Highly diastereoselective nucleophilic additions to cyclic nitrones derived from L-malic acid and D-arabinose have been used for the construction of enantiomerically pure polyhydroxylated pyrrolidines. The synthetic strategy adopted was based on an oxidation/reduction protocol involving hydroxylamine/nitrone pairs and demonstrates the use of reagent-and substrate-derived stereocontrol. In most cases reactions took place with total diastereoselectivity and in quantitative yield, with no purification being necessary. By this strategy, 2-(hydroxymethyl)-, 2-(aminomethyl)-, and 2-aryl-
The
Mycobacterium tuberculosis
(
Mtb
) LpqY-SugABC ATP-binding cassette transporter is a recycling system that imports trehalose released during remodeling of the
Mtb
cell-envelope. As this process is essential for the virulence of the
Mtb
pathogen, it may represent an important target for tuberculosis drug and diagnostic development, but the transporter specificity and molecular determinants of substrate recognition are unknown. To address this, we have determined the structural and biochemical basis of how mycobacteria transport trehalose using a combination of crystallography, saturation transfer difference NMR, molecular dynamics, site-directed mutagenesis, biochemical/biophysical assays, and the synthesis of trehalose analogs. This analysis pinpoints key residues of the LpqY substrate binding lipoprotein that dictate substrate-specific recognition and has revealed which disaccharide modifications are tolerated. These findings provide critical insights into how the essential
Mtb
LpqY-SugABC transporter reuses trehalose and modified analogs and specifies a framework that can be exploited for the design of new antitubercular agents and/or diagnostic tools.
FUT8
is an essential α-1,6-fucosyltransferase that fucosylates
the innermost GlcNAc of N-glycans, a process called core fucosylation.
In vitro
, FUT8 exhibits substrate preference for the biantennary
complex N-glycan oligosaccharide (G0), but the role of the underlying
protein/peptide to which N-glycans are attached remains unclear. Here,
we explored the FUT8 enzyme with a series of N-glycan oligosaccharides,
N-glycopeptides, and an Asn-linked oligosaccharide. We found that
the underlying peptide plays a role in fucosylation of paucimannose
(low mannose) and high-mannose N-glycans but not for complex-type
N-glycans. Using saturation transfer difference (STD) NMR spectroscopy,
we demonstrate that FUT8 recognizes all sugar units of the G0 N-glycan
and most of the amino acid residues (Asn-X-Thr) that serve as a recognition
sequon for the oligosaccharyltransferase (OST). The largest STD signals
were observed in the presence of GDP, suggesting that prior FUT8 binding
to GDP-β-
l
-fucose (GDP-Fuc) is required for an optimal
recognition of N-glycans. We applied genetic engineering of glycosylation
capacities in CHO cells to evaluate FUT8 core fucosylation of high-mannose
and complex-type N-glycans in cells with a panel of well-characterized
therapeutic N-glycoproteins. This confirmed that core fucosylation
mainly occurs on complex-type N-glycans, although clearly only at
selected glycosites. Eliminating the capacity for complex-type glycosylation
in cells (KO
mgat1
) revealed that glycosites with
complex-type N-glycans when converted to high mannose lost the core
Fuc. Interestingly, however, for erythropoietin that is uncommon among
the tested glycoproteins in efficiently acquiring tetra-antennary
N-glycans, two out of three N-glycosites obtained Fuc on the high-mannose
N-glycans. An examination of the N-glycosylation sites of several
protein crystal structures indicates that core fucosylation is mostly
affected by the accessibility and nature of the N-glycan and not by
the nature of the underlying peptide sequence. These data have further
elucidated the different FUT8 acceptor substrate specificities both
in vitro
and
in vivo
in cells, revealing
different mechanisms for promoting core fucosylation.
Here, we present a highly efficient approach to nucleobase-containing spiro-isoxazolidines with potential biological activity starting from isatinyl/indanyl nitrones.
The reaction of nitrones with enals through iminium activation can be modulated by using cooperative hydrogen‐bonding catalysis to induce the participation of a nitrone ylide (C‐N‐C) instead of the classical C‐N‐O dipole. As a consequence, N‐hydroxypyrrolidines are obtained, rather than the expected isoxazolidines. The reaction proceeds smoothly and high enantioselectivities are observed in all cases. By using the appropriate substrate, polysubstituted pyrrolidines incorporating quaternary stereocenters can be efficiently prepared.
This review will describe the recent advances in the field of aza-C-nucleosides with a particular emphasis on immucillins and related compounds. The review will cover both chemical and biological aspects concerning their preparation and/or occurrence in Nature as well as their biological properties which include glycosidase, glycosyl transferase, and nucleoside hydrolase and phosphorylase inhibition, among others. These enzymatic inhibitory properties are the basis for the potential use of the title compounds in viral and parasitic infections, cancer and genetic disorders.
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