Synthetic, structural, and biosynthetic studies of an unusual phospho-glycopeptide derived from α-dystroglycan

Aberrant glycosylation of α-dystroglycan (α-DG) results in loss of interactions with the extracellular matrix and is central to the pathogenesis of several disorders. To examine protein glycosylation of α-DG, a facile synthetic approach has been developed for the preparation of unusual phosphorylated O-mannosyl glycopeptides derived from α-DG by a strategy in which properly protected phospho-mannosides are coupled with a Fmoc protected threonine derivative, followed by the use of the resulting derivatives in automated solid-phase glycopeptide synthesis using hyper-acid-sensitive Sieber amide resin. Synthetic efforts also provided a reduced phospho-trisaccharide, and the NMR data of this derivative confirmed the proper structural assignment of the unusual phospho-glycan structure. The glycopeptides made it possible to explore factors that regulate the elaboration of critical glycans. It was established that a glycopeptide having a 6-phospho-O-mannosyl residue is not an acceptor for action by the enzyme POMGnT1, which attaches β(1,2)-GlcNAc to O-mannosyl moietes, whereas the unphosphorylated derivate was readily extended by the enzyme. This finding implies a specific sequence of events in determining the structural fate of the O-glycan. It has also been found that the activity of POMGnT1 is dependent on the location of the acceptor site in the context of the underlying polypeptide/glycopeptide sequence. Conformational analysis by NMR has shown that the O-mannosyl modification does not exert major conformational effect on the peptide backbone. It is, however, proposed that these residues, introduced at the early stages of glycoprotein glycosylation, have an ability to regulate the loci of subsequent O-GalNAc additions, which do exert conformational effects. The studies show that through access to discrete glycopeptide structures, it is possible to reveal complex regulation of O-glycan processing on α-DG that has significant implications both for its normal post-translational maturation, and the mechanisms of the pathologies associated with hypoglycosylated α-DG.     

A single Cu(II) catalyst for the three-component coupling of diverse nitrogen sources with aldehydes and alkynes

A single Cu(II) catalyst without the addition of ligand or base couples a diverse range of nitrogen sources with alkynes and aldehydes bearing alkyl, halogenated, silyl, aryl, and heteroaryl groups. The first example of a copper-catalyzed alkynylation involving p-toluenesulfonamide provides high yields of N-Ts-protected propargylamines. The superior activity of copper(II) triflate also allows this three-component alkynylation to incorporate a ketone.     

Silver(I)-promoted conversion of thioamides to amidines: divergent synthesis of a key series of vancomycin aglycon residue 4 amidines that clarify binding behavior to model ligands

Development of a general Ag(I)-promoted reaction for the conversion of thioamides to amidines is disclosed. This reaction was employed to prepare a key series of vancomycin aglycon residue 4 substituted amidines that were used to clarify their interaction with model ligands of peptidoglycan precursors and explore their resulting impact on antimicrobial properties.     

Diffusion of small penetrant molecules in polybutadienes

The diffusion coefficient D in the dilute limit for three different penetrants – oxygen, water, and methanol – in three different conformations of polybutadiene (all cis-1,4, all trans-1,4, and a random copolymer containing 50% trans-1,4, 40% cis-1,4, and 10% vinyl-1,2 repeat units) has been computed using molecular dynamics simulations for temperatures in the range T?=?300–400?K. Simulation runs of 25 and 50?ns were made for each of the 45 combinations of penetrant, conformation, and temperature studied. Over this temperature range the density of the all-cis-1,4 conformation is higher than that of the all-trans-1,4 and random copolymer conformations, which are approximately equal. For all three conformations, D for oxygen and water are comparable and larger than that of methanol. However for a given penetrant, strong differences were observed in the rate of increase of D for the three conformations. We find that the activation barriers for the three penetrants are generally between 20 and 30?kJ?mol^?1, in agreement with experimental results. The magnitude of the activation energy is directly proportional to the size, rather than the mass, of the penetrant molecule.     

Model-theory of vector-spaces over unspecified fields

Vector spaces over unspecified fields can be axiomatized as one-sorted structures, namely, abelian groups with the relation of parallelism. Parallelism is binary linear dependence. When equipped with the n-ary relation of linear dependence for some positive integer n, a vector-space is existentially closed if and only if it is n-dimensional over an algebraically closed field. In the signature with an n-ary predicate for linear dependence for each positive integer n, the theory of infinite-dimensional vector spaces over algebraically closed fields is the model-completion of the theory of vector spaces.      

Existentially complete lattice-ordered groups

We investigate existentially complete lattice-ordered groups in this paper. In particular, we list some of their algebraic properties and show that there are continuum many countable pairwise non-elementarily equivalent such latticeordered groups. In particular, existentially complete lattice-ordered groups give rise to a new class of simple groups. This paper is dedicated to the memory of Abraham Robinson. Without his pioneer work in model-theoretic forcing, none of this research would have been possible. Research supported in part by a grant from Bowling Green State University Faculty Research Committee. Research conducted in part while on sabbatical leave from the University of Missouri.