Chemistry and biology of trehazolins

Trehazolin (1) is a unique natural pseudodisaccharide possessing strong trehalase-specific inhibitory activity. To determine its argued correct stereochemistry, the syntheses of trehazolin (1), its components, the aglycon moiety, trehalamine (4) and its aminocyclitol hexaacetate (6), were accomplished from d-glucose using intramolecular [3+2] cycloaddition as the key step. In order to investigate the structure–activity relationships with regard to the stereochemistry of the aminocyclitol moiety and that of the anomeric position of trehazolin (1), trehalostatin (2) (trehazolin C-5 epimer), trehazolin β-anomer (32) and, trehazolin C-6 epimer (33) were all synthesized. In particular, with respect to the synthesis of trehazolin C-6 epimer (33), a tandem aldol–Wittig type reaction was developed as the key step to synthesize the highly functionalized 5-membered cyclitol. Moreover, on the basis of the outcome of these synthetic studies, a number of trehazolin-related compounds (49–52), modified at the terminal amino group of trehalamine (4), were synthesized to be evaluated as candidates directed to anti-NIDDM (non-insulin-dependent diabetes mellitus) drugs.     

Chemistry and biology of vision

Visual perception in humans occurs through absorption of electromagnetic radiation from 400 to 780 nm by photoreceptors in the retina. A photon of visible light carries a sufficient amount of energy to cause, when absorbed, a cis,trans-geometric isomerization of the 11-cis-retinal chromophore, a vitamin A derivative bound to rhodopsin and cone opsins of retinal photoreceptors. The unique biochemistry of these complexes allows us to reliably and reproducibly collect continuous visual information about our environment. Moreover, other nonconventional retinal opsins such as the circadian rhythm regulator melanopsin also initiate light-activated signaling based on similar photochemistry.     

Chemistry and biology of boron.

Boron is an essential nutrient for certain organisms, notably vascular plants and diatoms. Cyanobacteria require boron for formation of nitrogen-fixing heterocysts and boron may be beneficial to animals. Boron deficiency in plants produces manifold symptoms: many functions have been postulated. Deficiency symptoms first appear at growing points, within hours in root tips and within minutes or seconds in pollen tube tips, and are characterized by cell wall abnormalities. Boron-deficient tissues are brittle or fragile, while plants grown on high boron levels may have unusually flexible or resilient tissues. Borate forms cyclic diesters with appropriate diols or polyols. The most stable are formed with cis-diols on a furanoid ring. Two compounds have this structure physiologically: ribose in ribonucleotides and RNA, and apiose in the plant cell wall. Germanium can substitute for boron in carrot cell cultures. Both boron and germanium are localized primarily in the cell wall. We postulate that borate-apiofuranose ester cross-links are the auxin-sensitive acid-growth link in vascular plants, that the cyanobacterial heterocyst envelope depends on borate cross-linking of mannopyranose and/or galactopyranose residues in a polysaccharide-lipid environment, and that boron in diatoms forms ester cross-links in the polysaccharide cell wall matrix rather than boron-silicon interactions. Complexing of ribonucleotides is probably a factor in boron toxicity.     

Reconstructing eukaryotic NAD metabolism

In addition to its well-known role as a coenzyme in oxidation-reduction reactions, the distinct role of NAD as a precursor for molecules involved in cell regulation has been clearly established. The involvement of NAD in these regulatory processes is based on its ability to function as a donor of ADP-ribose; NAD synthesis is therefore required to avoid depletion of the intracellular pool. The rising interest in the biosynthetic routes leading to NAD formation and the highly conserved nature of the enzymes involved prompted us to reconstruct the NAD biosynthetic routes operating in distinct eukaryotic organisms. The evidence obtained from biochemical and computational analysis provides a good example of how complex metabolic pathways may evolve. In particular, it is proposed that the development of several NAD biosynthetic routes during evolution has led to partial functional redundancy, allowing a given pathway to freely acquire novel functions unrelated to NAD biosynthesis.     

Chemistry and biology of mammalian metallothioneins

Metallothioneins (MTs) are a class of ubiquitously occurring low molecular mass, cysteine- and metal-rich proteins containing sulfur-based metal clusters formed with Zn(II), Cd(II), and Cu(I) ions. In mammals, four distinct MT isoforms designated MT-1 through MT-4 exist. The first discovered MT-1/MT-2 are widely expressed isoforms, whose biosynthesis is inducible by a wide range of stimuli, including metals, drugs, and inflammatory mediators. In contrast, MT-3 and MT-4 are noninducible proteins, with their expression primarily confined to the central nervous system and certain squamous epithelia, respectively. MT-1 through MT-3 have been reported to be secreted, suggesting that they may play different biological roles in the intracellular and extracellular space. Recent reports established that these isoforms play an important protective role in brain injury and metal-linked neurodegenerative diseases. In the postgenomic era, it is becoming increasingly clear that MTs fulfill multiple functions, including the involvement in zinc and copper homeostasis, protection against heavy metal toxicity, and oxidative damage. All mammalian MTs are monomeric proteins, containing two metal–thiolate clusters. In this review, after a brief summary of the historical milestones of the MT-1/MT-2 research, the recent advances in the structure, chemistry, and biological function of MT-3 and MT-4 are discussed.     

Regulation of eukaryotic phospholipid metabolism

Phospholipids have diverse and critical roles in cellular metabolism and function. Questions about the mechanisms of regulation of phospholipid synthesis are being investigated with a variety of systems and approaches. For example, the yeast Saccharomyces cerevisiae is an organism in which both biochemical and genetic analyses are used. Biochemical approaches have yielded considerable information on the regulatory properties of enzymes of phospholipid biosynthesis. Studies of the activity of purified phosphatidylserine synthase have suggested how that enzyme is influenced by membrane phospholipids in the cell. The enzyme that regulates mammalian phosphatidylcholine biosynthesis, CTP:phosphocholine cytidylyltransferase, is also influenced by phospholipids. In addition, the activity of this enzyme often correlates with its translocation to membranes. The location of such enzymes in the cell is of particular interest in light of the possibility that the enzymatic reactions may be efficiently coupled in vivo. Techniques to render cultured cells permeable to phosphorylated molecules indicated that the enzymes of phosphatidylcholine biosynthesis may exist in an organized compartment so that the precursors of phosphatidylcholine are efficiently channeled through the pathway. To ask how phospholipids are transported in the cell, a combined biochemical and genetic approach has been used. These studies have revealed that the phosphatidylinositol/phosphatidylcholine transfer protein, considered to mediate intracellular phospholipid transfer, is a critical component of the secretory pathway for proteins. These results have allowed formulation of a number of new questions on the regulation of phospholipid metabolism and its relationship to general membrane processes.     

Systems biology of eukaryotic superorganisms and the holobiont concept

The founders of modern biology (Jean Lamarck, Charles Darwin, August Weismann etc.) were organismic life scientists who attempted to understand the morphology and evolution of living beings as a whole (i.e., the phenotype). However, with the emergence of the study of animal and plant physiology in the nineteenth century, this “holistic view” of the living world changed and was ultimately replaced by a reductionistic perspective. Here, I summarize the history of systems biology, i.e., the modern approach to understand living beings as integrative organisms, from genotype to phenotype. It is documented that the physiologists Claude Bernard and Julius Sachs, who studied humans and plants, respectively, were early pioneers of this discipline, which was formally founded 50 years ago. In 1968, two influential monographs, authored by Ludwig von Bertalanffy and Mihajlo D. Mesarovi?, were published, wherein a “systems theory of biology” was outlined. Definitions of systems biology are presented with reference to metabolic or cell signaling networks, analyzed via genomics, proteomics, and other methods, combined with computer simulations/mathematical modeling. Then, key insights of this discipline with respect to epiphytic microbes (Methylobacterium sp.) and simple bacteria (Mycoplasma sp.) are described. The principles of homeostasis, molecular systems energetics, gnotobiology, and holobionts (i.e., complexities of host–microbiota interactions) are outlined, and the significance of systems biology for evolutionary theories is addressed. Based on the microbe—Homo sapiens—symbiosis, it is concluded that human biology and health should be interpreted in light of a view of the biomedical sciences that is based on the holobiont concept.     

Coming into view: eukaryotic iron chaperones and intracellular iron delivery

Eukaryotic cells contain hundreds of metalloproteins, and ensuring that each protein receives the correct metal ion is a critical task for cells. Recent work in budding yeast and mammalian cells has uncovered a system of iron delivery operating in the cytosolic compartment that involves monothiol glutaredoxins, which bind iron in the form of iron-sulfur clusters, and poly(rC)-binding proteins, which bind Fe(II) directly. In yeast cells, cytosolic monothiol glutaredoxins are required for the formation of heme and iron-sulfur clusters and the metallation of some non-heme iron enzymes. Poly(rC)-binding proteins can act as iron chaperones, delivering iron to target non-heme enzymes through direct protein-protein interactions. Although the molecular details have yet to be explored, these proteins, acting independently or together, may represent the basic cellular machinery for intracellular iron delivery.     

Chemistry and clinical biology of the bryostatins

Bryostatins are a class of antineoplastic compounds isolated from the bryozoans Bugula neritina. A wide range of scientific research is currently underway, studying different aspects of the bryostatins. In this review we try to summarize the latest findings, including all the topics involved, from marine biology to medicinal chemistry.     

GIP biology and fat metabolism

The gastrointestinal hormone, gastric inhibitory polypeptide (GIP), is synthesized and released from the duodenum and proximal jejunum postprandially. Its release depends upon several factors including meal content and pre-existing health status (ie. obesity, diabetes, age, etc.). It was initially discovered and named for its gastric acid inhibitory properties. However, its more physiologically relevant role appears to be as an insulinotropic agent with a stimulatory effect on insulin release and synthesis. Accordingly, it was later renamed glucose-dependent insulinotropic polypeptide because its action on insulin release depends upon an increase in circulating levels of glucose. GIP is considered to be one of the principle incretin factors of the enteroinsular axis. The GIP receptor is a G-protein-coupled receptor belonging to the family of secretin/VIP receptors. GIP receptor mRNA is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex, and brain, suggesting it may have other functions in addition to the ones mentioned above. An overactive enteroinsular axis has been suggested to play a role in the pathogenesis of diabetes and obesity. In addition to stimulating insulin release, GIP has been shown to amplify the effect of insulin on target tissues. In adipose tissue, GIP has been reported to (1) stimulate fatty acid synthesis, (2) enhance insulin-stimulated incorporation of fatty acids into triglycerides, (3) increase insulin receptor affinity, and (4) increase sensitivity of insulin-stimulated glucose transport. In addition, although controversial, lipolytic properties of GIP have been proposed. The mechanism of action of GIP-induced effects on adipocytes is unknown, and it is unclear whether these effects of GIP on adipocytes are direct or indirect. However, there is now evidence that GIP receptors are expressed on adipocytes and that these receptors respond to GIP stimulation. Given the location of its release and the timing of its release, GIP is an ideal anabolic agent and expanding our understanding of its physiology will be needed to determine its exact role in the etiology of diabetes mellitus and obesity.     

Lipids and lipid metabolism in eukaryotic algae

Eukaryotic algae are a very diverse group of organisms which inhabit a huge range of ecosystems from the Antarctic to deserts. They account for over half the primary productivity at the base of the food chain. In recent years studies on the lipid biochemistry of algae has shifted from experiments with a few model organisms to encompass a much larger number of, often unusual, algae. This has led to the discovery of new compounds, including major membrane components, as well as the elucidation of lipid signalling pathways. A major drive in recent research have been attempts to discover genes that code for expression of the various proteins involved in the production of very long-chain polyunsaturated fatty acids such as arachidonic, eicosapentaenoic and docosahexaenoic acids. Such work is described here together with information about how environmental factors, such as light, temperature or minerals, can change algal lipid metabolism and how adaptation may take place.     

Chemistry and biology of arabinofuranosyl- and galactofuranosyl-containing polysaccharides

Polysaccharides containing galactofuranosyl and arabinofuranosyl residues are key components of many microorganisms. Recent investigations have provided a greater understanding of the biosynthetic pathways by which these glycans are assembled. Concomitant with these biochemical studies, an increasing number of chemical syntheses of oligofuranosides have been reported and new methods for their assembly have been developed.     

Chemistry and biology of enzymes in protein glutathionylation

Protein S-glutathionylation is emerging as a central oxidation that regulates redox signaling and biological processes linked to diseases. In recent years, the field of protein S-glutathionylation has expanded by developing biochemical tools for the identification and functional analyses of S-glutathionylation, investigating knockout mouse models, and developing and evaluating chemical inhibitors for enzymes involved in glutathionylation. This review will highlight recent studies of two enzymes, glutathione transferase omega 1 (GSTO1) and glutaredoxin 1 (Grx1), especially introducing their glutathionylation substrates associated with inflammation, cancer, and neurodegeneration and showcasing the advancement of their chemical inhibitors. Lastly, we will feature protein substrates and chemical inducers of LanC-like protein (LanCL), the first enzyme in protein C-glutathionylation.