Lysine degradation has remained elusive in many organisms including Escherichia coli. Here we report catabolism of lysine to succinate in E. coli involving glutarate and L-2-hydroxyglutarate as intermediates. We show that CsiD acts as an α-ketoglutarate-dependent dioxygenase catalysing hydroxylation of glutarate to L-2-hydroxyglutarate. CsiD is found widespread in bacteria. We present crystal structures of CsiD in complex with glutarate, succinate, and the inhibitor N-oxalyl-glycine, demonstrating strong discrimination between the structurally related ligands. We show that L-2-hydroxyglutarate is converted to α-ketoglutarate by LhgO acting as a membrane-bound, ubiquinone-linked dehydrogenase. Lysine enters the pathway via 5-aminovalerate by the promiscuous enzymes GabT and GabD. We demonstrate that repression of the pathway by CsiR is relieved upon glutarate binding. In conclusion, lysine degradation provides an important link in central metabolism. Our results imply the gut microbiome as a potential source of glutarate and L-2-hydroxyglutarate associated with human diseases such as cancer and organic acidurias.

Deoxyribonucleic acid (DNA) is the genetic material of living organisms. In the past, double-stranded DNA (dsDNA) with its ubiquitous architecture has not been regarded as a catalytic species, since the duplex structure precludes the formation of catalytically competent tertiary structures.[1] To date, although no naturally occurring catalytic DNA has been reported, DNA for nonbiological applications has aroused much interest in chemists for applications in areas such as catalysis, encoding, and stereocontrol.[2] Among these applications, a series of DNA-based asymmetric catalysis have been developed, which use a hybrid catalyst composed of dsDNA and a copper(II) complex.[3] This same strategy was later applied to G-quadruplex DNA (G4DNA) and modest enantioselectivities in the Diels-Alder (D-A) reaction were obtained.[4] Very recently, a G4DNA metalloenzyme composed of G4DNA and copper(II) ions has been reported to be able to catalyze an enantioselective Friedel-Crafts reaction. [5] This biology/chemistry interface is an attractive area of research and awaits further extensive exploration. Herein, we report an enantioselective D-A reaction achieved through the use of human telomeric G4DNA-based catalysts. We show that the absolute configuration of the products can be reversed when the conformation of the G4DNA is switched from antiparallel to parallel. Furthermore, both the reaction rate and the enantioselectivity of the reaction were found to be dependent on the DNA sequence.The D-A reaction is an important carbon-carbon bond forming reaction in organic synthesis. In the past few decades, it has received much attention in the development of innovative catalytic strategies to control the creation of the new carbon-carbon bonds and stereocenters. Among those strategies, biological molecules have been viewed as interesting and promising catalysts.[6] Herein, human telomeric G4DNA (ODN-1, 5'-G 3 (T 2 AG 3 ) 3 -3') was selected owing to its tunable conformation. As an initial attempt, a model D-A reaction [7] between aza-chalcone (1 a) and cyclopentadiene (2) was chosen to probe the catalytic performance of ODN-1. We found that ODN-1 alone in its antiparallel conformation [8] could promote the D-A reaction and the enantiomeric excess of the endo isomer of product 3 a is 17 % (Table 1, entry 2).The enantioselectivity of the ODN-1 promoted D-A reaction is significantly higher than that of the uncatalyzed reaction (Table 1, entry 2 vs. entry 1), which suggests that ODN-1 might function as an enantioselective catalyst for the D-A reaction.We assembled a complex between Cu(NO 3 ) 2 and ODN-1 (ODN-1-Cu 2+ ) and tested its ability to enantioselectively catalyze the D-A reaction. ODN-1-Cu 2+ provides a significant enhancement in the reaction rate ( entry 3). We also observed an excellent diastereoselectivity for product 3 a (endo/exo of 98:2) and a good enantioselectivity (74 % ee). These results suggest that ODN-1-Cu 2+ can serve as a potent catalyst, providing stereoselectivity and enhancement in reaction rates. To furthe...

A human telomeric G-quadruplex (G4DNA) metalloenzyme, assembled with G4DNA and Cu(2+) ions, can catalyze the enantioselective Friedel-Crafts (F-C) reaction in water with good enantioselectivity (up to 75% ee). Furthermore, we found that the absolute configuration and the enantioselectivity of the product largely depend on the conformation and the sequence of G4DNA.

Here we found that the enantioselectivity of G-quadruplex DNA-based Diels-Alder reaction can be switched by just changing Na + to K + , which † Electronic supplementary information (ESI) available: Experimental details, supplementary figures and tables, NMR spectra and HPLC traces. See

A highly stereospecific G-quadruplex DNA metalloenzyme was found by exploring the G-quadruplex targeting ligand pool.

The cyclic dinucleotides (CDNs) c-di-GMP, c-di-AMP, and c-AMP-GMP are widely utilized as second messengers in bacteria, where they signal lifestyle changes such as motility and biofilm formation, cell wall and membrane homeostasis, virulence, and exo-electrogenesis. For all known bacterial CDNs, specific riboswitches have been identified that alter gene expression in response to the second messengers. In addition, bacterial CDNs trigger potent immune responses, making them attractive as adjuvants in immune therapies. Besides the three naturally occurring CDNs, seven further CDNs containing canonical 3'-5'-linkages are possible by combining the four natural ribonucleotides. Herein, we have synthesized all ten possible combinations of 3'-5'-linked CDNs. The binding affinity of novel CDNs and GEMM riboswitch variants was assessed utilizing a spinach aptamer fluorescence assay and in-line probing assays. The immune-stimulatory effect of CDNs was evaluated by induction of type I interferons (IFNs), and a novel CDN c-AMP-CMP was identified as a new immune-stimulatory agent.

No abstract

Acute myeloid leukemia (AML) is an aggressive malignancy with only a handful of therapeutic options. About 30% of AML patients harbor mutated FLT3 kinase, and thus, this cancer-driver has become a hotly pursued AML target. Herein we report a new class of FLT3 inhibitors, which potently inhibit the proliferation of acute myeloid leukemia (AML) cells at nanomolar concentrations.