Atractyloside

Structural formula
protonated form of atractyloside, stereochemical representation
General
Surname	Atractyloside
other names	ATR
Molecular formula	C 30 H 46 O 16 S 2
External identifiers / databases
CAS number 102130-43-8 EC number 634-446-8 ECHA InfoCard 100.162.426 PubChem 442005 ChemSpider 390564 Wikidata Q640671
properties
Molar mass	726.81 g mol −1
solubility	soluble water: 20 mg ml −1 (dipotassium salt)
safety instructions
GHS labeling of hazardous substances danger H and P phrases H: 301-311-331 P: 261-280-301 + 310-311
Toxicological data	143 mg kg −1 ( LD 50 ,  rat ,  ip )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Atractylosid (ATR) is a natural, toxic glycoside and an effective inhibitor of the ATP / ADP translocator .

Occurrence

Gum spindleweed ( Atractylis gummifera ) contains atractyloside

The glycoside is synthesized by some plant species, such as Atractylis gummifera (glue thistle) from the sunflower family (Asteraceae). Other plants, also from the sunflower family, are the species Callilepis laureola , Xanthium strumarium , Iphiona aucheri , Pascalia glauca or Wedelia glauca , which are native to different parts of the world .

History

The poisonous effect of the glue thistle ( Atractylis gummifera , Syn .: Carlina gummifera ), which goes back to atractylosid, was already known in antiquity . The plant, which grows in the Mediterranean region , was therefore often used for suicides or murders . Examples of accidental poisoning are documented in Italy in 1955 and in Algeria in 1975, when children ate parts of the plant. There are also known cases of poisoning caused by incorrect dosage of traditional herbal medicine in South and North Africa.

In 1868 Ed Lefranc isolated the glycoside from the rhizome of the glue thistle. The structure was determined about 100 years later.

properties

General structural formula of atractylosid (R = H) or carboxyatractylosid (R = COOH) with partial numbering of the carbon atoms.

Atractylosid is a hydrophilic glycoside. A modified glucose is β-glycosidically linked to the hydrophobic diterpene atractyligenin, a kauran derivative. Atractyligenin is thus the aglycon . In this, a carboxy group is positioned in the axial position at the C4 position. The glucose part is esterified with isovaleric acid on the C2 'atom and with sulfuric acid on the C3' and C4 'atoms . As a result, one molecule each of D - (+) - glucose, isovaleric acid and atractyligenin and two molecules of sulfuric acid are obtained by hydrolysis . The two sulfate groups and the carboxy group in ATR are in a deprotonated form under physiological conditions. ATR is then negatively charged three times.

A modified variant of the atractyloside has an additional carboxy group on the C4 atom of the atractyligenin, it is then referred to as carboxyatractyloside (CATR), sometimes also as gummiferin . However, this is decarboxylated spontaneously or by heating after some time . This creates epi -ATR, in which the remaining carboxy group on the C4 atom is in an equatorial position. Analyzes of X-ray crystallographic recordings show that CATR bound to the ATP / ADP translocase is also present as β-glucoside.

Pharmacological properties

In biochemical studies of mitochondria , the specific effect of the glycoside on ADP / ATP transport was recognized even before the actual transporter was identified. ATR and CATR bind to the ATP / ADP translocase, which is located on the inner membrane of the mitochondrion. This binds the side of the protein that is directed towards the intermembrane space. ATR binds to the translocase competitively up to a concentration of 5 mmol and CATR in a non-competitive manner. As a result, the exchange of ADP or ATP is no longer carried out and the cell dies due to a lack of energy.

The chemical structure and the charge distribution of atractyloside is similar to that of ADP: the sulfate groups correspond to the phosphate groups, the glucose part to the ribose part and the hydrophobic atractyligenin residue to the hydrophobic purine residue of ADP.

The carboxy group on the C4 atom of atractyligenin is important for toxicity. If this is reduced to a hydroxyl group , for example (atractylitriol), the substance becomes non-toxic. When the sulfate groups are lost in ATR, it can no longer bind to the ADP / ATP translocator and thus also loses its toxic effect.

In contrast, the free hydroxyl group on the C6 'atom of the glucose part can be modified without affecting the toxicity of ATRs.

The aglycon is about 150 times less toxic than ATR, while CATR is 10 times more toxic than ATR due to its irreversible binding.

poisoning

Atractyloside and carboxyatractyloside cause gastrointestinal bleeding and liver necrosis. The mean lethal dose (LD ₅₀ ) in rats ( ip ) is 143 mg kg ⁻¹ for ATR and 2.9 mg kg ^- for CATR . In dogs ( iv ) the ATR is 15 mg kg ⁻¹ .

Similar glycosides

Structural formula of Wedeloside

Structural formula of "coffee atractyloside"

The glycoside from Wedelia asperrima , Wedelosid, is similar to ATR. The coffee plant Coffea arabica also produces an ATR-like glycoside. Roasted coffee beans contain 2- O -β- D -glucopyranosylatractyligenin, as well as its variant 2- O -β- D -glucopyranosylcarboxyatractyligenin, which is carboxylated on the C4 atom . Although the sulfate groups are absent in all cases, they also inhibit the ADP / ATP translocator with high affinity. The biological significance is not yet known. However, quantitative studies show that as a result of the roasting process, the toxic glycosides contained in coffee are completely broken down.

Individual evidence

1. ↑ ^{a b c} data sheet Atractyloside potassium salt from Sigma-Aldrich , accessed on March 9, 2011 ( PDF ).
2. ^ MJ Stewart, V. Steenkamp: The biochemistry and toxicity of atractyloside: a review. In: Ther Drug Monit . 22 (6), 2000, pp. 641-619. PMID 11128230
3. ↑ ^{a b c d e f} Roman Lang et al .: 2-O-β-D-Glucopyranosyl-carboxyatractyligenin from Coffea L. inhibits adenine nucleotide translocase in isolated mitochondria but is quantitatively degraded during coffee roasting . In: Phytochemistry . tape 93 , September 2013, p. 124-135 , doi : 10.1016 / j.phytochem.2013.03.022 , PMID 23642386 .
4. ^ R. Santi, G. Cascio: Ricerche farmacologiche sul principio attivo dell 'Atractylis gummifera. 1. Accione generale. In: Arch Ital Sci Farmacol. 5, 1955, pp. 534-563.
5. ↑ G. Lemaigre et al .: Fulminating hepatitis caused by glue thistle (Atractylis glummifera-L.), Poisoning. Anatomo-pathological study of 4 cases. In: Nouv Presse Med. 4 (40), 1975, pp. 2565-2568. PMID 1215192 .
6. ^ E. Lefranc: Sur l'acide atractylique et les atractylates, produits immédiats de la racine de l'Atractylis gummifera. In: Compt. Rend. 67, 1868, pp. 954-961.
7. ↑ F. Piozzi: inter alia: The structure and stereochemistry of atractyligenin. In: Tetrahedron. 22 (Supplement 8), 1966, pp. 515-529; doi: 10.1016 / S0040-4020 (01) 90959-7 .
8. ^ B. Danieli et al .: Structure of the diterpenoid carboxyatractyloside. In: Phytochemistry . 11 (12), 1972, pp. 3501-3504, doi: 10.1016 / S0031-9422 (00) 89846-5 .
9. ↑ PV Vignais include: Adenosine diphosphate translocation in mitochondria. Nature of the receptor site for carboxy atractyloside (gummiferin). In: Biochemistry . 12 (8), 1973, pp. 1508-1519. PMID 4699983 , doi: 10.1021 / bi00732a007 .
10. ^ M. Klingenberg: The ADP and ATP transport in mitochondria and its carrier. In: Biochim Biophys Acta 1778 (10), 2008, pp. 1978-2021. PMID 18510943 , doi: 10.1016 / j.bbamem.2008.04.011 .
11. ↑ Jean-Frédéric Sanchez et al: Unambiguous structure of atractyloside and carboxyatractyloside . In: Bioorganic & Medicinal Chemistry Letters . tape 22 , no. 8 , April 15, 2012, p. 2973-2975 , doi : 10.1016 / j.bmcl.2012.02.040 , PMID 22425567 .
12. ↑ ^{a b} P. V. Vignais et al: Effects of atractyligenin and its structural analogues on oxidative phosphorylation and on the translocation of adenine nucleotides in mitochondria. In: Biochim Biophys Acta. 118 (3), 1966, pp. 465-483. PMID 4226320 .
13. ↑ Jean-Frédéric Sanchez et al: Unambiguous structure of atractyloside and carboxyatractyloside . In: Bioorganic & Medicinal Chemistry Letters . tape 22 , no. 8 , April 15, 2012, p. 2973-2975 , doi : 10.1016 / j.bmcl.2012.02.040 , PMID 22425567 .
14. ↑ IAS Lewis et al.: The toxic extractives from wedelia asperrima — II: The structure of wedeloside, a novel diterpenoid aminoglycoside. In: Tetrahedron. 37 (24), 1981, pp. 4305-4311, doi: 10.1016 / 0040-4020 (81) 85026-0 .
15. ↑ H. Obermann, G. Spiteller: The structures of the coffee atractyloside. In: Chemical Reports. 109 (10), 1976, pp. 3450-3461, doi: 10.1002 / cber.19761091024 .

literature

• C. Dahout-Gonzalez et al: Molecular, functional, and pathological aspects of the mitochondrial ADP / ATP carrier. In: Physiology (Bethesda). 21, 2006, pp. 242-249. PMID 16868313 , doi: 10.1152 / physiol.00005.2006 .
• M. Klingenberg: The ADP and ATP transport in mitochondria and its carrier. In: Biochim Biophys Acta. 1778 (10), 2008, pp. 1978-2021. PMID 18510943 , doi: 10.1016 / j.bbamem.2008.04.011
• MJ Stewart, V. Steenkamp: The biochemistry and toxicity of atractyloside: a review. In: Ther Drug Monit. 22 (6), 2000, pp. 641-619. PMID 11128230