Current Chemical Biology - Volume 4, Issue 1, 2010

P53 is one of the most important tumour suppressor proteins. While its activity seems to be dispensable for normal proliferating cells, this protein is required to maintain genomic integrity after DNA damage. In response to cellular stress, the amount of p53 protein accumulates and fulfils its function as a transcription factor. Most of the genes that are regulated by p53 control progression through the cell cycle or initiate cell death. A large number of proteins have been identified in recent years that control the activity of this important tumour suppressor protein. These proteins regulate the turnover of p53, its association with co-repressor and co-activator proteins and target gene promoters or impinge on p53 oligomerisation. This review shall give an overview of our current knowledge on how the activity of the p53 protein is controlled.

Gankyrin, a newly defined oncoprotein also known as PSMD10 and P28, functions as a dual-negative regulator of the two most prominent tumor suppressor pathways, the CDK/pRb and MDM2/P53 pathways. Its aberrant expression has been prevalently found in human hepatocellular carcinomas (HCC) and esophagus squamous cell carcinomas (ESCC), indicative of the potential of gankyrin as a rational diagnostic and therapeutic target in cancers. Here, we review the unique structural features and functional diversity of gankyrin, and discuss its implication in cancer diagnostics and therapeutics from the perspective of chemical biology.

Heparan sulfate proteoglycans (HSPGs) play vital roles in every step of tumor progression allowing cancer cells to proliferate, escape from immune response, invade neighboring tissues, and metastasize to distal sites away from the primary site. Several cancers including breast, lung, brain, pancreatic, skin, and colorectal cancers show aberrant modulation of several key HS biosynthetic enzymes such as 3-O Sulfotransferase and 6-O Sulfotransferase, and also catabolic enzymes such as HSulf-1, HSulf-2 and heparanase. The resulting tumor specific HS fine structures assist cancer cells to breakdown ECM to spread, misregulate signaling pathways to facilitate their proliferation, promote angiogenesis to receive nutrients, and protect themselves against natural killer cells. This review focuses on the changes in the expression of HS biosynthetic and catabolic enzymes in several cancers, the resulting changes in HS fine structures, and the effects of these tumor specific HS signatures on promoting invasion, proliferation, and metastasis. It is possible to retard tumor progression by modulating the deregulated biosynthetic and catabolic pathways of HS chains through novel chemical biology approaches.

The relationship between genotype and phenotype in mitochondrial diseases is complicated and poorly understood. The clinical manifestations of mitochondrial diseases vary dramatically in terms of symptoms, severity and age of onset. Furthermore, the same genetic defect can result in different symptoms amongst various individuals whereas different mutations can lead to the same phenotype. Such variation makes it impossible to predict the phenotypes of mitochondrial disease based on genetic defects. Since mitochondria are crucial for energy supply, it has traditionally been accepted that ATP depletion is the main contributing factor to the symptoms associated with mitochondrial diseases. However, as mitochondria participate in such a diverse range of cellular functions and since the phenotypes of mitochondrial disease are extremely variable, the pathology of human mitochondrial diseases may be due to alterations in any of the various mitochondrial functions. For example, the tissue dysfunction associated with specific mitochondrial diseases may be due to excessive ROS production, altered calcium homeostasis which stimulates apoptosis or, as recent work has shown, activation of stress-sensitive signalling pathways. This review highlights these various mechanisms implicated in the cytopathology of mitochondrial disease and dysfunction.

Overwhelming evidence that implicates aberrant activations of the canonical Wnt/β-catenin signaling pathway in oncogenesis and cancer progression has emerged in recent times. Accordingly, disruption of this signaling pathway offers an opportunity for effective cancer therapy. Despite various approaches to target components of the Wnt/β-catenin signaling pathway, safe and efficacious therapeutic agents have yet to be identified. As the search for novel small molecule inhibitors remains pressing and continues, natural products, which are traditionally excellent sources of lead compounds in the drug discovery and development process, are gaining prominence as effective antagonists of the signaling pathway. In this review, we will provide a comprehensive summary on the current use of natural compounds ranging from plant-derived polyphenols, anti-malarial artemisinins to several antimicrobial products as Wnt therapeutics and the development of more efficacious semi-synthetic analogues using these compounds as lead structures. We will also discuss pertinent issues that are limiting the rate of drug development based on these compounds and the chemical-biological significance across the diverse classes of natural compounds. The findings reviewed here should inspire and motivate more efforts to harness rich and diverse plant and other natural sources in the search for new leads as effective antagonists of the Wnt/β-catenin pathway.

Whereas the ability to recognize and measure the kinetics of slow-onset enzyme inhibition is fully developed, our understanding of the structural mechanisms is still evolving. This literature review focuses on the two-step process in which a rapid-equilibrium enzyme/ inhibitor (EI) complex isomerizes slowly and reversibly to a tighter EI* complex. Although structural details are still mostly lacking, some generalities have been realized. The most central finding is that protein conformational changes are often subtle and sometimes even difficult to identify. Most interactions occur in the initial complex formation and the isomerization represents critical but minor adjustments. When available, energetic estimates based on these structural refinements match the differences in free energy of interaction calculated from equilibrium constants for EI and EI* and thus are sufficient to explain the kinetics. Less often described and defined for two-step slow inhibition, larger polypeptide movement induced by inhibitor binding such as loop or flap rearrangements has been observed or hypothesized. Separately, ionization of inhibitor has been critical in several systems and implies poor solvent accessibility of bound inhibitor. Finally, as described for the two cyclooxygenase isozymes, movement of inhibitor into and through the protein matrix can give rise to slow-onset kinetics.

Micro-organisms that thrive at low temperatures produce cold-adapted enzymes which generally display high catalytic efficiency making these biocatalysts particularly interesting either for investigating stability/flexibility relationships, or for their quite wide applications. Psychrophilic lipases and esterases have attracted attention because of their increasing use in the organic synthesis of chiral intermediates due to their low optimum temperature and high activity in cold conditions, which are favourable properties for the production of relatively frail compounds. In addition, these enzymes have an advantage under low water conditions due to their inherent greater flexibility, wherein the activity of mesophilic and thermophilic enzymes is severely impaired by an excess of rigidity. In this review we present an up to date overview on some psychrophilic esterases and lipases from microbial sources. The different experimental strategies available for the search of psychrophilic biocatalysts and their application to discover novel cold-adapted lipolytic enzymes will be outlined. Some structural features that justify the unusually high enzymatic activity at low temperature will be discussed, in view of the recent achievements concerning the use of cold-adapted lipases and esterases in the synthesis of fine chemicals.

Heart failure is a leading cause of mortality in North America and most other parts of the world. Its development is secondary to diseases such as hypertension, coronary artery disease, valvular heart disease or cardiomyopathies. Current therapies for preventing heart failure include the use of diuretics, inhibitors of the renin-angiotensin-aldosterone system and β-adrenergic receptor blockers. These treatments have been moderately successful; however, the incidence of heart failure is on the rise. In view of the limited success with existing therapies it has become very important to pursue alternative strategies. One such approach could be the use of food-derived compounds that have medical benefits, and can be administered as dietary supplements. In this context, resveratrol, a polyphenol, found predominantly in grapes and berries, and a major component of red wine, has been recently drawing significant attention for its cardioprotective properties. Current research on resveratrol has focused on examining its potential in preventing or regressing defects in cardiac structure and function in experimental models of heart disease. In this paper, we will discuss the potential of resveratrol as a nutraceutical in preventing the development of heart failure in the future.