Asparagusic acid

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Asparagusic acid[1]
Asparagusic acid
Asparagusic acid
Names
IUPAC name
1,2-Dithiolane-4-carboxylic acid
Other names
1,2-Dithiacyclopentane-4-carboxylic acid
Identifiers
2224-02-4 YesY
ChEBI CHEBI:18091 YesY
ChemSpider 15819 YesY
Jmol 3D model Interactive image
KEGG C01892 YesY
PubChem 16682
UNII VAD3XV509R N
Properties
C4H6O2S2
Molar mass 150.21 g·mol−1
Appearance Colorless solid
Density 1.50 g cm−3
Melting point 75.7 to 76.5 °C (168.3 to 169.7 °F; 348.8 to 349.6 K)[2]
Boiling point 323.9 °C (615.0 °F; 597.0 K) at 760mmHg
Hazards
Flash point 149.7 °C (301.5 °F; 422.8 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Asparagusic acid is an organosulfur compound with the molecular formula C4H6O2S2 and is systematically named 1,2-dithiolane-4-carboxylic acid. The molecule consists of a cyclic disulfide functional group (a 1,2-dithiolane) with a carboxylic acid side chain. It is found in asparagus and is believed to be the metabolic precursor to odorous sulfur compounds responsible for the distinctive smell of urine which has long been associated with eating asparagus.[3][4]

Isolation and biosynthesis[edit]

The material was originally isolated from an aqueous extract of Asparagus officinalis, a spring vegetable.[5] It is a derivative of the cyclic disulfide organic compound 1,2-dithiolane with a carboxylic acid functional group bound to carbon-4 of the heterocycle. Biosynthetic studies revealed that asparagusic acid is derived from isobutyric acid.[6] Asparagusic acid is a colorless solid with a melting point of 75.7–76.5 °C,[2] higher than that of the corresponding dithiol, dihydroasparagusic acid (or γ,γ-dimercaptoisobutyric acid), at 59.5–60.5 °C.[7]

Laboratory synthesis[edit]

A convenient synthesis of asparagusic acid has been developed from a commercially-available diethyl malonate derivative starting material, improving on the prior method of Jansen.[5] Diethyl bis(hydroxymethyl)malonate is treated with hydroiodic acid to yield β,β'-diiodoisobutyric acid after decarboxylation and ester hydrolysis (with removal of volatile ethanol and carbon dioxide). Dihydroasparagusic acid, the reduced (dithiol) form of asparagusic acid, is produced by sequential reaction with sodium trithiocarbonate (Na2CS3) and sulfuric acid; subsequent oxidation with hot dimethyl sulfoxide yields asparagusic acid.[1]

Synthesis of asparagusic acid.png

Effect on urine[edit]

Observations that eating asparagus results in a detectable change in the odour of urine have been recorded over time. In 1702, Louis Lémery noted "a powerful and disagreeable smell in the urine",[8] whilst John Arbuthnot noted that "asparagus ... affects the urine with a foetid smell."[9][10] Benjamin Franklin described the odour as "disagreable" in Fart Proudly, his essay on flatulence[11] whilst Marcel Proust claimed that asparagus "transforms my chamber-pot into a flask of perfume."[10][12] As early as 1891, Marceli Nencki had attributed the smell to methanethiol[13][14] which is also a component of flatus and bad breath.[15] More recent research has attributed the odour to a mixture of sulfur-containing metabolites of asparagusic acid which have been detected in urine;[3][4][16][17] these include methanethiol and span at least seven distinct functional groups, as shown in the table below. Most of the metabolites are volatile organic compounds with a high vapour pressure, meaning that they readily enter the gaseous state and spread through the air at room temperature and hence are available for detection by the olfactory system.[10]

Compound name Formula Structure Class of compound
methanethiol CH4S Methaanthiol.png thiol
dimethyl sulfide C2H6S Dimethyl sulfide structure.svg thioether
dimethyl disulfide C2H6S2 DMDS.svg disulfide
bis(methylthio)methane C3H8S2 2,4-dithiapentane.svg dithioacetal
dimethyl sulfoxide C2H6OS Dimethylsulfoxid.svg sulfoxide
dimethyl sulfone C2H6O2S Me2SO2.png sulfone
S-methyl thioacrylate C4H6OS S-methyl-thioacrylate-2D-skeletal.png thioester

Scientific investigation[edit]

Asparagus has been eaten and cultivated for at least two millennia but the association between odorous urine and asparagus consumption was not observed until the late 17th century when sulfur-rich fertilisers become common in agriculture.[3] Small-scale studies noted that the "asparagus urine" odour was not produced by all individuals and estimates as to the proportion of the population who are excretors (reporting a noticeable asparagus urine odour after eating asparagus) has ranged from about 40%[18] to as high as 79%[19] In a 91 subject population study 82 participants (90%) reported "asparagus urine" odour.[20] When excretors are exposed to non-excretor urine after asparagus consumption, however, the characteristic asparagus urine odour is usually reported.[3] More recent work has confirmed that a small proportion of individuals do not produce asparagus urine, and amongst those that do, some cannot detect the odour due to a single-nucleotide polymorphism within a cluster of olfactory receptors.[4]

The (R) enantiomer of α-lipoic acid, an organic compound essential for aerobic metabolism

Recent research is consistent with attributing the origin of asparagus urine to asparagusic acid, a substance unique to this vegetable.[21][22] Most studies of the compounds responsible for the odour of asparagus urine have correlated the appearance of the compounds above with asparagus consumption; they appear as little as 15 minutes after consumption.[10] However, this does not provide information on the biochemical processes which lead to their formation. Asparagusic acid and lipoic acid are similar in that both possess a 1,2-dithiolane ring with a carboxylic acid tethered to it; indeed, it has been reported that asparagusic acid can substitute for lipoic acid in α-keto-acid oxidation systems such as the citric acid cycle.[22] The (R)-(+)-enantiomer of α-lipoic acid is a cofactor in the pyruvate dehydrogenase complex and is essential for aerobic metabolism. The degradation pathway of lipoic acid has been well studied and includes evidence of reduction of the disulfide bridge, S-methylation, and oxidation to produce sulfoxides.[23] Similar transformations of asparagusic acid would lead to metabolites like this detected in asparagus urine. Synthetic work has confirmed the relative ease of oxidation of asparagusic acid to yield S-oxides of the dithiolane ring.[1] The rate of degradation appears highly variably between subjects; the typical half-life for odour disappearance is around 4 h with a between subject variability of 43.4%.[20]

In the small minority of people who do not produce these metabolites after consuming asparagus, the reason may be as simple as asparagusic acid not being taken into the body from the digestive tract[3] or that these individuals metabolise it in such a way as to minimise the release of volatile sulfur-containing products.[10]

References[edit]

  1. ^ a b c Yanagawa, H.; Kato, T.; Sagami, H.; Kitahara, Y. (1973). "Convenient procedure for the synthesis of asparagusic acids". Synthesis (10): 607–608. doi:10.1055/s-1973-22265. 
  2. ^ a b Foss, O.; Tjomsland, O. (1958). "Crystal and molecular structure of 1,2-dithiolane-4-carboxylic acid". Acta Chemica Scandinavica. 12: 1810–1818. doi:10.3891/acta.chem.scand.12-1810. 
  3. ^ a b c d e Mitchell, S. C. (2001). "Food idiosyncrasies: Beetroot and asparagus". Drug Metabolism and Disposition. 29 (4): 539–543. PMID 11259347. 
  4. ^ a b c Pelchat, M. L.; Bykowski, C.; Duke, F. F.; Reed, D. R. (2011). "Excretion and perception of a characteristic odor in urine after asparagus ingestion: A psychophysical and genetic study". Chemical Senses. 36 (1): 9–17. doi:10.1093/chemse/bjq081. 
  5. ^ a b Jansen, E. F. (1948). "The isolation and identification of 2,2'-dithiolisobutyric acid from asparagus". Journal of Biological Chemistry. 176 (2): 657–664. PMID 18889921. 
  6. ^ Parry, R. J.; Mizusawa, A. E.; Chiu, I. C.; Naidu, M. V.; Ricciardone, M. (1985). "Biosynthesis of sulfur compounds. Investigations of the biosynthesis of asparagusic acid". Journal of the American Chemical Society. 107 (8): 2512–2521. doi:10.1021/ja00294a051. 
  7. ^ Singh, R.; Whitesides, G. M. (1990). "Comparisons of rate constants for thiolate-disulfide interchange in water and in polar aprotic solvents using dynamic 1H NMR line shape analysis". Journal of the American Chemical Society. 112 (3): 1190–1197. doi:10.1021/ja00159a046. 
  8. ^ McGee, H. (2007). On Food and Cooking: The Science and Lore of the Kitchen (Illustrated ed.). Simon and Schuster. p. 315. ISBN 9781416556374. 
  9. ^ Arbuthnot, J. (1735). An Essay Concerning the Nature of Aliments, and the Choice of Them, According to the Different Constitutions of Human Bodies: In which the Different Effects, Advantages, and Disadvantages of Animal and Vegetable Diet, are Explain'd (3rd ed.). London: Jacob Tonson. p. 64. 
  10. ^ a b c d e Stromberg, J. (3 May 2013). "Why Asparagus Makes Your Urine Smell". smithsonian.com. Retrieved 19 June 2016. 
  11. ^ Franklin, Benjamin (1781). Japikse, Carl, ed. "Fart Proudly: Writings of Benjamin Franklin You Never Read in School" (Revised ed.). ISBN 9780898048018. 
  12. ^ Proust, Marcel (1988). Du côté de chez Swann (in French). Gallimard. changer mon pot de chambre en un vase de parfum 
  13. ^ Nencki, M. (1891). "Ueber das vorkommen von methylmercaptan im menschlichen harn nach spargelgenuss". Archiv für experimentelle Pathologie und Pharmakologie. 28 (3): 206–209. doi:10.1007/BF01824333. 
  14. ^ Richer, C.; Decker, N.; Belin, J.; Imbs, J. L.; Montastruc, J. L.; Giudicelli, J. F. (1989). "Odorous urine in man after asparagus". British Journal of Clinical Pharmacology. 27 (5): 640–641. doi:10.1111/j.1365-2125.1989.tb03431.x. PMC 1379934free to read. 
  15. ^ Tangerman, A.; Winkel, E. G. (2010). "Extra-oral halitosis: An overview". Journal of Breath Research. 4 (1). doi:10.1088/1752-7155/4/1/017003. 
  16. ^ White, R. H. (1975). "Occurrence of S-methyl thioesters in urines of humans after they have eaten asparagus". Science. 189 (4205): 810–811. doi:10.1126/science.1162354. 
  17. ^ Waring, R. H.; Mitchell, S. C.; Fenwick, G. R. (1987). "The chemical nature of the urinary odour produced by man after asparagus ingestion". Xenobiotica. 17 (11): 1363–1371. doi:10.3109/00498258709047166. 
  18. ^ Allison, A. C.; McWhirter, K. G. (1956). "Two unifactorial characters for which man is polymorphic". Nature. 178: 748–749. doi:10.1038/178748c0. 
  19. ^ Sugarman, J.; Neelon, F. A. (1985). "You're in for a treat: Asparagus". North Carolina Medical Journal. 46 (6): 332–334. PMID 3860737. 
  20. ^ a b van Hasselt, J. G. C.; Elassaiss-Schaap, J.; Ramamoorthy, A.; Sadler, B. M.; Kasichayanula, S.; Edwards, Y.; van der Graaf, P. H.; Zhang, L.; Wagner, J. A. (2016). "The proof is in the pee: Population asparagus urinary odor kinetics". PAGE: Abstracts of the Annual Meeting of the Population Approach Group in Europe. 25. ISSN 1871-6032. Retrieved 7 July 2016. 
  21. ^ Mitchell, S. C. (2013). "Asparagus, urinary odor, and 1,2-dithiolane-4-carboxylic acid". Perspectives in Biology and Medicine. 56 (3): 341–351. doi:10.1353/pbm.2013.0031. PMID 24375116. 
  22. ^ a b Mitchell, S. C.; Waring, R. H. (2014). "Asparagusic acid". Phytochemistry. 97: 5–10. doi:10.1016/j.phytochem.2013.09.014. 
  23. ^ Schupke, H.; Hempel, R.; Peter, G.; Hermann, R.; Wessel, K.; Engel, J.; Kronbach, T. (2001). "New metabolic pathways of α-lipoic acid". Drug Metabolism and Disposition. 29 (6): 855–862. PMID 11353754. 

External links[edit]