Structural Insights in Mammalian Sialyltransferases and Fucosyltransferases: We Have Come a Long Way, but It Is Still a Long Way Down

Mammalian cell surfaces are modified with complex arrays of glycans that play major roles in health and disease. Abnormal glycosylation is a hallmark of cancer; terminal sialic acid and fucose in particular have high levels in tumor cells, with positive implications for malignancy. Increased sialylation and fucosylation are due to the upregulation of a set of sialyltransferases (STs) and fucosyltransferases (FUTs), which are potential drug targets in cancer. In the past, several advances in glycostructural biology have been made with the determination of crystal structures of several important STs and FUTs in mammals. Additionally, how the independent evolution of STs and FUTs occurred with a limited set of global folds and the diverse modular ability of catalytic domains toward substrates has been elucidated. This review highlights advances in the understanding of the structural architecture, substrate binding interactions, and catalysis of STs and FUTs in mammals. While this general understanding is emerging, use of this information to design inhibitors of STs and FUTs will be helpful in providing further insights into their role in the manifestation of cancer and developing targeted therapeutics in cancer.

Download Full-text

Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of Mycobacterium tuberculosis

Biochemical Journal ◽

10.1042/bj20110002 ◽

2011 ◽

Vol 436 (3) ◽

pp. 729-739 ◽

Cited By ~ 23

Author(s):

Marcio V. B. Dias ◽

William C. Snee ◽

Karen M. Bromfield ◽

Richard J. Payne ◽

Satheesh K. Palaninathan ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Targets ◽

Structural Investigation ◽

Catalytic Mechanism ◽

Shikimate Pathway ◽

Structural Rearrangement ◽

Competitive Inhibitors ◽

Structural Insights ◽

Potential Drug Targets

The shikimate pathway is essential in Mycobacterium tuberculosis and its absence from humans makes the enzymes of this pathway potential drug targets. In the present paper, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from M. tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analogue of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active-site subpocket inducing significant structural rearrangement. The flexible extensions of inhibitors designed to form π-stacking interactions with the catalytic Tyr24 have been investigated. The high-resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19–24 in MtDHQase ligand binding and catalytic mechanism and provide a rationale for the design and efficacy of inhibitors.

Download Full-text

In Silico Analysis of Effect of Non-synonymous SNPs associated with Permanent Neonatal Diabetes Mellitus on Stability and Structure of Human Insulin

10.1101/2020.09.01.278002 ◽

2020 ◽

Author(s):

Nishat Tabassum

Keyword(s):

Human Insulin ◽

Drug Targets ◽

In Silico Analysis ◽

Neonatal Diabetes ◽

Building Blocks ◽

Permanent Neonatal Diabetes ◽

The Impact ◽

Potential Drug Targets ◽

Analysis Determination

AbstractMotivationProteins are the building-blocks of life. However with the deluge of data on protein sequences and their association with diseases, it is imperative to use computational tools to aid experimental analysis. Determination of the impact of disease-causing SNPs on protein’s structure is crucial in discovering how a disease affects the functions on a fundamental level and thereafter, determining potential drug targets.ResultsSNPs associated with the genetic disease permanent neonatal diabetus mellitus (PNDM) were studied to determine their impact on human insulin. Out of 16 missense variants, eight were predicted to be deleterious. 6 of the SNPs resulted in high structural differences (RMSD > 0.9, H bonds > 35). Stability changes were also determined.

Download Full-text

Vaccine Interactions With the Infant Microbiome: Do They Define Health and Disease?

Frontiers in Pediatrics ◽

10.3389/fped.2020.565368 ◽

2020 ◽

Vol 8 ◽

Author(s):

Candice E. Ruck ◽

Oludare A. Odumade ◽

Kinga K. Smolen

Keyword(s):

Precise Determination ◽

Vital Role ◽

Therapeutic Interventions ◽

Research Strategies ◽

Vaccine Responses ◽

The Past ◽

Early Results ◽

Health And Disease

Over the past decade, there has been a growing awareness of the vital role of the microbiome in the function of the immune system. Recently, several studies have demonstrated a relationship between the composition of the microbiome and the vaccine-specific immune response. As a result of these findings, the administration of probiotics has been proposed as a means of boosting vaccine-specific immunity. Early results have so far been highly inconsistent, with little evidence of sustained benefit. To date, a precise determination of the aspects of the microbiome that impact immunity is still lacking, and the mechanisms of action are also unknown. Further investigations into these questions are necessary to effectively manipulate the microbiome for the purpose of boosting immunity and enhancing vaccine-specific responses in infants. In this review, we summarize recent studies aimed at altering the neonatal gut microbiome to enhance vaccine responses and highlight gaps in knowledge and understanding. We also discuss research strategies aimed at filling these gaps and developing potential therapeutic interventions.

Download Full-text

MicroRNAs differentially regulated in cardiac and skeletal muscle in health and disease: Potential drug targets?

Clinical and Experimental Pharmacology and Physiology ◽

10.1111/1440-1681.12281 ◽

2014 ◽

pp. n/a-n/a ◽

Cited By ~ 2

Author(s):

Catherine E. Winbanks ◽

Jenny Y.Y. Ooi ◽

Sally S. Nguyen ◽

Julie R. McMullen ◽

Bianca C. Bernardo

Keyword(s):

Skeletal Muscle ◽

Drug Targets ◽

Potential Drug ◽

Health And Disease ◽

Potential Drug Targets

Download Full-text

Transmission Electron Microscopy of Protein Macromolecules

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100066176 ◽

1971 ◽

Vol 29 ◽

pp. 424-425

Author(s):

Henry S. Slayter

Keyword(s):

Biological Systems ◽

Metal Vapor ◽

Resolving Power ◽

Electron Microscopic ◽

Chemical Methods ◽

Molecular Weights ◽

The Past ◽

Physical Chemical ◽

Transmission Electron

Electron microscopic methods have been applied increasingly during the past fifteen years, to problems in structural molecular biology. Used in conjunction with physical chemical methods and/or Fourier methods of analysis, they constitute powerful tools for determining sizes, shapes and modes of aggregation of biopolymers with molecular weights greater than 50, 000. However, the application of the e.m. to the determination of very fine structure approaching the limit of instrumental resolving power in biological systems has not been productive, due to various difficulties such as the destructive effects of dehydration, damage to the specimen by the electron beam, and lack of adequate and specific contrast. One of the most satisfactory methods for contrasting individual macromolecules involves the deposition of heavy metal vapor upon the specimen. We have investigated this process, and present here what we believe to be the more important considerations for optimizing it. Results of the application of these methods to several biological systems including muscle proteins, fibrinogen, ribosomes and chromatin will be discussed.

Download Full-text