroxyl group C(2) atom is favourably transferred to Asp108 instead of Glu182 with a lower activation energy of 6.2 kcal/mol. Natural bond analysis also demonstrated that pathway I involving the transfer of proton to Asp108 has a higher intermolecular interaction and charge transfer that were associated with higher stabilization energy. The QM/MM transition state stepwise catalytic mechanism of ICL agrees with the in vitro enzymatic assay whereby Asp108Ala and Cys191Ser ICL mutants lost their isocitrate cleavage activities.

Shuttle Arylation by Rh(I) Catalyzed Reversible Carbon–Carbon Bond Activation of Unstrained Alcohols

The advent of transfer hydrogenation and borrowing hydrogen reactions paved the way to manipulate simple alcohols in previously unthinkable manners and circumvent the need for hydrogen gas. Analogously, transfer hydrocarbylation could greatly increase the versatility of tertiary alcohols. However, this reaction remains unexplored because of the challenges associated with the catalytic cleavage of unactivated C–C bonds. Herein, we report a rhodium(I)-catalyzed shuttle arylation cleaving the C(sp²)–C(sp³) bond in unstrained triaryl alcohols via a redox-neutral <i>β</i>-carbon elimination mechanism. A selective transfer hydrocarbylation of substituted (hetero)aryl groups from tertiary alcohols to ketones was realized, employing benign alcohols as latent <i>C</i>-nucleophiles. All preliminary mechanistic experiments support a reversible <i>β</i>-carbon elimination/migratory insertion mechanism. In a broader context, this novel reactivity offers a new platform for the manipulation of tertiary alcohols in catalysis.

Shuttle Arylation by Rh(I) Catalyzed Reversible Carbon–Carbon Bond Activation of Unstrained Alcohols

The advent of transfer hydrogenation and borrowing hydrogen reactions paved the way to manipulate simple alcohols in previously unthinkable manners and circumvent the need for hydrogen gas. Analogously, transfer hydrocarbylation could greatly increase the versatility of tertiary alcohols. However, this reaction remains unexplored because of the challenges associated with the catalytic cleavage of unactivated C–C bonds. Herein, we report a rhodium(I)-catalyzed shuttle arylation cleaving the C(sp²)–C(sp³) bond in unstrained triaryl alcohols via a redox-neutral <i>β</i>-carbon elimination mechanism. A selective transfer hydrocarbylation of substituted (hetero)aryl groups from tertiary alcohols to ketones was realized, employing benign alcohols as latent <i>C</i>-nucleophiles. All preliminary mechanistic experiments support a reversible <i>β</i>-carbon elimination/migratory insertion mechanism. In a broader context, this novel reactivity offers a new platform for the manipulation of tertiary alcohols in catalysis.