Betaenones are phytotoxins found in the fungus Pleospora betae . [1] The compounds were found to inhibit a variety of protein kinases. [2]
Two further betaenones were found in a species of the fungus Microsphaeropsis , which was isolated from the marine sponge Aplysina aerophoba . [3]
In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen synthase (GS), GSK-3 has since been identified as a protein kinase for over 100 different proteins in a variety of different pathways. In mammals, including humans, GSK-3 exists in two isozymes encoded by two homologous genes GSK-3α (GSK3A) and GSK-3β (GSK3B). GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, addiction and bipolar disorder.
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.
Okadaic acid, C44H68O13, is a toxin produced by several species of dinoflagellates, and is known to accumulate in both marine sponges and shellfish. One of the primary causes of diarrhetic shellfish poisoning, okadaic acid is a potent inhibitor of specific protein phosphatases and is known to have a variety of negative effects on cells. A polyketide, polyether derivative of a C38 fatty acid, okadaic acid and other members of its family have shined light upon many biological processes both with respect to dinoflagellete polyketide synthesis as well as the role of protein phosphatases in cell growth.
Aralkylamine N-acetyltransferase (AANAT), also known as arylalkylamine N-acetyltransferase or serotonin N-acetyltransferase (SNAT), is an enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. It is in humans encoded by the ~2.5 kb AANAT gene containing four exons, located on chromosome 17q25. The gene is translated into a 23 kDa large enzyme. It is well conserved through evolution and the human form of the protein is 80 percent identical to sheep and rat AANAT. It is an acetyl-CoA-dependent enzyme of the GCN5-related family of N-acetyltransferases (GNATs). It may contribute to multifactorial genetic diseases such as altered behavior in sleep/wake cycle and research is on-going with the aim of developing drugs that regulate AANAT function.
Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.
Alexander Levitzki is an Israeli biochemist who is a professor of biochemistry at the Alexander Silberman Institute of Life Sciences, the Hebrew University of Jerusalem.
Adenosine kinase is an enzyme that catalyzes the transfer of gamma-phosphate from Adenosine triphosphate (ATP) to adenosine (Ado) leading to formation of Adenosine monophosphate (AMP). In addition to its well-studied role in controlling the cellular concentration of Ado, AdK also plays an important role in the maintenance of methylation reactions. All S-adenosylmethionine-dependent transmethylation reactions in cells lead to production of S-adenosylhomocysteine (SAH), which is cleaved by SAH hydrolase into Ado and homocysteine. The failure to efficiently remove these end products can result in buildup of SAH, which is a potent inhibitor of all transmethylation reactions. The disruption of AdK gene (-/-) in mice causes neonatal hepatic steatosis, a fatal condition characterized by rapid microvesicular fat infiltration, leading to early postnatal death. The liver was the main organ affected in these animals and in it the levels of adenine nucleotides were decreased, while those of SAH were elevated. Recently, missense mutations in the AdK gene in humans which result in AdK deficiency have also been shown to cause hypermethioninemia, encephalopathy and abnormal liver function.
Serine/threonine-protein kinase N2 is an enzyme that in humans and Strongylocentrotus purpuratus is encoded by the PKN2 gene.
Indolocarbazoles (ICZs) are a class of compounds that are under current study due to their potential as anti-cancer drugs and the prospective number of derivatives and uses found from the basic backbone alone. First isolated in 1977, a wide range of structures and derivatives have been found or developed throughout the world. Due to the extensive number of structures available, this review will focus on the more important groups here while covering their occurrence, biological activity, biosynthesis, and laboratory synthesis.
Betaenone B, like other betaenones, is a secondary metabolite isolated from the fungus Pleospora betae, a plant pathogen. Its phytotoxic properties have been shown to cause sugar beet leaf spots, which is characterized by black, pycnidia containing, concentric circles eventually leading to necrosis of the leaf tissue. Of the seven phytotoxins isolated in fungal leaf spots from sugar beet, betaenone B showed the least amount of phytotoxicity showing only 8% inhibition of growth while betaenone A and C showed 73% and 89% growth inhibition, respectively. Betaenone B is therefore not considered toxic to the plant, but will produce leaf spots when present in high concentrations (0.33 μg/μL). While the mechanism of action of betaenone B has yet to be elucidated, betaenone C has been shown to inhibit RNA and protein synthesis. Most of the major work on betaenone B, including the initial structure elucidation of betaenone A, B and C as well as the partial elucidation mechanism of biosynthesis, was presented in three short papers published between 1983–88. The compounds were found to inhibit a variety of protein kinases signifying a possible role in cancer treatment.
The calphostins are a class of closely related chemical compounds isolated from the fungus Cladosporium cladosporioides. The known calphostins include calphostin A, calphostin B, calphostin C, calphostin D, and calphostin I. The calphostins are inhibitors of protein kinase C (PKC). The most potent member of the series, calphostin C, has found use as a biochemical tool because of this activity.
BIM-1 and the related compounds BIM-2, BIM-3, and BIM-8 are bisindolylmaleimide-based protein kinase C (PKC) inhibitors. These inhibitors also inhibit PDK1 explaining the higher inhibitory potential of LY33331 compared to the other BIM compounds a bisindolylmaleimide inhibitor toward PDK1.
Streptomyces scabies or Streptomyces scabiei is a streptomycete bacterium species found in soils around the world. Unlike most of the 500 or so Streptomyces species it is a plant pathogen causing corky lesions to form on tuber and root crops as well as decreasing the growth of seedlings. Along with other closely related species it causes the potato disease common scab, which is an economically important disease in many potato growing areas. It was first described in 1892, being classified as a fungus, before being renamed in 1914 and again in 1948. Several other species of Streptomyces cause similar diseases to S. scabies but other, more closely related species, do not.
Balanol is a fungal metabolite produced by the fungus Verticillium balanoides. It is a potent inhibitor of the serine/threonine kinases protein kinase A (PKA) and protein kinase C (PKC), binding in a similar manner with that of ATP. Balanol was discovered in 1993 in the search for novel inhibitors of PKC, a member of a family of serine/threonine kinases whose overactivation is associated with numerous human diseases of signal transduction including cancer. However, much of the research on balanol focuses on how chemical modifications of the molecular structure affect binding to PKA. Indeed, balanol, its chemically altered analogs, and their interactions with PKA in particular are used to illuminate the roles of selectivity and protein flexibility in the inhibition of kinases. For instance, the X-ray crystal structure of balanol in complex with PKA was used in order to confer selectivity and to improve pharmacological efficacy of inhibitors of the H. sapiens Akt (PKB), another serine/threonine protein kinase implicated in the proper functioning of many cellular processes.
The cortistatins are a group of steroidal alkaloids first isolated in 2006 from the marine sponge Corticium simplex. The cortistatins were first discovered in a search for naturally occurring compounds that inhibit proliferation of human umbilical vein endothelial cells (HUVECs), with cortistatin A being the most potent compound in the class.
Betaenone A, like other betaenones, is a secondary metabolite isolated from the fungus Pleospora betae, a plant pathogen. Of the seven phytotoxins isolated in fungal leaf spots from sugar beet, it showed 73% growth inhibition.
Betaenone C, like other betaenones, is a secondary metabolite isolated from the fungus Pleospora betae, a plant pathogen. Of the seven phytotoxins isolated in fungal leaf spots from sugar beet, it showed 89% growth inhibition. Betaenone C has been shown to act by inhibiting RNA and protein synthesis.
Lacking an immune system, protective shell, or mobility, sponges have developed an ability to synthesize a variety of unusual compounds for survival. C-nucleosides isolated from Caribbean Cryptotethya crypta, were the basis for the synthesis of zidovudine (AZT), aciclovir (Cyclovir), cytarabine (Depocyt), and cytarabine derivative gemcitabine (Gemzar).
Onnamide A is a bioactive natural product found in Theonella swinhoei, a species of marine sponge whose genus is well known for yielding a diverse set of biologically active natural products, including the swinholides and polytheonamides. It bears structural similarities to the pederins, a family of compounds known to inhibit protein synthesis in eukaryotic cells. Onnamide A and its analogues have attracted academic interest due to their cytotoxicity and potential for combating the growth and proliferation of cancer cells.