Advances in carbohydrate chemistry and biochemistry最新文献

The glycosaminoglycan hyaluronan (HA) is a key component of the microenvironment surrounding cells. In healthy tissues, HA molecules have extremely high molecular mass and consequently large hydrodynamic volumes. Tethered to the cell surface by clustered receptor proteins, HA molecules crowd each other, as well as other macromolecular species. This leads to severe nonideality in physical properties of the biomatrix, because steric exclusion leads to an increase in effective concentration of the macromolecules. The excluded volume depends on both polymer concentration and hydrodynamic volume/molecular mass. The biomechanical properties of the extracellular matrix, tissue hydration, receptor clustering, and receptor-ligand interactions are strongly affected by the presence of HA and by its molecular mass. In inflammation, reactive oxygen and nitrogen species fragment the HA chains. Depending on the rate of chain degradation relative to the rates of new synthesis and removal of damaged chains, short fragments of the HA molecules can be present at significant levels. Not only are the physical properties of the extracellular matrix affected, but the HA fragments decluster their primary receptors and act as endogenous danger signals. Bioanalytical methods to isolate and quantify HA fragments have been developed to determine profiles of HA content and size in healthy and diseased biological fluids and tissues. These methods have potential use in medical diagnostic tests. Therapeutic agents that modulate signaling by HA fragments show promise in wound healing and tissue repair without fibrosis.

There is a growing interest in using a range of porous materials to meet research needs in carbohydrate chemistry and glycoscience in general. Among the applications of porous materials reviewed in this chapter, enrichment of glycans from biological samples prior to separation and analysis by mass spectrometry is a major emphasis. Porous materials offer high surface area, adjustable pore sizes, and tunable surface chemistry for interacting with glycans, by boronate affinity, hydrophilic interactions, molecular imprinting, and polar interactions. Among the materials covered in this review are mesoporous silica and related materials, porous graphitic carbon, mesoporous carbon, porous polymers, and nanoporous gold. In some applications, glycans are enzymatically or chemically released from glycoproteins or glycopeptides, and the porous materials have the advantage of size selectivity admitting only the glycans into the pores and excluding proteins. Immobilization of lectins onto porous materials of suitable pore size allows for the use of lectin-carbohydrate interactions in capture or separation of glycoproteins. Porous material surfaces modified with carbohydrates can be used for the selective capture of lectins. Controlled release of therapeutics from porous materials mediated by glycans has been reported, and so has therapeutic targeting using carbohydrate-modified porous particles. Additional applications of porous materials in glycoscience include their use in the supported synthesis of oligosaccharides and in the development of biosensors for glycans.

Carcinomas express unique carbohydrates, known as tumor-associated carbohydrate antigens (TACAs), on their surface. These are potential targets for anticancer vaccines; however, to date, no such vaccine has reached the clinic. One factor that may complicate the success of this effort is the lability of the glycosidic bond. Acetal-free carbohydrates are analogues that lack the glycosidic linkage by replacing either the endo or exo oxygen with a methylene. This chapter summarizes the seminal syntheses of the mucin TACAs, provides an overview of common techniques for the synthesis of carbasugars and C-glycosides, reviews the syntheses published to date of acetal-free TACA analogues, and provides an overview of their observed biological activity. We conclude by offering a summation of the challenges remaining to the field biologically and the potential that acetal-free TACAs have of answering several basic questions in carbohydrate immunology.

The article reviews the significant contributions to, and the present status of, applications of computational methods for the characterization and prediction of protein-carbohydrate interactions. After a presentation of the specific features of carbohydrate modeling, along with a brief description of the experimental data and general features of carbohydrate-protein interactions, the survey provides a thorough coverage of the available computational methods and tools. At the quantum-mechanical level, the use of both molecular orbitals and density-functional theory is critically assessed. These are followed by a presentation and critical evaluation of the applications of semiempirical and empirical methods: QM/MM, molecular dynamics, free-energy calculations, metadynamics, molecular robotics, and others. The usefulness of molecular docking in structural glycobiology is evaluated by considering recent docking- validation studies on a range of protein targets. The range of applications of these theoretical methods provides insights into the structural, energetic, and mechanistic facets that occur in the course of the recognition processes. Selected examples are provided to exemplify the usefulness and the present limitations of these computational methods in their ability to assist in elucidation of the structural basis underlying the diverse function and biological roles of carbohydrates in their dialogue with proteins. These test cases cover the field of both carbohydrate biosynthesis and glycosyltransferases, as well as glycoside hydrolases. The phenomenon of (macro)molecular recognition is illustrated for the interactions of carbohydrates with such proteins as lectins, monoclonal antibodies, GAG-binding proteins, porins, and viruses.

This article covers recent developments in the design and application of activity-based probes (ABPs) for glycosidases, with emphasis on the different enzymes involved in metabolism of glucosylceramide in humans. Described are the various catalytic reaction mechanisms employed by inverting and retaining glycosidases. An understanding of catalysis at the molecular level has stimulated the design of different types of ABPs for glycosidases. Such compounds range from (1) transition-state mimics tagged with reactive moieties, which associate with the target active site—forming covalent bonds in a relatively nonspecific manner in or near the catalytic pocket—to (2) enzyme substrates that exploit the catalytic mechanism of retaining glycosidase targets to release a highly reactive species within the active site of the enzyme, to (3) probes based on mechanism-based, covalent, and irreversible glycosidase inhibitors. Some applications in biochemical and biological research of the activity-based glycosidase probes are discussed, including specific quantitative visualization of active enzyme molecules in vitro and in vivo, and as strategies for unambiguously identifying catalytic residues in glycosidases in vitro.

Saponins are a large family of amphiphilic glycosides of steroids and triterpenes found in plants and some marine organisms. By expressing a large diversity of structures on both sugar chains and aglycones, saponins exhibit a wide range of biological and pharmacological properties and serve as major active principles in folk medicines, especially in traditional Chinese medicines. Isolation of saponins from natural sources is usually a formidable task due to the microheterogeneity of saponins in Nature. Chemical synthesis can provide access to large amounts of natural saponins as well as congeners for understanding their structure-activity relationships and mechanisms of action. This article presents a comprehensive account on chemical synthesis of saponins. First highlighted are general considerations on saponin synthesis, including preparation of aglycones and carbohydrate building blocks, assembly strategies, and protecting-group strategies. Next described is the state of the art in the synthesis of each type of saponins, with an emphasis on those representative saponins having sophisticated structures and potent biological activities.

Nitrogen-containing macrocyclic compounds (amines, amides, and N-heterocyclic derivatives) are important targets in supramolecular chemistry. This chapter discusses the importance of aza-macrocycles in general and, in particular, those receptors containing sugar unit(s). The combination of a carbohydrate scaffold bearing nitrogen-containing functional groups in macrocyclic molecules opens a convenient route to chiral receptors having potentially useful properties. The carbohydrate-based macrocycles discussed are classified into several general groups: (1) aza-crown ethers containing a carbohydrate subunit, (2) cyclic homooligomers from amino sugars, (3) sugar-based cryptands, (4) cyclic peptides containing amino sugar units (including C2- and C3-symmetrical macrocyclic glycopeptides), (5) nitrogen- containing glycophanes, and (6) 1,2,3-triazoles containing synthetic cyclodextrin analogues. The general strategies employed, as well as specific ones leading to such complex derivatives, are surveyed. Applications of such carbohydrate receptors, pointing to their importance as hosts in supramolecular chemistry, are discussed.