Pumiliotoxin 251D
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Pumiliotoxin 251D is a toxic organic compound. It is found in the skin of poison frogs from the genera ''
Dendrobates ''Dendrobates'' is a genus of poison dart frogs native to Central and South America. It once contained numerous species, but most originally placed in this genus have been split off into other genera such as ''Adelphobates'', '' Ameerega'', '' A ...
'', ''
Epipedobates ''Epipedobates'' is a genus of poison dart frogs native to northern South America (Colombia and Ecuador) west of the Andes, including the western slopes. Common name phantasmal poison frogs has been suggested for the genus. Taxonomy ''Epipedoba ...
'', '' Minyobates'', and ''
Phyllobates ''Phyllobates'' is a genus of poison dart frogs native to Central and South America, from Nicaragua to Colombia. There are 3 different Colombian species of ''Phyllobates'', considered highly toxic species due to the poison they contain in the wil ...
'' and toads from the genus '' Melanophryniscus''. Its name comes from the pumiliotoxin family (PTXs) and its molecular mass of 251 Daltons. When the toxin enters the bloodstream through cuts in the skin or by ingestion, it can cause
hyperactivity Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
,
convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a s ...
s,
cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
and ultimately death. It is especially toxic to
arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
s (e.g. mosquitoes), even at low (naturally occurring) concentrations.


Chemical properties


Structure

The chiral centers in pumiliotoxin 251D can give several stereoisomers of the compound. Only one form of the toxin is present in nature and has toxic properties. Two
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
s of pumiliotoxin 251D. On the left the plus enantiomer is shown which is toxic. On the right side the minus enantiomer, which is not toxic, is shown. The side chain conformation of substituents at the C-2’ position plays an important role in the toxicity of the compound.


Synthesis

The synthesis of pumiliotoxin 251D is quite complex and contains multiple steps. One of the starting materials of the synthesis include the N-Boc derivative of L-proline methyl ester (1). Then, a Wittig type of reaction followed by dehydration with thionyl chloride and pyridine results in alkene 2. When alkene 2 undergoes epoxidation with m-chloroperbenzoic acid (MCPBA), epoxide 3 is formed. This then reacts with the lithium salt of dibromoalkene (6) to afford compound 7. Deprotection of compound 7 followed by cyclization and iodination results in vinyl iodide 8. After purification, this yields the hydrochloride of pumiliotoxin (+)-251D (9). Pumiliotoxin (−)-251D can be synthesized in a similar way with minor alterations to the overall synthesis.


Accumulation

Like many other frog poisons, pumiliotoxin 251D originates from
arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
s. The frogs have a diet of
insect Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three pairs ...
s that could contain the toxin then it is accumulated in secretory granular glands of the skin of the frog. Some frog species of the Dendrobates genera can convert pumiliotoxin 251D in allopumiliotoxin 267A which is five times more toxic than pumiliotoxin 251D. Only one of the enantiomers can be hydroxylated to this more potent form of the toxin. The lack of pumiliotoxin 251D in eggs and tadpoles confirms that the toxin is not passed over from adult frogs to their offspring. The tadpoles are therefore not readily protected from predators.


Toxicity


Mechanism of action

In general, pumiliotoxins are known as positive modulators of
voltage-gated sodium channels Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
(VGSCs,
membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
s). Pumiliotoxin 251D is not such a poison. However, it does block the influx of Na+ ions in mammalian VGSCs. Pumiliotoxin 251D is able to shift the V1/2. This is the potential at which the sodium open probability is half maximal. Both the steady-state activation and inactivation curves of each mammalian VGSCs are shifted to a more negative potential. PTX 251D shifts the V1/2 of insect VGSCs even further than the mammalian VSGCs. This explains why it is especially toxic to insects, like mosquitoes. Furthermore, the presence of PTX 251D results in a six time higher permeability of the VGSCs for K+ ions. This severely disturbs the delicate sodium-potassium equilibrium in the nerve system. The effect of pumiliotoxin 251D on the
voltage-gated potassium channels Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized ce ...
(VGPCs) currents is quite small. The toxic has an effect on the deactivation kinetics of the potassium channel. It inhibits its inactivation. This effect is still under investigation. PTX 251D also completely inhibits the activity of Ca2+-stimulated
ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
. This results in a decreased reuptake of Ca2+ and thus a high concentration of free Ca2+ in the organism. This may be related to the
potentiation In clinical terms, a potentiator is a reagent that enhances sensitization of an antigen. Potentiators are used in the clinical laboratory for performing blood banking procedures that require enhancement of Agglutination (biology), agglutination to ...
and
prolongation In music theory, prolongation is the process in tonal music through which a pitch, interval, or consonant triad is considered to govern spans of music when not physically sounding. It is a central principle in the music-analytic methodology of ...
of muscle twitch caused by the inhibition. The mechanism of
biotransformation Biotransformation is the biochemical modification of one chemical compound or a mixture of chemical compounds. Biotransformations can be conducted with whole cells, their lysates, or purified enzymes. Increasingly, biotransformations are effected w ...
of PTX 251D is still unknown.


Effects

Pumiliotoxin is a toxin found in poison dart frogs (genus Dendrobates and Phyllobates). It affects the calcium channels, interfering with muscle contraction in the heart and skeletal muscle. PTX 251D has several effects. It rapidly induces convulsions and death to mice and insects (
LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...
being, respectively, 10 mg/kg and 150 ng/larvae). These convulsions are the result of the uncontrollable distortion of the sodium-potassium equilibrium in the
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s. This is caused by the inhibition of the VGSCs. It also acts as cardiac depressor, causing cardiac arrest. This can be explained by its negative effect on the cardiac VGSC hNav1.5/β1. Although nothing is known of how well PTX 251D penetrates into the brain where convulsions are originated, the observation of convulsions can be explained through inhibition of VGPCs.


Treatment

Symptomatic treatment of PTX 251D poisoning include reducing the convulsions using
carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...
. This drug targets the affected VGSCs.
Phenobarbital Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
also shows positive effects by interacting with the affected Ca2+ channels. Ineffective drugs include
diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
and
dizocilpine Dizocilpine (INN), also known as MK-801, is a pore blocker of the ''N''-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is ...
.


References

{{Poison frog alkaloids Vertebrate toxins Alkaloids Ion channel toxins Indolizidines Tertiary alcohols