Current Enzyme Inhibition - Volume 6, Issue 1, 2010

Mitochondrial uncoupling proteins (UCPs), members of a family of mitochondrial anion carrier proteins (MACP), are nuclear-encoded transmembrane transporter proteins located in the mitochondrial inner membrane. UCP1, mainly expressed in brown adipose tissue (BAT), was the first to be discovered and is responsible for animal thermogenesis; UCP2, originally thought to play a role in nonshivering thermogenesis, obesity and diabetes, its main function appears to be in the control of mitochondria-derived reactive oxygen species (ROS). Another uncoupling protein homologue, the UCP3 is mainly expressed in skeletal muscle and brown adipose tissue and its gene is transcribed from tissue-specific promoters in humans but not in rodents. All the members of this protein family possess a common feature of shunting protons across the mitochondrial inner membrane and reduce ATP synthesis; however, this common mechanism of action is used to carry out different functions by the different UCPs. The distribution and abundance of UCPs are tissue specific, which is also reflected into the processes that these proteins are thought to be participating. UCPs other than UCP1 are involved in several biological processes such as fatty acid (FA) metabolism, insulin secretion, oxidative stress (OS), heart pathophysiology and macrophage activation. New discoveries are advancing our understanding of UCP's roles in cardiovascular physiology.

Protein kinases are phosphorylation enzymes that regulate signaling events in the cell and when impaired may be responsible for the pathophysiology seen in a number of disease states. Since these kinases only have activity when actively engaged in signaling events, most diseases are associated with dysregulation, dismutation, or impaired cellular regulation. The small GTP-binding protein, RhoA, and its downstream effector, Rho-kinase, have been implicated in the pathogenesis of a number of cardiovascular diseases. The activation of Rho-kinase is involved in the development of increased vascular tone, endothelial dysfunction, inflammation and restenosis, whereas the inhibition of Rho-kinase has been shown to have a beneficial effect in treatment of disease states involving dysregulation of Rho kinase. The X-ray analysis of the crystal structure of these protein complexes has revealed complex intermolecular interactions that are responsible for ligand binding and may allow for future design to optimize inhibitory protein kinase activity. The objective of this mini-review is to improve our current understanding of the role of RhoA/Rho-kinase pathway in the pathogenesis of cardiovascular diseases through the use of the Rho-kinase inhibitors, fasudil and Y-27632.

Aurora kinases play pivotal role in mitosis. Aurora kinase A controls centrosome duplication, spindle pole integrity as well as bipolar spindle formation. Aurora kinase B is part of the chromosome passenger complex (CPC) and through its co-factors, drives chromosome congression, bidirectional tension on kinetochores and spindle checkpoint signaling, as well as cytokinesis completion. Both CPC and Aurora kinases are exclusively expressed during mitosis and are up regulated in many tumors. Their overexpression correlates with the level of genomic instability within tumors and these proteins are therefore proposed as potential targets for cancer therapy. This review describes the interplay between Aurora kinases in mitosis and the different strategies that have been developed towards their targeting.

Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) belongs to the mitogen-activated protein kinase (MAPK) family and plays an important role in many biological contexts. JNK is deeply involved in several serious human disorders, including inflammation, obesity, diabetes, neuronal disease and cancer. Accordingly, JNK has been recognized as an appropriate target for the treatment of these diseases, and much effort has been expended over the past 15 years to isolate JNK inhibitors that can inactivate this kinase. In 2001, the compound SP600125 was reported as the first JNK-specific inhibitor. Many researchers have subsequently employed SP600125 in in vitro and in vivo models to evaluate whether certain disease-associated events are JNK-dependent. Indeed, more than 1300 studies citing the use of SP600125 as a JNK inhibitor in cell cultures and animal models have been reported. However, although SP600125 has been employed successfully to inhibit JNK in several situations, there have been questions about its specificity for JNK. SP600125 can bind to a broad range of protein kinases and inhibit some of them with similar or greater potency than JNK, confirming that many additional kinases may be targets of SP600125. In this article, we review both the usefulness of SP60125 as a JNK inhibitor and the limitations to its specificity.

The formation of advanced glycation end-products (AGEs), also called the Maillard reaction, occurs ubiquitously and irreversibly in patients with diabetes mellitus and its consequences are especially relevant to many inflammatory events leading to vascular dysfunctions and organ injury. The present review intends to highlight some relevant aspects of nitric oxide synthases, advanced glycation end-products and their receptors as well as the mechanisms by which AGEs are able to modulate the synthesis of nitric oxide (NO), either by NO quenching, modification of enzyme structure or regulation of gene expression. Finally, other RAGE ligands different from AGEs, but relevant to the context of inflammation, are presented as new modulators of nitric oxide synthesis.

We would like to review the recent study of the inhibitors for peptidyl-prolyl cis/trans isomerase (PPIase), such as cyclophilin (Cyp), FK506- binding protein (FKBP) and Pin1. The inhibitors of Cyp and FKBP, CsA and FK506 respectively are well known potent immunosuppressive drugs. However, they cause a variety of side- effects. Therefore efforts are under way to identify PPIase inhibitors with less side- effects. In this review, efforts of discovering small molecule inhibitors are emphasized. While Cyp and FKBP inhibitors have been explored fairly thoroughly, the number of efforts to screen inhibitors of Pin1 is still limited so far. We think that the inhibitor of Pin1 has high potential as a drug.