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Bafilomycin AI simulator
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Bafilomycin AI simulator
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Bafilomycin
The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.
Bafilomycin A1 specifically targets the vacuolar-type H+ -ATPase (V-ATPase) enzyme, a membrane-spanning proton pump that acidifies either the extracellular environment or intracellular organelles such as the lysosome of animal cells or the vacuole of plants and fungi. At higher micromolar concentrations, bafilomycin A1 also acts on P-type ATPases, which have a phosphorylated transitional state.
Bafilomycin A1 serves as an important tool compound in many in vitro research applications; however, its clinical use is limited by a substantial toxicity profile.
Bafilomycin A1, B1 and C1 were first isolated from Streptomyces griseus in 1983. During a screen seeking to identify microbial secondary metabolites whose activity mimicked that of two cardiac glycosides, bafilomycin C1 was identified as an inhibitor of P-ATPase with a ki of 11 μM. Bafilomycin C1 was found to have activity against Caenorhabditis elegans, ticks, and tapeworms, in addition to stimulating the release of γ-aminobutyruc acid (GABA) from rat synaptosomes. Independently, bafilomycin A1 and other derivatives were isolated from S. griseus and shown to have antibiotic activity against some yeast, Gram-positive bacteria and fungi. Bafilomycin A1 was also shown to have an anti-proliferative effect on concanavalin-A-stimulated T cells. However, its high toxicity has prevented use in clinical trials.
Two years later, bafilomycins D and E were also isolated from S. griseus. In 2010, 9-hydroxy-bafilomycin D, 29-hydroxy-bafilomycin D and a number of other bafilomycins were identified from the endophytic microorganism Streptomyces sp. YIM56209. From 2004 to 2011, bafilomycins F-K were isolated from other Streptomyces sp.
As one of the first identified and most commonly used, bafilomycin A1 is of particular importance, especially as its structure serves as the core of all other bafilomycins. With its large structure, bafilomycin has multiple chiral centers and functional groups, which makes modifying its structure difficult, a task that has been attempted to reduce the compound's associated toxicity.
Within the cell, bafilomycin A1 specifically interacts with the proton pump V-ATPase. This large protein depends on Adenosine triphosphate (ATP) hydrolysis to pump protons across a biological membrane. When bafilomycin and other inhibitors of V-ATPase, such as concanamycin, were first discovered in the 1980s they were used to establish the presence of V-ATPase in specialized cells types and tissues, characterizing the proton pump's distribution. Structurally, V-ATPase consists of 13 distinct subunits that together make up the membrane spanning Vo and cytosolic V1 domains of the enzyme. The V1 domain in the cytosol is made up of subunits A through H whereas the Vo domain is made up of subunits a, d, e, c, and c".
In order to move protons across the membrane, a proton first enters subunit a within the Vo domain through a cytoplasmic hemichannel. This allows conserved glutamic acid residues within the proteolipid ring of Vo subunits c and c" to become protonated. Adenosine triphosphate (ATP) is then hydrolyzed by the V1 domain of the enzyme, enabling both the rotation of the central stalk of the pump, made up of subunits D, F and d, and the rotation of the proteolipid ring. This rotation puts the protonated glutamic acid residues in contact with a luminal hemichannel located in subunit a. Within subunit a, arginine residues serve to stabilize the deprotonated form of glutamic acid and allow the release of their protons. This rotation and proton transfer brings the protons through the pump and across the membrane.
Bafilomycin
The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.
Bafilomycin A1 specifically targets the vacuolar-type H+ -ATPase (V-ATPase) enzyme, a membrane-spanning proton pump that acidifies either the extracellular environment or intracellular organelles such as the lysosome of animal cells or the vacuole of plants and fungi. At higher micromolar concentrations, bafilomycin A1 also acts on P-type ATPases, which have a phosphorylated transitional state.
Bafilomycin A1 serves as an important tool compound in many in vitro research applications; however, its clinical use is limited by a substantial toxicity profile.
Bafilomycin A1, B1 and C1 were first isolated from Streptomyces griseus in 1983. During a screen seeking to identify microbial secondary metabolites whose activity mimicked that of two cardiac glycosides, bafilomycin C1 was identified as an inhibitor of P-ATPase with a ki of 11 μM. Bafilomycin C1 was found to have activity against Caenorhabditis elegans, ticks, and tapeworms, in addition to stimulating the release of γ-aminobutyruc acid (GABA) from rat synaptosomes. Independently, bafilomycin A1 and other derivatives were isolated from S. griseus and shown to have antibiotic activity against some yeast, Gram-positive bacteria and fungi. Bafilomycin A1 was also shown to have an anti-proliferative effect on concanavalin-A-stimulated T cells. However, its high toxicity has prevented use in clinical trials.
Two years later, bafilomycins D and E were also isolated from S. griseus. In 2010, 9-hydroxy-bafilomycin D, 29-hydroxy-bafilomycin D and a number of other bafilomycins were identified from the endophytic microorganism Streptomyces sp. YIM56209. From 2004 to 2011, bafilomycins F-K were isolated from other Streptomyces sp.
As one of the first identified and most commonly used, bafilomycin A1 is of particular importance, especially as its structure serves as the core of all other bafilomycins. With its large structure, bafilomycin has multiple chiral centers and functional groups, which makes modifying its structure difficult, a task that has been attempted to reduce the compound's associated toxicity.
Within the cell, bafilomycin A1 specifically interacts with the proton pump V-ATPase. This large protein depends on Adenosine triphosphate (ATP) hydrolysis to pump protons across a biological membrane. When bafilomycin and other inhibitors of V-ATPase, such as concanamycin, were first discovered in the 1980s they were used to establish the presence of V-ATPase in specialized cells types and tissues, characterizing the proton pump's distribution. Structurally, V-ATPase consists of 13 distinct subunits that together make up the membrane spanning Vo and cytosolic V1 domains of the enzyme. The V1 domain in the cytosol is made up of subunits A through H whereas the Vo domain is made up of subunits a, d, e, c, and c".
In order to move protons across the membrane, a proton first enters subunit a within the Vo domain through a cytoplasmic hemichannel. This allows conserved glutamic acid residues within the proteolipid ring of Vo subunits c and c" to become protonated. Adenosine triphosphate (ATP) is then hydrolyzed by the V1 domain of the enzyme, enabling both the rotation of the central stalk of the pump, made up of subunits D, F and d, and the rotation of the proteolipid ring. This rotation puts the protonated glutamic acid residues in contact with a luminal hemichannel located in subunit a. Within subunit a, arginine residues serve to stabilize the deprotonated form of glutamic acid and allow the release of their protons. This rotation and proton transfer brings the protons through the pump and across the membrane.
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