Thapsigargin
Encyclopedia
Thapsigargin is non-competitive
inhibitor
of a class of enzyme
s known by the acronym SERCA
, which stands for sarco / endoplasmic reticulum
Ca2+
ATPase
. Structurally, thapsigargin is classified as a sesquiterpene lactone
, and is extracted from a plant, Thapsia garganica. It is a tumor promoter in mammalian cells. The anti-malarial drug artemisinin
is also a sesquiterpene lactone, leading to a proposal that this class of drugs works by inhibiting the SERCA of malaria parasites such as Plasmodium falciparum
; this hypothesis awaits confirmation.
Thapsigargin raises cytosol
ic calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula which causes these stores to become depleted. Store-depletion can secondarily activate plasma membrane calcium channel
s, allowing an influx of calcium into the cytosol.
Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations.
Potential medical uses of thapsigargin
Thapsigargin is mentioned as a possible treatment for posterior capsular opacification.
. The first step, I, is controlled by the enzyme germacrene B synthase. For step II, the C(8) position is easily activated for an allylic oxidation due to the position of the double bond. The next step is the addition of the acyloxy moiety by a P450 acetyltransferase; which is a well known reaction for the synthesis of the diterpene, taxol. In step III, the lactone
ring is formed by a cytochrome P450 enzyme using NADP+. With the butyloxy group on the C(8), the formation will only generate the 6,12-lactone
ring. Step IV is an epoxidation that initiates the last step of the base guaianolide formation. In step V, a P450 enzyme closes the 5 + 7 guaianolide structure. The ring closing is important, because it will proceed via 1,10 - epoxidation in order to retain the 4,5 - double bond needed in thapsigargin. It is not known whether the secondary modifications to the guaianolide occur before, or after the formation of thapsigargin, but will need to be considered when elucidating the true biosynthesis. It should also be noted, that several of these enzymes are P450's, therefore oxygen and NADPH are likely crucial to this biosynthesis as well as other cofactors
such as Mg2+ and Mn2+ may be needed.
Non-competitive inhibition
Non-competitive inhibition is a type of enzyme inhibition where the inhibitor reduces the activity of the enzyme, by binding not to the active site on the enzyme, but to a different site...
inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of a class of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s known by the acronym SERCA
SERCA
SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase.-Function:SERCA resides in the sarcoplasmic reticulum within muscle cells...
, which stands for sarco / endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
ATPase
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
. Structurally, thapsigargin is classified as a sesquiterpene lactone
Sesquiterpene lactone
Sesquiterpene lactones are a class of chemical compounds; they are sesquiterpenoids and contain a lactone ring, hence the name....
, and is extracted from a plant, Thapsia garganica. It is a tumor promoter in mammalian cells. The anti-malarial drug artemisinin
Artemisinin
Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...
is also a sesquiterpene lactone, leading to a proposal that this class of drugs works by inhibiting the SERCA of malaria parasites such as Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
; this hypothesis awaits confirmation.
Thapsigargin raises cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
ic calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula which causes these stores to become depleted. Store-depletion can secondarily activate plasma membrane calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
s, allowing an influx of calcium into the cytosol.
Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations.
Potential medical uses of thapsigargin
Thapsigargin is mentioned as a possible treatment for posterior capsular opacification.
Biosynthesis
The complete biosynthesis of thapsigargin has yet to be elucidated. A proposed biosynthetic pathway is shown below. The biosynthesis starts with the common terpene farnesyl pyrophosphateFarnesyl pyrophosphate
Farnesyl pyrophosphate is an intermediate in the HMG-CoA reductase pathway used by organisms in the biosynthesis of terpenes, terpenoids, and sterols...
. The first step, I, is controlled by the enzyme germacrene B synthase. For step II, the C(8) position is easily activated for an allylic oxidation due to the position of the double bond. The next step is the addition of the acyloxy moiety by a P450 acetyltransferase; which is a well known reaction for the synthesis of the diterpene, taxol. In step III, the lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
ring is formed by a cytochrome P450 enzyme using NADP+. With the butyloxy group on the C(8), the formation will only generate the 6,12-lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
ring. Step IV is an epoxidation that initiates the last step of the base guaianolide formation. In step V, a P450 enzyme closes the 5 + 7 guaianolide structure. The ring closing is important, because it will proceed via 1,10 - epoxidation in order to retain the 4,5 - double bond needed in thapsigargin. It is not known whether the secondary modifications to the guaianolide occur before, or after the formation of thapsigargin, but will need to be considered when elucidating the true biosynthesis. It should also be noted, that several of these enzymes are P450's, therefore oxygen and NADPH are likely crucial to this biosynthesis as well as other cofactors
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
such as Mg2+ and Mn2+ may be needed.
External links
- Thapsigargin product page from FermentekFermentekFermentek Ltd. is a biotechnological company, located in Atarot industrial zone, Jerusalem, Israel, specializing in the research, development and manufacture of biologically active, natural products isolated from microorganisms as well as from other natural sources such as plants and algae.The main...
.