Current Enzyme Inhibition - Volume 4, Issue 4, 2008

Alzheimer's disease is the most common neurodegenerative disorder, clinically characterized by a noticeable cognitive decline defined by a loss of memory and learning ability, together with a reduced ability to perform basic activities of daily living, and a diverse array of neuropsychiatric symptoms such as apathy, verbal and physical agitation, irritability, depression etc. Pharmacotherapy of Alzheimer's disease has progressed in the past ten years from the use of psychotropic medications for sedation to the use of rational treatments aimed at neurotransmitter replacement. Only one class of medications has been extensively evaluated in clinical trials with patients with Alzheimer's disease and is approved by the US Food and Drug Administration for Alzheimer's disease treatment. These medications are cholinesterase inhibitors and have a significant, although modest, effect on the cognitive status of patients with Alzheimer's disease.

Oil palm (OP) is prone to a rot by the fungus Ganoderma which may be capable of being controlled by enzyme inhibitors. Palm oil is used in the production of vegetable oil for foods, cosmetics, pharmaceuticals and, most recently, biodiesel. However, the fundamental process of the disease as “white rot” has been ignored by researchers. White rot fungi are capable of degrading lignin ultimately to carbon dioxide and water: Celluloses become available as nutrients for the fungus. One potential control method is to inhibit the ligninolytic enzymes. There are few data on the lignin of OP and none on how it is degraded by OP Ganoderma and so specific examples on how to inhibit the enzymes of the fungus is impossible. Fortunately, there is more information on lignin and lignin model compounds degraded by other fungi. The taxonomy of Ganoderma is confused; hence drawing direct comparisons between other taxa within the genus in terms of ligninolysis is of limited utility. In general, ligninolytic enzymes can be inhibited by (a) temperature, pH and aeration, (b) high carbon and high nitrogen and (c) halides, metal chelators, heavy metals, and reducing agents. These factors require to be tested against the enzymes from Ganoderma from OPs in vitro with a view to developing control methods in the field, and this is how the area requires to be progressed. Furthermore, the procedures may be useful to control other rots of trees and wood products. In the case of OP, such compounds could be (a) injected into (b) sprayed onto and/or (c) added to the soil of the OP. In conclusion, the control of Ganoderma of OP would benefit from investigating the effect of inhibitors on the lignin degrading enzymes in vitro to enable this to be applied in plantations.

Several lichen metabolites, such as usnic acid, inhibit both HIV-1 and HIV-2 integrase activities, as well as mammalian topoisomerase I. Some of them are phenolics, which also inhibit leukotriene B4 biosynthesis in polymorphonuclear leukocytes. Their effect is not due to an antioxidant effect against peroxidation , free radical scavenging or free radicals production. (-)-Usnic acid specifically bleaches the cotyledonary tissues and decreases chlorophylls and carotenoids; it also inhibits protophorphyrinogen oxidase activity. Bleaching appears to be caused by the competitive binding of (-)-usnic acid, inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase. (-)-Usnic acid also promotes the secretion of active bacterial glucosamine phosphate isomerase and lactate dehydrogenase. Usnic acids are able to bind several enzymatic and non-enzymatic proteins, for example urease, which is inhibited by the formation of large inactive aggregates. L-Cysteine partially reverses urease inhibition by binding to usnic acid via their thiol groups, thus preventing its effect on the enzyme. Consistent with this, reducing reagents such as DTT also relieve urease inhibition by usnic acid. In addition, alanine and proline partially reverse urease inhibition and formation of large aggregates. These amino acids also prevent the binding of (-)-usnic acid to the low affinity sites for the ligand. The involvement of proline in the polymerization process is related to the biplanar, steric conformation of (-)-usnic acid. Other lichen phenolics, such as evernic acid, possessing a monoplanar structure, also inhibit the enzyme without polymerization, by interaction with the L-histidine and L-serine residues. This review focuses on the mechanisms of urease inhibition by these metabolites and their regulation, postulating a mechanism of action for these inhibitors related to their potential applications in drug development.

Opportunistic fungal infections are a growing problem as larger populations have become immunocompromised due to chemotherapy, organ transplant conditioning or infections such as HIV. Traditional approaches to identify drug targets in fungi are often focused on essential genes that are either not present in their mammalian host or differ sufficiently to allow chemotherapeutic discrimination. A complementary approach involves exploration of pathways involved in virulence (the so-called ‘virulome’), to identify potential ‘weak links,’ essential to successful infection by the pathogen. As an example, we will summarize work identifying virulence determinants within regulatory networks of the fungal pathogen, Cryptococccus neoformans. C. neoformans, is a fungal pathogen afflicting large numbers of AIDSrelated patients, and has become the most common cause of meningitis in the developing world. Molecular dissection of pathways related to the virulence factor laccase has identified cellular processes that are particularly important during infection including copper acquisition and phospholipid metabolism. Molecular analyses of these pathways have identified genetic predictions of infectious outcomes of cryptococcosis in organ transplant patients and has suggested novel synergistic drug combinations. These analyses may thus identify potential pathways sensitive to pharmacological intervention.

This review article tries to summarize investigation about natural products with the ability to inhibit enzymes that play a crucial role in DNA metabolism such as replication, transcription, recombination, and chromosome segregation during mitosis. The focus is placed on DNA polymerases, topoisomerases and reverse transcriptase inhibitors because the vast of literature emphasized on the action of these compounds. It was found that a great diversity of chemical structures encompassing triterpenes, flavonoids, chromones, lipids, iridoids, phytosterols, coumarins, anthracyclines, quinones, protoberberines, tannins and other natural products, are produced by organism species.