Hypoglycin A is a naturally occurring
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
derivative found in the unripened fruit of the
Ackee
The ackee, also known as ankye, achee, akee, ackee apple or ayee (''Blighia sapida'') is a fruit of the Sapindaceae ( soapberry) family, as are the lychee and the longan. It is native to tropical West Africa. The scientific name honours Captain ...
tree (''
Blighia sapida'')
and in the seeds of the box elder tree (''
Acer negundo'').
It is toxic if ingested, and is the causative agent of
Jamaican vomiting sickness.
A 2017 Lancet report established a link between the consumption of unripened lychees (containing hypoglycin A or methylenecyclopropylglycine (MCPG)) resulting in hypoglycaemia and death from acute toxic encephalopathy.
Sources
The entirety of the unripe Ackee fruit is toxic and contains large amounts of hypoglycin. The fruit is safe to eat only when the fruit is allowed to fully open and expose the large black seeds while on the tree. The levels of the toxin decrease over time though from approximately 1000 ppm to around 0.1 ppm in the mature fruit.
Relatives of Ackee, including
lychee
Lychee (US: ; UK: ; ''Litchi chinensis''; ) is a monotypic taxon and the sole member in the genus ''Litchi'' in the soapberry family, ''Sapindaceae''.
It is a tropical tree native to Southeast and Southwest China (the Guangdong, Fujian, Yun ...
,
longan
''Dimocarpus longan'', commonly known as the longan () and dragon's eye, is a tropical tree species that produces edible fruit. It is one of the better-known tropical members of the soapberry family Sapindaceae, to which the lychee and rambu ...
, and
rambutan
Rambutan (; taxonomic name: ''Nephelium lappaceum'') is a medium-sized tropical tree in the family Sapindaceae. The name also refers to the edible fruit produced by this tree. The rambutan is native to Southeast Asia. It is closely related to s ...
, can contain enough α-(methylenecyclopropyl)glycine, a
homologue of hypoglycin A, in their fruit to cause
hypoglycemic encephalopathy
Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...
in undernourished children, when consumed in large quantities.
Toxicity
Hypoglycin A is a
protoxin
Toxication, toxification or toxicity exaltation is the conversion of a chemical compound into a more toxic form in living organisms or in substrates such as soil or water. The conversion can be caused by enzymatic metabolism in the organisms, as we ...
, meaning that the molecule is not toxic in itself but is broken down into toxic products when ingested. The
branched-chain alpha-keto acid dehydrogenase complex
The branched-chain α-ketoacid dehydrogenase complex (BCKDC or BCKDH complex) is a multi-subunit complex of enzymes that is found on the mitochondrial inner membrane. This enzyme complex catalyzes the oxidative decarboxylation of branched, short-c ...
, that normally converts
leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- ...
,
isoleucine, or
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
into
acyl-CoA derivatives, converts Hypoglycin A into highly toxic
MCPA
MCPA (2-methyl-4-chlorophenoxyacetic acid) is a powerful, selective, widely used phenoxy herbicide. The pure compound is a brown-colored powder. MCPA has been extensively used in agriculture to control broad-leaf weeds as a growth regulator prima ...
-
CoA. The
FAD
A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period.
Fads are objects or behaviors that achieve short- ...
cofactor necessary for the
beta oxidation
In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cyc ...
of
fatty acids
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
associates with the alpha carbon of MCPA-CoA creating an irreversible complex that disables the enzyme. In addition, MCPA-CoA blocks some enzymes that are required for
gluconeogenesis.
[
The reduction in gluconeogenesis and the reduction in fatty acid oxidation are thought to be the cause of most of the symptoms of Jamaican vomiting sickness. The blocking of fatty acid metabolism causes cells to start using glycogen for energy. Once glycogen is depleted, the body is unable to produce more, which leads to severe hypoglycemia. These biochemical effects are detected by an excess of medium chain fatty acids in urine and ]acidosis
Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma.
The term ''acidemia'' describes ...
. Key treatments are aimed at circumventing or counteracting the biochemical changes, and include IV fluids and glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
, and hemodialysis
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
in the case of renal failure
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
.
Synthesis
In 1958, John Carbon, William Martin, and Leo Swett were the first to synthesize hypoglycin A, in racemic
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
form, starting from 2-bromopropene and ethyl diazoacetate
Ethyl diazoacetate (N=N=CHC(O)OC2H5) is a diazo compound and a reagent in organic chemistry. It was discovered by Theodor Curtius in 1883. The compound can be prepared by reaction of the ethyl ester of glycine with sodium nitrite and sodium aceta ...
to form the cyclopropane ring.
In 1992, Jack Baldwin, Robert Adlington, David Bebbington, and Andrew Russell accomplished the first asymmetric total synthesis of the individual diastereoisomers of hypoglycin A, using the Sharpless epoxidation
The Sharpless epoxidation reaction is an enantioselective chemical reaction to prepare 2,3-epoxyalcohols from primary and secondary allylic alcohols. The oxidizing agent is ''tert''-butyl hydroperoxide. The method relies on a catalyst formed fro ...
to permit an asymmetric methylene cyclopropane synthesis. 1H NMR and circular dichroism studies identifies the major diastereoisomer of natural hypogycin A as (2''S'', 4''R'') and the minor diastereoisomer as (2''S'', 4''S'').
See also
* Hypoglycin B
References
{{reflist
Amino acids
Cyclopropanes
Toxic amino acids
Plant toxins