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Annonacin is a chemical compound with toxic effects, especially in the
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
, found in some fruits such as the paw paw, custard apples,
soursop Soursop (also called ''graviola, guyabano'', and in Hispanic America, ''guanábana'') is the fruit of ''Annona muricata'', a broadleaf, flowering, evergreen tree. It is native to the tropical regions of the Americas and the Caribbean and is wi ...
, and others from the family ''
Annonaceae The Annonaceae are a family of flowering plants consisting of trees, shrubs, or rarely lianas commonly known as the custard apple family or soursop family. With 108 accepted genera and about 2400 known species, it is the largest family in the Ma ...
''. It is a member of the class of compounds known as
acetogenin 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, ketones, epoxides, tetrahydro ...
s. Annonacin-containing fruit products are regularly consumed throughout the
West Indies The West Indies is a subregion of North America, surrounded by the North Atlantic Ocean and the Caribbean Sea that includes 13 independent island countries and 18 dependencies and other territories in three major archipelagos: the Greate ...
for their
traditional medicine Traditional medicine (also known as indigenous medicine or folk medicine) comprises medical aspects of traditional knowledge that developed over generations within the folk beliefs of various societies, including indigenous peoples, before the ...
uses.


Traditional medicine

Historically, plants and fruits of Annonaceae (particularly ''
Annona muricata Soursop (also called ''graviola, guyabano'', and in Hispanic America, ''guanábana'') is the fruit of ''Annona muricata'', a broadleaf, flowering, evergreen tree. It is native to the tropical regions of the Americas and the Caribbean and is wi ...
'' and '' Annona squamosa'') have been consumed in various forms throughout the West Indies, usually as hot water extracts of leaves.Ross, I. A. (2003). Annona muricata L. Medicinal Plants of the World, Vol. 1: Chemical Constituents, Traditional and Modern Medicinal Uses,1, 133-142. These annonacin-containing herbal teas are thought to be useful in
folk medicine Traditional medicine (also known as indigenous medicine or folk medicine) comprises medical aspects of traditional knowledge that developed over generations within the folk beliefs of various societies, including indigenous peoples, before the ...
. On the Caribbean island of
Guadeloupe Guadeloupe (; ; gcf, label= Antillean Creole, Gwadloup, ) is an archipelago and overseas department and region of France in the Caribbean. It consists of six inhabited islands— Basse-Terre, Grande-Terre, Marie-Galante, La Désirade, and ...
, such teas are consumed mainly for their sedative qualities. Use of annonacin products in Guadeloupe often lasts from early childhood through old age, and daily consumption is not uncommon. It was discovered in Guadeloupe that atypical Parkinsonism was predominant in elderly males, who regularly consume annonacin-containing herbal teas. Of 87 people with Parkinsonism transferred to one clinic between 1996 and 1998, 25% had Parkinson's, while 36% had progressive supranuclear palsy and 39% had atypical Parkinsonism.Caparros-Lefebvre, D., & Elbaz, A. (1999). Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plants: a case-control study. The Lancet, 354(9175), 281-286.


Neurotoxicity

Annonacin is a disabling and potentially lethal
neurotoxin Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature nerv ...
. Like other acetogenins, it is a mitochondrial complex I (
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
-dehydrogenase) inhibitor. As NADH-dehydrogenase is responsible for the conversion of
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
to NAD+ as well as the establishment of a proton gradient in the mitochondria, annonacin disables the ability of a cell to generate ATP through oxidative phosphorylation, leading to cell
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
or
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...
. The
LC50 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 ...
of annonacin is 0.018 μM to dopaminergic neurons, and it is the damage done to these neurons that results in the neurodegenerative effects of the toxin. Annonacin is 100 times more toxic than
1-methyl-4-phenylpyridinium MPP+ (1-methyl-4-phenylpyridinium) is a positively charged organic molecule with the chemical formula C12H12N+. It is a neurotoxin that acts by interfering with oxidative phosphorylation in mitochondria by inhibiting complex I, leading to the de ...
(MPP+), another potent mitochondrial complex I inhibitor. Compared to MPP+, annonacin produces a wider and more dramatic loss of neurons, not only in the nigro-striatal system, but in the
basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...
and
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...
nuclei as well. Annonacin has been linked to the abnormally high incidence of
progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a late-onset degenerative disease involving the gradual deterioration and death of specific volumes of the brain. The condition leads to symptoms including loss of balance, slowing of movement, difficulty ...
as well as atypical Parkinsonism in the Caribbean island of Guadeloupe where consumption of fruits such as the
soursop Soursop (also called ''graviola, guyabano'', and in Hispanic America, ''guanábana'') is the fruit of ''Annona muricata'', a broadleaf, flowering, evergreen tree. It is native to the tropical regions of the Americas and the Caribbean and is wi ...
(''Annona muricata'') is common. An average-sized soursop fruit contains 15 mg of annonacin, while a can of commercial nectar contains 36 mg and a cup of infusion, 140 μg. Studies in rodents indicate that consumption of annonacin (3.8 and 7.6 mg per kg per day for 28 days) caused brain lesions consistent with
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...
. An adult who consumes a fruit or can of nectar daily over the course of a year is estimated to ingest the same amount of annonacin that induced brain lesions in the rodents receiving purified annonacin intravenously.


Biosynthesis

Based on basic polyketide synthesis, the biosynthesis of annonacin is likely accomplished by a modular
polyketide synthase Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene groups: (-CO-CH2-). First studied in the early 20th century, discovery, biosynth ...
(PKS). The biosynthesis likely involves the use of 17 modules consisting of a number of enzymes commonly found in PKS. These include the
acyl carrier protein The acyl carrier protein (ACP) is a cofactor of both fatty acid and polyketide Polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone (or reduced forms of a ketone) and methylene ...
(ACP), acetyl transferase (AT),
ketosynthase Ketoacyl synthases (KSs) catalyze the condensation reaction of acyl-CoA or acyl-acyl ACP with malonyl-CoA to form 3-ketoacyl-CoA or with malonyl-ACP to form 3-ketoacyl-ACP. This reaction is a key step in the fatty acid synthesis cycle, as the result ...
(KS), malonyl transferase (MT; which can come carrying a variety of functionalities), ketoreductase (KR),
dehydratase Dehydratases are a group of lyase enzymes that form double and triple bonds in a substrate through the removal of water. They can be found in many places including the mitochondria, peroxisome and cytosol. There are more than 150 different dehydrat ...
(DH), and enoyl reductase (ER). An example of the possible modular biosynthetic pathway detailing the combination of these enzymes and the subsequent modules can be seen in the figure below.


References

{{reflist, 30em Furanones Tetrahydrofurans Polyols Polyketides Neurotoxins NADH dehydrogenase inhibitors Respiratory toxins Plant toxins