抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

http://www.chem.uwec.edu/Chem454/BiochemDiabetes.pdf

Biochemistry and molecular cell biology of diabetic complications

The adhesive interactions of cells with other cells and with the extracellular matrix are crucial to all developmental processes, but have a central role in the functions of the immune system throughout life Three families of cell-surface molecules regulate the migration of lymphocytes and the interactions of activated cells during immune responses

Adhesion receptors of the immune system.

The Carbohydrate-Active Enzymes database (CAZy; http://www.cazy.org) provides online and continuously updated access to a sequence-based family classification linking the sequence to the specificity and 3D structure of the enzymes that assemble, modify and breakdown oligo- and polysaccharides. Functional and 3D structural information is added and curated on a regular basis based on the available literature. In addition to the use of the database by enzymologists seeking curated information on CAZymes, the dissemination of a stable nomenclature for these enzymes is probably a major contribution of CAZy. The past few years have seen the expansion of the CAZy classification scheme to new families, the development of subfamilies in several families and the power of CAZy for the analysis of genomes and metagenomes. This article outlines the changes that have occurred in CAZy during the past 5 years and presents our novel effort to display the resolution and the carbohydrate ligands in crystallographic complexes of CAZymes.

/pdf/the-carbohydrate-active-enzymes-database-cazy-in-2013-37p3bw39e7.pdf

The carbohydrate-active enzymes database (CAZy) in 2013

It’s a great honor to join the exceptional club of Banting Award winners, many of whom were my role models and mentors. In addition, giving the Banting Lecture also has a very personal meaning to me, because without Frederick Banting, I would have died from type 1 diabetes when I was 8 years old. However, it was already apparent at the time I was diagnosed that for too many people like me, Banting’s discovery of insulin only allowed them to live just long enough to develop blindness, renal failure, and coronary disease. For example, when I started college, the American Diabetes Association’s Diabetes Textbook had this to say to my parents: “The person with type 1 diabetes can be reassured that it is highly likely that he will live at least into his 30s.” Not surprisingly, my parents did not find this particularly reassuring.

At the same time we were reading this in 1967, however, the first basic research discovery about the pathobiology of diabetic complications had just been published in Science the previous year. In my Banting Lecture today, I am thus going to tell you a scientific story that is also profoundly personal.

I’ve divided my talk into three parts. The first part is called “pieces of the puzzle,” and in it I describe what was learned about the pathobiology of diabetic complications starting with that 1966 Science paper and continuing through the end of the 1990s. In the second part, I present a unified mechanism that links together all of the seemingly unconnected pieces of the puzzle. Finally, in the third part, I focus on three examples of novel therapeutic approaches for the prevention and treatment of diabetic complications, which are all based on the new paradigm of a unifying mechanism for the pathogenesis of diabetic complications. …

/pdf/the-pathobiology-of-diabetic-complications-a-unifying-10rf12tje8.pdf

The pathobiology of diabetic complications: a unifying mechanism.

General principles - historical background and overview saccharide structure and nomenclature evolution of glycan diversity protein-glycan Interactions exploring the biological roles of glycans biosynthesis, metabolism, and function - monosaccharide metabolism N-glycans O-glycans glycosphingolipids glycophospholipid anchors proteoglycans and glycosaminoglycans other classes of golgi-derived glycans nuclear and cytoplasmic glycosylation the O-GlcNAc modification sialic acids structures common to different types of glycans glycosyltransferases degradation and turnover of glycans glycosylation in "model" organisms glycobiology of plant cells bacterial polysaccharides proteins that recognize glycans - discovery and classification of animal lectins P-type lectins I-type lectins C-type lectins selectins S-type lectins (galectins) microbial glycan-binding proteins glycosaminoglycan-binding proteins plant lectins glycans in genetic disorders and disease - genetic disorders of glycosylation in cultured cells naturally occurring genetic disorders of glycosylation in animals determining glycan function using genetically modified mice glycosylation changes in ontogeny and cell activation glycosylation changes in cancer glycobiology of protozoal and helminthic parasites acquired glycosylation changes in human disease methods and applications - structural analysis and sequencing of glycans chemical and enzymatic synthesis of glycans natural and synthetic inhibitors of glycosylation glycobiology in biotechnology and medicine.

Essentials of Glycobiology

All animals and plants dynamically attach and remove O-linked β-N-acetylglucosamine (O-GlcNAc) at serine and threonine residues on myriad nuclear and cytoplasmic proteins. O-GlcNAc cycling, which is tightly regulated by the concerted actions of two highly conserved enzymes, serves as a nutrient and stress sensor. On some proteins, O-GlcNAc competes directly with phosphate for serine/threonine residues. Glycosylation with O-GlcNAc modulates signalling, and influences protein expression, degradation and trafficking. Emerging data indicate that O-GlcNAc glycosylation has a role in the aetiology of diabetes and neurodegeneration.

Cycling of O-linked β- N -acetylglucosamine on nucleocytoplasmic proteins

O-GlcNAcylation is the addition of β-D-N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins. O-linked N-acetylglucosamine (O-GlcNAc) was not discovered until the early 1980s and still remains difficult to detect and quantify. Nonetheless, O-GlcNAc is highly abundant and cycles on proteins with a timescale similar to protein phosphorylation. O-GlcNAc occurs in organisms ranging from some bacteria to protozoans and metazoans, including plants and nematodes up the evolutionary tree to man. O-GlcNAcylation is mostly on nuclear proteins, but it occurs in all intracellular compartments, including mitochondria. Recent glycomic analyses have shown that O-GlcNAcylation has surprisingly extensive cross talk with phosphorylation, where it serves as a nutrient/stress sensor to modulate signaling, transcription, and cytoskeletal functions. Abnormal amounts of O-GlcNAcylation underlie the etiology of insulin resistance and glucose toxicity in diabetes, and this type of modification plays a direct role in neurodegenerative disease. Many oncogenic proteins and tumor suppressor proteins are also regulated by O-GlcNAcylation. Current data justify extensive efforts toward a better understanding of this invisible, yet abundant, modification. As tools for the study of O-GlcNAc become more facile and available, exponential growth in this area of research will eventually take place.

/pdf/cross-talk-between-o-glcnacylation-and-phosphorylation-roles-3zv4d63tlr.pdf

Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.

http://www.jbc.org/content/259/5/3308.full.pdf

Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc.

The dynamic glycosylation of serine or threonine residues on nuclear and cytosolic proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is abundant in all multicellular eukaryotes. On several proteins, O-GlcNAc and O-phosphate alternatively occupy the same or adjacent sites, leading to the hypothesis that one function of this saccharide is to transiently block phosphorylation. The diversity of proteins modified by O-GlcNAc implies its importance in many basic cellular and disease processes. Here we systematically examine the current data implicating O-GlcNAc as a regulatory modification important to signal transduction cascades.

https://science.sciencemag.org/content/sci/291/5512/2376.full.pdf

Gerald W. Hart

Papers

Essentials of Glycobiology

Cycling of O-linked β- N -acetylglucosamine on nucleocytoplasmic proteins

Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease.

Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc.

Glycosylation of Nucleocytoplasmic Proteins: Signal Transduction and O-GlcNAc