Asparagusic acid

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Asparagusic acid [1]
Asparagusic acid Asparagusic-acid.png
Asparagusic acid
Asparagusic acid Asparagusic-acid-3D-balls.png
Asparagusic acid
Names
Preferred IUPAC name
1,2-Dithiolane-4-carboxylic acid
Other names
1,2-Dithiacyclopentane-4-carboxylic acid
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C4H6O2S2/c5-4(6)3-1-7-8-2-3/h3H,1-2H2,(H,5,6) Yes check.svgY
    Key: AYGMEFRECNWRJC-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C4H6O2S2/c5-4(6)3-1-7-8-2-3/h3H,1-2H2,(H,5,6)
    Key: AYGMEFRECNWRJC-UHFFFAOYAA
  • O=C(O)C1CSSC1
Properties
C4H6O2S2
Molar mass 150.21 g·mol−1
AppearanceColorless 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).
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Asparagusic acid is an organosulfur compound with the molecular formula C4H6O2S2 and systematically named 1,2-dithiolane-4-carboxylic acid. The molecule consists of a heterocyclic 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

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

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

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", [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] The odour is attributed to a mixture of sulfur-containing metabolites of asparagusic acid. [3] [4] [15] [16]

The origin of asparagus urine is asparagusic acid, a substance unique to this vegetable. [17] [18] 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 that 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. [18] 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. [19] 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]

Related Research Articles

<span class="mw-page-title-main">Sulfur</span> Chemical element, symbol S and atomic number 16

Sulfur (also spelled sulphur in British English) is a chemical element with the symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms form cyclic octatomic molecules with a chemical formula S8. Elemental sulfur is a bright yellow, crystalline solid at room temperature.

<span class="mw-page-title-main">Asparagus</span> Species of flowering plant in the family Asparagaceae

Asparagus, or garden asparagus, folk name sparrow grass, scientific name Asparagus officinalis, is a perennial flowering plant species in the genus Asparagus. Its young shoots are used as a spring vegetable.

In biochemistry, a disulfide refers to a functional group with the structure R−S−S−R′. The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In biology, disulfide bridges formed between thiol groups in two cysteine residues are an important component of the secondary and tertiary structure of proteins. Persulfide usually refers to R−S−S−H compounds.

<span class="mw-page-title-main">Thiol</span> Any organic compound having a sulfanyl group (–SH)

In organic chemistry, a thiol, or thiol derivative, is any organosulfur compound of the form R−SH, where R represents an alkyl or other organic substituent. The −SH functional group itself is referred to as either a thiol group or a sulfhydryl group, or a sulfanyl group. Thiols are the sulfur analogue of alcohols, and the word is a blend of "thio-" with "alcohol".

<span class="mw-page-title-main">Lipoic acid</span> Chemical compound

Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ALA is made in animals normally, and is essential for aerobic metabolism. It is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries. Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. Only the (R)-(+)-enantiomer (RLA) exists in nature and is essential for aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.

<span class="mw-page-title-main">Methanethiol</span> Chemical compound

Methanethiol is an organosulfur compound with the chemical formula CH
3SH. It is a colorless gas with a distinctive putrid smell. It is a natural substance found in the blood, brain and feces of animals, as well as in plant tissues. It also occurs naturally in certain foods, such as some nuts and cheese. It is one of the chemical compounds responsible for bad breath and the smell of flatus. Methanethiol is the simplest thiol and is sometimes abbreviated as MeSH. It is very flammable.

Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extensive substitution reactions. It is a colorless liquid with a benzene-like odor. In most of its reactions, it resembles benzene. Compounds analogous to thiophene include furan (C4H4O), selenophene (C4H4Se) and pyrrole (C4H4NH), which each vary by the heteroatom in the ring.

<span class="mw-page-title-main">Trimethylaminuria</span> Medical condition

Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome, is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3 (FMO3). When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly convert trimethylamine (TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO), through a process called N-oxidation. Trimethylamine then builds up and is released in the person's sweat, urine, and breath, giving off a fishy odor. Primary trimethylaminuria is caused by genetic mutations that affect the FMO3 function of the liver. Symptoms matching TMAU can also occur when there is no genetic cause, yet excessive TMA is excreted - this has been described as secondary trimethylaminuria (TMAU2). TMAU2 can be caused by a precursor overload, hormonal issues related to menstrual cycles, liver damage, or liver and kidney failure. As a symptom rather than a disease, TMAU2 is temporary and will resolve as the underlying cause is remedied.

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<span class="mw-page-title-main">Dimethyl sulfide</span> Chemical compound

Dimethyl sulfide (DMS) or methylthiomethane is an organosulfur compound with the formula (CH3)2S. The simplest thioether, it is a flammable liquid that boils at 37 °C (99 °F) and has a characteristic disagreeable odor. It is a component of the smell produced from cooking of certain vegetables, notably maize, cabbage, beetroot, and seafoods. It is also an indication of bacterial contamination in malt production and brewing. It is a breakdown product of dimethylsulfoniopropionate (DMSP), and is also produced by the bacterial metabolism of methanethiol.

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<span class="mw-page-title-main">3-Methylbutanoic acid</span> Carboxylic acid with chemical formula (CH3)2CHCH2CO2H CH3CH2

3-Methylbutanoic acid, also known as β-methylbutyric acid or more commonly isovaleric acid, is a branched-chain alkyl carboxylic acid with the chemical formula (CH3)2CHCH2CO2H. It is classified as a short-chain fatty acid. Like other low-molecular-weight carboxylic acids, it has an unpleasant odor. The compound occurs naturally and can be found in many foods, such as cheese, soy milk, and apple juice.

<span class="mw-page-title-main">Diphenyl disulfide</span> Chemical compound

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<span class="mw-page-title-main">Dithiolane</span> Chemical compound

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<span class="mw-page-title-main">Felinine</span> Chemical compound

Felinine, also known as (R)-2-amino-3-(4-hydroxy-2-methylbutan-2-ylthio)propanoic acid, is a chemical compound and amino acid found in cat urine and a precursor via microbial lyase of the putative cat pheromone and thiol called 3-mercapto-3-methylbutan-1-ol (MMB). Felinine is excreted by selected Felidae species including bobcats, Chinese desert cats, the kodkod, and domestic cats.

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References

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  3. 1 2 3 Mitchell, S. C. (2001). "Food idiosyncrasies: Beetroot and asparagus". Drug Metabolism and Disposition . 29 (4): 539–543. PMID   11259347.
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  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. An Essay Concerning the Nature of Ailments.
  10. 1 2 3 4 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. S2CID   26430677.
  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   1379934 . PMID   2757887.
  15. ↑ White, R. H. (1975). "Occurrence of S-methyl thioesters in urines of humans after they have eaten asparagus". Science . 189 (4205): 810–811. Bibcode:1975Sci...189..810W. doi:10.1126/science.1162354. PMID   1162354.
  16. ↑ 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. PMID   3433805.
  17. ↑ 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. S2CID   20606694.
  18. 1 2 Mitchell, S. C.; Waring, R. H. (2014). "Asparagusic acid". Phytochemistry . 97: 5–10. Bibcode:2014PChem..97....5M. doi:10.1016/j.phytochem.2013.09.014. PMID   24099657.
  19. ↑ 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.
  20. ↑ 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.
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