Calcineurin is a calcium and calmodulin dependent serine/threonine protein phosphatase. It can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic, a transcription factor, by dephosphorylating it; the activated NFATc is translocated into the nucleus, where it upregulates the expression of interleukin 2, which, in turn, stimulates the growth and differentiation of the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin and tacrolimus. Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca2+-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene and two isoforms of the regulatory encoded by separate genes; when an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which activates calcineurin by binding a regulatory subunit and activating calmodulin binding.
Calcineurin induces transcription factors. IL-2 induces the production of other cytokines. In this way, it governs the action of cytotoxic lymphocytes; the amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly. Calcineurin inhibitors are prescribed for adult rheumatoid arthritis as a single drug or in combination with methotrexate; the microemulsion formulation is approved by the U. S. Food and Drug Administration for treatment of active RA, it is prescribed for: psoriatic arthritis, acute ocular Behçet’s disease, juvenile idiopathic arthritis and juvenile polymyositis and dermatomyositis and juvenile systemic lupus erythematosus, adult lupus membranous nephritis, systemic sclerosis, aplastic anemia, steroid-resistant nephrotic syndrome, atopic dermatitis, severe corticosteroid-dependent asthma, severe ulcerative colitis, pemphigus vulgaris, myasthenia gravis, dry eye disease, with or without Sjögren's syndrome. Calcineurin is linked to receptors for several brain chemicals including glutamate, dopamine and GABA.
An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with schizophrenia: impairment in working memory, attention deficits, aberrant social behavior, several other abnormalities characteristic of schizophrenia. Calcineurin along with NFAT, may improve the function of diabetics' pancreatic beta cells, thus tacrolimus contributes to the frequent development of new diabetes following renal transplantation. Calcineurin/NFAT signaling is required for function. Calcineurin inhibitors such as tacrolimus are used to suppress the immune system in organ allotransplant recipients to prevent rejection of the transplanted tissue. Calcineurin has been shown to interact with DSCR1 and AKAP5. Calcineurin at the US National Library of Medicine Medical Subject Headings
A natural product is a chemical compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can be prepared by chemical synthesis and have played a central role in the development of the field of organic chemistry by providing challenging synthetic targets; the term natural product has been extended for commercial purposes to refer to cosmetics, dietary supplements, foods produced from natural sources without added artificial ingredients. Within the field of organic chemistry, the definition of natural products is restricted to mean purified organic compounds isolated from natural sources that are produced by the pathways of primary or secondary metabolism. Within the field of medicinal chemistry, the definition is further restricted to secondary metabolites. Secondary metabolites are not essential for survival, but provide organisms that produce them an evolutionary advantage. Many secondary metabolites are cytotoxic and have been selected and optimized through evolution for use as "chemical warfare" agents against prey and competing organisms.
Natural products sometimes have therapeutic benefit as traditional medicines for treating diseases, yielding knowledge to derive active components as lead compounds for drug discovery. Although natural products have inspired numerous U. S. Food and Drug Administration-approved drugs, drug development from natural sources has received declining attention by pharmaceutical companies due to unreliable access and supply, intellectual property concerns, seasonal or environmental variability of composition, loss of sources due to rising extinction rates; the broadest definition of natural product is anything, produced by life, includes the likes of biotic materials, bio-based materials, bodily fluids, other natural materials. A more restrictive definition of a natural product is an organic compound, synthesized by a living organism; the remainder of this article restricts itself to this more narrow definition. Natural products may be classified according to their biological function, biosynthetic pathway, or source as described below.
Following Albrecht Kossel's original proposal in 1891, natural products are divided into two major classes, the primary and secondary metabolites. Primary metabolites have an intrinsic function, essential to the survival of the organism that produces them. Secondary metabolites in contrast have an extrinsic function that affects other organisms. Secondary metabolites are not essential to survival but do increase the competitiveness of the organism within its environment; because of their ability to modulate biochemical and signal transduction pathways, some secondary metabolites have useful medicinal properties. Natural products within the field of organic chemistry are defined as primary and secondary metabolites. A more restrictive definition limiting natural products to secondary metabolites is used within the fields of medicinal chemistry and pharmacognosy. Primary metabolites as defined by Kossel are components of basic metabolic pathways that are required for life, they are associated with essential cellular functions such as nutrient assimilation, energy production, growth/development.
They have a wide species distribution that span many phyla and more than one kingdom. Primary metabolites include carbohydrates, amino acids, nucleic acids which are the basic building blocks of life. Primary metabolites that are involved with energy production include respiratory and photosynthetic enzymes. Enzymes in turn are composed of amino acids and non-peptidic cofactors that are essential for enzyme function; the basic structure of cells and of organisms are composed of primary metabolites. These include cell membranes, cell walls, cytoskeletons. Primary metabolite enzymatic cofactors include members of the vitamin B family. Vitamin B1 as thiamine diphosphate is a coenzyme for pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, transketolase which are all involved in carbohydrate metabolism. Vitamin B2 is a constituent of FAD which are necessary for many redox reactions. Vitamin B3, synthesized from tryptophan is a component of the coenzymes NAD+ and NADP+ which in turn are required for electron transport in the Krebs cycle, oxidative phosphorylation, as well as many other redox reactions.
Vitamin B5 is a constituent of coenzyme A, a basic component of carbohydrate and amino acid metabolism as well as the biosynthesis of fatty acids and polyketides. Vitamin B6 as pyridoxal 5′-phosphate is a cofactor for many enzymes transaminases involve in amino acid metabolism. Vitamin B12 contain a corrin ring similar in structure to porphyrin and is an essential coenzyme for the catabolism of fatty acids as well for the biosynthesis of methionine. DNA and RNA which store and transmit genetic information are composed of nucleic acid primary metabolites. First messengers are signaling molecules that control cellular differentiation; these signaling molecules include hormones and growth factors in turn are composed of peptides, biogenic amines, steroid hormones, gibberellins etc. These first messengers interact with cellular receptors. Cellular receptors in turn activate second messengers are used to relay the extracellular message to intracellular targets; these si
Acetogenins are a class of polyketide natural products found in plants of the family Annonaceae. They are characterized by linear 32- or 34-carbon chains containing oxygenated functional groups including hydroxyls, epoxides and tetrahydropyrans, they are terminated with a lactone or butenolide. Over 400 members of this family of compounds have been isolated from 51 different species of plants. Many acetogenins are characterized by neurotoxicity. Examples include: Annonacin Annonins Bullatacin Uvaricin Structurally, acetogenins are a series of C-35/C-37 compounds characterized by a long aliphatic chain bearing a terminal methyl-substituted α,β-unsaturated γ-lactone ring, as well as one to three tetrahydrofuran rings; these THF rings are located along the hydrocarbon chain, along with a number of oxygenated moieties and/or double bonds. Acetogenins have been investigated for their potential therapeutic use in treating cancer, but this potential is tempered with concerns about neurotoxicity. Purified acetogenins and crude extracts of the common North American pawpaw or the Brazilian pawpaw remain under basic research for their possible biological properties.
Media related to Acetogenins at Wikimedia Commons
Antiparasitics are a class of medications which are indicated for the treatment of parasitic diseases, such as those caused by helminths, ectoparasites, parasitic fungi, protozoa, among others. Antiparasitics target the parasitic agents of the infections by destroying them or inhibiting their growth. Antiparasitics are one of the antimicrobial drugs which include antibiotics that target bacteria, antifungals that target fungi, they may be administered intravenously or topically. Broad-Spectrum antiparasitics, analogous to broad-spectrum antibiotics for bacteria, are antiparasitic drugs with efficacy in treating a wide range of parasitic infections caused by parasites from different classes. Nitazoxanide Melarsoprol Eflornithine Metronidazole Tinidazole Miltefosine Mebendazole Pyrantel pamoate Thiabendazole Diethylcarbamazine Ivermectin Niclosamide Praziquantel Albendazole Praziquantel Rifampin Amphotericin B Fumagillin In the last decades, triazolopyrimidines and their metal complexes have been employed as an alternative drug to the exisisting commercial antimonials, searching for a decrease in side effects and the development of parasite drug resistance.
The use of metal compounds as antiparasitic agents has been reviewed. Antiparasitics treat parasitic diseases. Antiparastics may be given via a variety of routes depending on the specific medication, including oral and intravenous. Resistance to antiparasitics has been growing concern in veterinary medicine; the Egg hatch assay can be used to determine whether a parasite causing an infection has become resistant to standard drug treatments. Early antiparasitics were ineffective toxic to patients, difficult to administer due to the difficulty in distinguishing between the host and the parasite. Between 1975 and 1999 only 13 of 1,300 new drugs were antiparasitics, which raised concerns that insufficient incentives existed to drive development of new treatments for diseases that disproportionately target low-income countries; this led to new public sector and public-private partnerships, including investment by the Bill and Melinda Gates Foundation. Between 2000 and 2005, twenty new antiparasitic agents were developed or in development.
In 2005, a new antimalarial cost $300 million to develop with a 50% failure rate. Balsam of Peru, which has antiparasitic attributes Naegleria fowleri Balamuthia mandrillaris
Polyenes are poly-unsaturated organic compounds that contain at least three alternating double and single carbon–carbon bonds. These carbon–carbon double bonds interact in a process known as conjugation resulting in some unusual optical properties. Related to polyenes are dienes, where there are only two alternating single bonds; the following polyenes are used as antibiotics for humans: amphotericin B, candicidin, methyl partricin, trichomycin. Some polyenes are brightly colored, an otherwise rare property for a hydrocarbon. Alkenes absorb in the ultraviolet region of a spectrum, but the absorption energy state of polyenes with numerous conjugated double bonds can be lowered such that they enter the visible region of the spectrum, resulting in compounds which are coloured, thus many natural dyes contain linear polyenes, e.g. beta-carotene, responsible for the color of carrots. Polyenes tend to be more reactive than simpler alkenes. For example, polyene-containing triglycerides are reactive towards atmospheric oxygen.
Polyacetylene, which oxidized or reduced, exhibits high electrical conductivity. Most conductive polymers are polyenes, many have conjugated structures. A few fatty acids are polyenes. Another class of important polyenes are polyene antimycotics, Representative Polyenes
Enzymes are macromolecular biological catalysts. Enzymes accelerate chemical reactions; the molecules upon which enzymes may act are called substrates and the enzyme converts the substrates into different molecules known as products. All metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps; the study of enzymes is called enzymology and a new field of pseudoenzyme analysis has grown up, recognising that during evolution, some enzymes have lost the ability to carry out biological catalysis, reflected in their amino acid sequences and unusual'pseudocatalytic' properties. Enzymes are known to catalyze more than 5,000 biochemical reaction types. Most enzymes are proteins; the latter are called ribozymes. Enzymes' specificity comes from their unique three-dimensional structures. Like all catalysts, enzymes increase the reaction rate by lowering its activation energy; some enzymes can make their conversion of substrate to product occur many millions of times faster.
An extreme example is orotidine 5'-phosphate decarboxylase, which allows a reaction that would otherwise take millions of years to occur in milliseconds. Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, nor do they alter the equilibrium of a reaction. Enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules: inhibitors are molecules that decrease enzyme activity, activators are molecules that increase activity. Many therapeutic drugs and poisons are enzyme inhibitors. An enzyme's activity decreases markedly outside its optimal temperature and pH, many enzymes are denatured when exposed to excessive heat, losing their structure and catalytic properties; some enzymes are used commercially, in the synthesis of antibiotics. Some household products use enzymes to speed up chemical reactions: enzymes in biological washing powders break down protein, starch or fat stains on clothes, enzymes in meat tenderizer break down proteins into smaller molecules, making the meat easier to chew.
By the late 17th and early 18th centuries, the digestion of meat by stomach secretions and the conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified. French chemist Anselme Payen was the first to discover an enzyme, diastase, in 1833. A few decades when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that this fermentation was caused by a vital force contained within the yeast cells called "ferments", which were thought to function only within living organisms, he wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."In 1877, German physiologist Wilhelm Kühne first used the term enzyme, which comes from Greek ἔνζυμον, "leavened" or "in yeast", to describe this process. The word enzyme was used to refer to nonliving substances such as pepsin, the word ferment was used to refer to chemical activity produced by living organisms.
Eduard Buchner submitted his first paper on the study of yeast extracts in 1897. In a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts when there were no living yeast cells in the mixture, he named the enzyme that brought about the fermentation of sucrose "zymase". In 1907, he received the Nobel Prize in Chemistry for "his discovery of cell-free fermentation". Following Buchner's example, enzymes are named according to the reaction they carry out: the suffix -ase is combined with the name of the substrate or to the type of reaction; the biochemical identity of enzymes was still unknown in the early 1900s. Many scientists observed that enzymatic activity was associated with proteins, but others argued that proteins were carriers for the true enzymes and that proteins per se were incapable of catalysis. In 1926, James B. Sumner crystallized it; the conclusion that pure proteins can be enzymes was definitively demonstrated by John Howard Northrop and Wendell Meredith Stanley, who worked on the digestive enzymes pepsin and chymotrypsin.
These three scientists were awarded the 1946 Nobel Prize in Chemistry. The discovery that enzymes could be crystallized allowed their structures to be solved by x-ray crystallography; this was first done for lysozyme, an enzyme found in tears and egg whites that digests the coating of some bacteria. This high-resolution structure of lysozyme marked the beginning of the field of structural biology and the effort to understand how enzymes work at an atomic level of detail. An enzyme's name is derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase. Examples are alcohol dehydrogenase and DNA polymerase. Different enzymes that catalyze the same chemical reaction are called isozymes; the International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC numbers. The first number broadly classifies the enzyme based on its mechanism; the top-level classification is: EC 1, Oxidoreductases: catalyze oxidation/reducti