Hypoglycin A

Hypoglycin
Names
	IUPAC name 3-[(1R-2-Methylidenecyclopropyl]-L-alanine
	Systematic IUPAC name (2S)-2-Amino-3-[(1R)-2-methylidenecyclopropyl]propanoic acid
	Other names Hypoglycin A; Hypoglycine; 2-Methylenecyclopropanylalanine
Identifiers
CAS Number	156-56-9 ;
3D model (JSmol)	Interactive image ;
ChEMBL	ChEMBL1615355 ;
ChemSpider	9943349 ;
ECHA InfoCard	100.189.936
PubChem CID	11768666 ;
UNII	7GB7U7M282 ;
CompTox Dashboard (EPA)	DTXSID70878975 ;
	InChI InChI=1S/C7H11NO2/c1-4-2-5(4)3-6(8)7(9)10/h5-6H,1-3,8H2,(H,9,10)/t5-,6+/m1/s1 Key: OOJZCXFXPZGUBJ-RITPCOANSA-N ; InChI=1/C7H11NO2/c1-4-2-5(4)3-6(8)7(9)10/h5-6H,1-3,8H2,(H,9,10)/t5-,6+/m1/s1 Key: OOJZCXFXPZGUBJ-RITPCOANBH;
	SMILES O=C(O)[C@@H](N)C[C@@H]1C(=C)C1;
Properties
Chemical formula	C7H11NO2
Molar mass	141.170 g·mol−1
Melting point	282 °C (540 °F; 555 K)
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

Last updated November 28, 2023

Hypoglycin A is a naturally occurring amino acid derivative found in the unripened fruit of the Ackee tree ( Blighia sapida )^[1] and in the seeds of the box elder tree ( Acer negundo ).^[2] It is toxic if ingested, and is the causative agent of Jamaican vomiting sickness.^[1] 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.^[3]

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.^[4]

Relatives of Ackee, including lychee, longan, and rambutan, can contain enough α-(methylenecyclopropyl)glycine, a homologue of hypoglycin A, in their fruit to cause hypoglycemic encephalopathy in undernourished children, when consumed in large quantities.^[5]

Toxicity

Hypoglycin A is a protoxin, 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, that normally converts leucine, isoleucine, or valine into acyl-CoA derivatives, converts Hypoglycin A into highly toxic MCPA-CoA. The FAD cofactor necessary for the beta oxidation of fatty acids 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.^[4]

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. Key treatments are aimed at circumventing or counteracting the biochemical changes, and include IV fluids and glucose, and hemodialysis in the case of renal failure.^[6]

Synthesis

In 1958, John Carbon, William Martin, and Leo Swett were the first to synthesize hypoglycin A, in racemic form, starting from 2-bromopropene and ethyl diazoacetate to form the cyclopropane ring.^[7]

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 to permit an asymmetric methylene cyclopropane synthesis.^[8]^[9]¹H NMR and circular dichroism studies identifies the major diastereoisomer of natural hypogycin A as (2S, 4R) and the minor diastereoisomer as (2S, 4S).

Related Research Articles

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Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH⁺₃ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO⁻ form under biological conditions), and a hydrocarbon side chain with a branch (a central carbon atom bound to three other carbon atoms). It is classified as a non-polar, uncharged (at physiological pH), branched-chain, aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it. Essential amino acids are necessary in our diet. In plants isoleucine can be synthesized from threonine and methionine. In plants and bacteria, isoleucine is synthesized from pyruvate employing leucine biosynthesis enzymes. It is encoded by the codons AUU, AUC, and AUA.

Lychee is a monotypic taxon and the sole member in the genus Litchi in the soapberry family, Sapindaceae.

Glycogen storage disease type V, also known as McArdle's disease, is a metabolic disorder, one of the metabolic myopathies, more specifically a muscle glycogen storage disease, caused by a deficiency of myophosphorylase. Its incidence is reported as one in 100,000, roughly the same as glycogen storage disease type I.

<span class="mw-page-title-main">Glycogen storage disease</span> Medical condition

A glycogen storage disease is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells.

The ackee, also known as acki, akee, or ackee apple, 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 William Bligh who took the fruit from Jamaica to the Royal Botanic Gardens in Kew, England, in 1793. The English common name is derived from the West African Akan akye fufo.

<span class="mw-page-title-main">Sapindaceae</span> Family of flowering plants

The Sapindaceae are a family of flowering plants in the order Sapindales known as the soapberry family. It contains 138 genera and 1,858 accepted species. Examples include horse chestnut, maples, ackee and lychee.

Cyclopropene is an organic compound with the formula C₃H₄. It is the simplest cycloalkene. Because the ring is highly strained, cyclopropene is difficult to prepare and highly reactive. This colorless gas has been the subject for many fundamental studies of bonding and reactivity. It does not occur naturally, but derivatives are known in some fatty acids. Derivatives of cyclopropene are used commercially to control ripening of some fruit.

Alcoholic ketoacidosis (AKA) is a specific group of symptoms and metabolic state related to alcohol use. Symptoms often include abdominal pain, vomiting, agitation, a fast respiratory rate, and a specific "fruity" smell. Consciousness is generally normal. Complications may include sudden death.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

In endurance sports such as road cycling and long-distance running, hitting the wall or the bonk is a condition of sudden fatigue and loss of energy which is caused by the depletion of glycogen stores in the liver and muscles. Milder instances can be remedied by brief rest and the ingestion of food or drinks containing carbohydrates. Otherwise, it can remedied by attaining second wind by either resting for approximately 10 minutes or by slowing down considerably and increasing speed slowly over a period of 10 minutes. Ten minutes is approximately the time that it takes for free fatty acids to sufficiently produce ATP in response to increased demand.

Jamaican vomiting sickness, also known as toxic hypoglycemic syndrome (THS), acute ackee fruit intoxication, or ackee poisoning, is an acute illness caused by the toxins hypoglycin A and hypoglycin B, which are present in fruit of the ackee tree. While in the fully ripened arils, hypoglycin A is at levels of less than 0.1 ppm, in unripe arils it can be over 1000 ppm and can cause vomiting and even death. Some countries in the Caribbean and Western Africa experience frequent cases.

Hypoglycin B is a naturally occurring organic compound in the species Blighia sapida. It is particularly concentrated in the fruit of the plant especially in the seeds. Hypoglycin B is toxic if ingested and is one of the causative agents of Jamaican vomiting sickness. It is a dipeptide of glutamic acid and hypoglycin A.

Cyclopropane fatty acids (CPA) are a subgroup of fatty acids that contain a cyclopropane group. Although they are usually rare, the seed oil from lychee contains nearly 40% CPAs in the form of triglycerides.

Acute fatty liver of pregnancy is a rare life-threatening complication of pregnancy that occurs in the third trimester or the immediate period after delivery. It is thought to be caused by a disordered metabolism of fatty acids by mitochondria in the fetus, caused by long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. This leads to decreased metabolism of long chain fatty acids by the feto-placental unit, causing subsequent rise in hepatotoxic fatty acids in maternal plasma. The condition was previously thought to be universally fatal, but aggressive treatment by stabilizing the mother with intravenous fluids and blood products in anticipation of early delivery has improved prognosis.

Malvalic acid is a cyclopropene fatty acid found in baobab seed oil and cottonseed oil. The cyclopropene ring is thought to be one of the causes of abnormalities that develop in animals that ingest cottonseed oil. Refining processes, such as hydrogenation, can remove or destroy malvalic acid.

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Methylene cyclopropyl acetic acid (MCPA) is found in lychee seeds and also a toxic metabolite in mammalian digestion after eating hypoglycin, present in the unripe ackee fruit, grown in Jamaica and in Africa. By blocking coenzyme A and carnitine, MPCA causes a decrease in β-oxidation of fatty acids, and hence gluconeogenesis.

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References

1 2 "Ackee Fruit Toxicity". Medscape . 2018-06-13.
↑ Valberg, S. J.; Sponseller, B. T.; Hegeman, A. D.; Earing, J.; Bender, J. B.; Martinson, K. L.; Patterson, S. E.; Sweetman, L. (2013-07-01). "Seasonal pasture myopathy/atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree". Equine Veterinary Journal. 45 (4): 419–426. doi: 10.1111/j.2042-3306.2012.00684.x . ISSN 2042-3306. PMID 23167695. S2CID 206002430.
↑ Shrivastava, Aakash (2017). "Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study". The Lancet Global Health. 5 (4): e458–e466. doi: 10.1016/S2214-109X(17)30035-9 . PMID 28153514.
1 2 "THE ACKEE FRUIT (BLIGHIA SAPIDA) AND ITS ASSOCIATED TOXIC EFFECTS". University of British Columbia. 2005-11-17.
↑ Spencer, P. S.; Palmer, V. S.; Mazumder, R. (2015), "Probable Toxic Cause for Suspected Lychee-Linked Viral Encephalitis", Emerging Infectious Diseases , 21 (5): 904–5, doi:10.3201/eid2105.141650, PMC 4412228 , PMID 25897979
↑ "Hypoglycin". TOXNET.
↑ Carbon, J. A.; Martin, W. B.; Swett, L. R. (1958), "SYNTHESIS OF α-AMINO- METHYLENECYCLOPROPANEPROPIONIC ACID (HYPOGLYCIN A)", J. Am. Chem. Soc. , 80 (4): 1002, doi:10.1021/ja01537a066
↑ Baldwin, Jack E.; Adlington, Robert M.; Bebbington, David; Russell, Andrew T. (1992). "Asymmetric total synthesis of the individual diastereoisomers of hypoglycin A". Journal of the Chemical Society, Chemical Communications (17): 1249. doi:10.1039/c39920001249. ISSN 0022-4936.
↑ Baldwin, Jack E.; Adlington, Robert M.; Bebbington, David; T. Russell, Andrew (1994). "Asymmetric total synthesis of the individual diastereoisomers of hypoglycin A.". Tetrahedron. 50 (41): 12015–12028. doi:10.1016/s0040-4020(01)89313-3. ISSN 0040-4020.

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[medscape-1] 1 2 "Ackee Fruit Toxicity". Medscape . 2018-06-13.

[Valberg2013-2] Valberg, S. J.; Sponseller, B. T.; Hegeman, A. D.; Earing, J.; Bender, J. B.; Martinson, K. L.; Patterson, S. E.; Sweetman, L. (2013-07-01). "Seasonal pasture myopathy/atypical myopathy in North America associated with ingestion of hypoglycin A within seeds of the box elder tree". Equine Veterinary Journal. 45 (4): 419–426. doi: 10.1111/j.2042-3306.2012.00684.x . ISSN 2042-3306. PMID 23167695. S2CID 206002430.

[3] Shrivastava, Aakash (2017). "Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study". The Lancet Global Health. 5 (4): e458–e466. doi: 10.1016/S2214-109X(17)30035-9 . PMID 28153514.

[scq-4] 1 2 "THE ACKEE FRUIT (BLIGHIA SAPIDA) AND ITS ASSOCIATED TOXIC EFFECTS". University of British Columbia. 2005-11-17.

[EID-5] Spencer, P. S.; Palmer, V. S.; Mazumder, R. (2015), "Probable Toxic Cause for Suspected Lychee-Linked Viral Encephalitis", Emerging Infectious Diseases , 21 (5): 904–5, doi:10.3201/eid2105.141650, PMC 4412228 , PMID 25897979

[nih-6] "Hypoglycin". TOXNET.

[NAME_HERE-7] Carbon, J. A.; Martin, W. B.; Swett, L. R. (1958), "SYNTHESIS OF α-AMINO- METHYLENECYCLOPROPANEPROPIONIC ACID (HYPOGLYCIN A)", J. Am. Chem. Soc. , 80 (4): 1002, doi:10.1021/ja01537a066

[8] Baldwin, Jack E.; Adlington, Robert M.; Bebbington, David; Russell, Andrew T. (1992). "Asymmetric total synthesis of the individual diastereoisomers of hypoglycin A". Journal of the Chemical Society, Chemical Communications (17): 1249. doi:10.1039/c39920001249. ISSN 0022-4936.

[9] Baldwin, Jack E.; Adlington, Robert M.; Bebbington, David; T. Russell, Andrew (1994). "Asymmetric total synthesis of the individual diastereoisomers of hypoglycin A.". Tetrahedron. 50 (41): 12015–12028. doi:10.1016/s0040-4020(01)89313-3. ISSN 0040-4020.

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