Current Enzyme Inhibition - Volume 2, Issue 4, 2006

Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid plaques, containing the extracellular amorphous deposits of beta-amyloid protein and intracellular neurofibrillary tangles, comprising filaments of phosphorylated form of a microtubule-associated protein Tau, localized in the brain. It is considered that the major constituent of amyloid plaques, beta-amyloid peptide (Aβ), induces AD neuropathology. AD enzymatic pathway comprises several events: (i) beta-secretase cleaves amyloid precursor protein (APP) and releases a soluble fragment, beta-APPs, and (ii) gamma-secretase cleaves the C-terminal membrane bound C99 peptide within the transmembrane domain, thus generating two major amino acid isoforms of beta-amyloid: Aβ40 and Aβ42. This review is focused on the recent advances in the field of computational chemistry (molecular docking, 3D-QSAR (CoMFA (Comparative Molecular Field Analysis) and CoMSIA (Comparative Molecular Similarity Indices Analysis)), molecular dynamics and rational drug design) applied to inhibitions of beta and gamma secretases. Computational chemistry studies have been performed for different inhibitors of beta and gamma secretases (e.g. benzodiazepine, urethane and tetrapeptide derivatives) resulting in their predicted biological activities and free energies.

Sesquiterpene lactones (SLs) are biologically active compounds found in various medicinal plants. Although the compounds are reported to possess numerous biological activities, but the most important is their immunoregulatory role in inflammatory cells. This is because 1) over-activation of inflammatory cells secretes a large amount of different pro-inflammatory mediators such as cytokines, nitric oxide (NO) and prostaglandin (PG)E2 and 2) SLs can modulate these phenomena effectively through inhibiting the activation pathway of nuclear factor (NF)-κB via the reactivity of some functional groups in SLs such as α-methylene-γ- lactone. This review, therefore, discusses in detail the molecular mechanism and structural features of SLs in blocking NF-κB activation with a general introduction of NF-κB and proposes the possibility that SLs can be developed pharmaceutically useful drugs against NF-κB-mediated diseases and that they can be chemically modified to improve their anti-NF-κB efficacy.

Laccases are an interesting group of multicopper enzymes, which have received much attention of researchers in last decades due to their ability to oxidise both phenolic and non-phenolic lignin-related compounds as well as highly recalcitrant environmental pollutants. This makes these biocatalysts very useful for their application to several biotechnological processes. Soil and water contamination is often accompanied by several organic and inorganic compounds. Therefore, it is important to know the stability of laccases under the conditions present in such environments, since it can influence the effectiveness of the bioremediation technologies. Recently, the utility of laccases has also been applied to Nanobiotechnology. This is an increasing research field mainly due to the fact that laccases are able to catalyse electron transfer reactions without additional cofactors and to the development of several techniques for the immobilisation of biomolecules such as micropatterning, self-assembled monolayers and layer-by-layer technique. These techniques can be used to immobilise laccases preserving their enzymatic activity. This paper reviews the effect of the potential laccase inhibitors that can be found in polluted environments on laccase activity.

The renin-angiotensin (RAS) and endothelin/ET-1,-2,-3 systems comprise families of precursor peptides, angiotensinogen and big-endothelins respectively, activated by families of proteases. Angiotensinogen is activated by the sequential action of an aspartyl-protease, renin, then a metalloprotease, angiotensin converting enzyme (ACE). Big-endothelins are activated by the metalloproteases endothelin converting enzyme/ECE-1a-d, and to a lesser extent neprilysin (NEP/CD10). These proteolytic cascades produce the system-representative active peptides angiotensin II (Ang II) and endothelin-1 (ET-1). Then several exopeptidases, which include aminopeptidases or carboxypeptidases, and endopeptidases, in particular NEP, further process these active peptides to either inactive fragments or intermediate peptides with various biological activities. The RAS and ET systems have been mainly studied in the context of cardiovascular disorders, and either agonists or antagonists of their receptors, and inhibitors for the enzymes metabolizing the precursors and/or the active peptides have been developed for the treatment of these disorders. However, the RAS and ET systems, in addition to controlling the vascular tone and natriohydric balance, may be involved in cell growth and/or death in cancer, fibrotic or degenerative diseases. Therefore the protease inhibitors developed for treating cardiovascular disorders may have wider application in cancer than initially envisioned, which will be reviewed in this manuscript

A study of influence of exogenous (xenobiotic) molecules on enzymatic reactions provides a basis for prediction and interpretation of effects of toxic compounds on metabolic processes in complex organisms. A coupled system of two enzymatic reactions catalyzed by luciferase and NAD(P)H:FMN-oxidoreductase from luminous bacteria Photobacterium phosphoreum is considered as a simple model of a living organism. Three main mechanisms of xenobiotics' influence are: (1) change of electron-excited states population in a bioluminescent emitter; (2) change of rates of the coupled reactions; and (3) interactions with the enzymes. The paper mainly deals with the third case. The results of impacts of different molecular groups (fluorescent dyes, organic oxidizers, and haloid compounds) are summarized. Binding of the compounds with the enzymes is tracked through time-resolved fluorescence techniques. Results of an indirect fluorescent method for studying interactions of nonfluorescent compounds (quinones) with the enzymes are discussed. Correlations between physico-chemical characteristics of exogenous compounds (hydrophobicity or atomic weight of haloid substituents) and efficiency of their interactions with the enzymes are demonstrated.

Endothelin-1 (ET-1) is a peptide with various biological activities, such as vasoconstriction, mitogenesis and bronchoconstriction. It has been implicated in the pathogenesis of numerous disease processes. Suppression of the production of this peptide by inhibitors of endothelin-converting enzyme-1 (ECE-1), the key enzyme in ET-1 biosynthesis, may be a therapeutic option. There are three classes of ECE-1 inhibitors: selective ECE-1 inhibitors, dual ECE-1/neutral endopeptidase (NEP) 24.11 inhibitors and triple ECE-1/NEP/angiotensin-converting enzyme inhibitors. This review will focus briefly on the endothelin system and mainly on the ECE-1 inhibitor classes, their pharmacologic effects on animal models of various diseases and published clinical studies.

Superoxide dismutase (SODs, E.C.1.15.1.1) are metalloproteins, which are subdivided into four different catagories, as they contain different metals: copper/zinc (Cu/Zn) superoxide dismutase, manganese (Mn) superoxide dismutase, iron (Fe) superoxide dismutase, and nickel (Ni) superoxide dismutase. In mammalian tissues, due to location in cell, dismutases are divided into cytosolic dismutase - CuZnSOD (SOD- 1) that is present in cytoplasm and nucleus, mitochondrial dismutase - MnSOD (SOD-2) that is contained in mitochondrial matrix, and extracellular dismutase - EC-SOD (SOD-3) that exists in intracellular spaces of tissues and extracellular fluids (plasma, lymph, celebral-modulatory or synovial). SODs eliminate superoxide radicals from cell environment and prevents formation of reactive oxygen species and their derivatives. SODs are characterized by thier peroxidative activity: they degrades hydrogen peroxide at the participation of uric acid, HCO3 - and other substrates such as formate, glutamate, tyrosine, etc. Superoxide dismutases may be only damaged by some xenobiotics, e.g., azide, cyanides, chloric acid or diethyl-dithio-carbamate and hydrogen peroxide. They play an essential role in stabilization of blood pressure and correct astrocytes blood supply. They are responsible for male fertility, lung function, NO metabolism, and also for development of numerous diseases. In this review, we describe the effect of age and some physical (ionization) and chemical factors (hydrogen peroxide, 2-methoxyestradiol, diethyl-dithio-carbamate, chlorophenols, 2,3,7,8-tetrachlorodibenzo- p-dioxin, microcystin-LR) on the activity of SODs. As their activity is decreased in many diseases and under influence of many physical and chemical factors, it is supposed that SOD supplementation may be very important in therapy. Administration of recombined EC-SOD may prevent cells from damages caused by radical activity.