Aspergillomarasmine A

Aspergillomarasmine A
Names
IUPAC name
(R-(R*,R*))-N-(2-((2-Amino-2-carboxyethyl)amino)-2-carboxyethyl)-L-aspartic acid
Identifiers
3484-65-9 
ChemSpider 170641
Jmol-3D images Image
PubChem 197028
Properties
C10H17N3O8
Molar mass 307.257
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Aspergillomarasmine A is an polyamino acid naturally produced by the mold Aspergillus versicolor. The substance has been reported to inhibit two antibiotic resistance carbapenemase proteins in bacteria, New Delhi metallo-beta-lactamase 1 (NDM-1) and Verona integron-encoded metallo-beta-lactamase (VIM-2), and make those antibiotic-resistant bacteria susceptible to antibiotics.[1] Aspergillomarasmine A is toxic to leaves of barley and other plants, being termed as "Toxin C" when produced by Pyrenophora teres.[2]

The molecule is a tetracarboxylic acid with four -COOH groups. One section of the molecule is the amino acid aspartic acid. This has two alanine molecules attached. Aspergillomarasmine B differs in that the last alanine is replaced by glycine.

The name was given in 1965 by A. L. Haenni and colleagues, although the crystalline substance was first isolated in 1956 at the Société d’Etude et d’Applications Biologiques.[3]

In addition to Aspergillus versicolor, aspergillomarasmine A is also produced by the ascomycete Pyrenophora teres where it acts as a toxin in the barley net-spot blotch disease. In this organism the substance is produced using LL-N-(2-amino-2-carboxyethyl)-aspartic acid as an intermediate.[4]

Other producers of aspergillomarasmine A include Aspergillus flavus,[3] Aspergillus oryzae,[5] Colletotrichum gloeosporioides, and Fusarium oxysporum.[2]

In mice the LD50 toxic dose of aspergillomarasmine A is 159.8 mg/kg.[6]

Preparation

Aspergillomarasmine A can be made from a culture of molds that produce it. The liquid culture is filtered. Then from the filtrate, a precipitate is formed using calcium chloride, tricalcium phosphate and acetone. From the precipitate, the substance is redissolved at pH 9 in water. Then chromatographic separation in Amberlite IRC 50 with ammonia in water, and finally crystallisation at pH 3.0. At pH 2.5 aspergillomarasmine B crystallises.[5]

Properties

Aspergillomarasmine A takes the form of colourless crystals. They are insoluble in common organic solvents, but can dissolve in two normal hydrochloric acid or alkalis at pHs higher than 7.[3]

The lactam of aspergillomarasmine A: [1-(2-amino-2carboxyethyl)-6-carboxy-3-carboxymethyl-3-piperazinone] can also be found produced by Pyrenophora teres.[2] This lactam can be converted to aspergillomarasmine A by treating it with trifluoroacetic acid.[2]

Aspergillomarasmine A functions as a chelate, gripping Fe3+ ions.[7] It can inhibit endothelin converting enzymes even in the live rat, probably by chelating metals required by metalloproteases.[8]

When heated, aspergillomarasmine A decomposes between 225° and 236°C. Hydrolysis produces L-aspartic acid and racemic 2,3-diamino-propionic acid. [α]20°D at pH 7 is -48°.[3]

With nitrous acid aspergillomarasmine A is deaminated, and isoserine with aspartic acid is formed.[3]

Titration reveals changes in ionisation at pK 3.5 and 4.5 due to carboxylic acid groups, and pK 9.5 and 10 due to amino groups.[3]

Treatment with ninhydrin shows a purple colour.[3]

References

  1. ↑ King AM, Reid-Yu SA, Wang W, King DT, De Pascale G, Strynadka NC et al. (2014). "Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance". Nature 510 (7506): 503–6. Bibcode:2014Natur.510..503K. doi:10.1038/nature13445. PMID 24965651.
  2. ↑ 2.0 2.1 2.2 2.3 Weiergang, I.; H.J. Lyngs Jørgensen, I.M. Møller, P. Friis, V. Smedegaard-Petersen (2002). "Optimization of in vitro growth conditions of Pyrenophora teres for production of the phytotoxin aspergillomarasmine A". Physiological and Molecular Plant Pathology 60 (3): 131–140. doi:10.1006/pmpp.2002.0383. ISSN 0885-5765.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Haenni AL, Robert M, Vetter W, Roux L, Barbier M, Lederer E (1965). "[Chemical structure of aspergellomarasmines A and B]]". Helv. Chim. Acta (in French) 48 (4): 729–50. doi:10.1002/hlca.19650480409. PMID 14321962.
  4. ↑ Friis P, Olsen CE, Møller BL (15 July 1991). "Toxin production in Pyrenophora teres, the ascomycete causing the net-spot blotch disease of barley (Hordeum vulgare L.)". J. Biol. Chem. 266 (20): 13329–35. PMID 2071605.
  5. ↑ 5.0 5.1 Wagman, G.H.; Cooper, R. (1988-12-01). Natural Products Isolation: Separation Methods for Antimicrobials, Antivirals and Enzyme Inhibitors. Elsevier. p. 499. ISBN 9780080858487. Retrieved 27 June 2014.
  6. ↑ Matsuura A, Okumura H, Asakura R, Ashizawa N, Takahashi M, Kobayashi F et al. (1993). "Pharmacological profiles of aspergillomarasmines as endothelin converting enzyme inhibitors". Jpn. J. Pharmacol. 63 (2): 187–93. doi:10.1254/jjp.63.187. PMID 8283829.
  7. ↑ Barbier, M. (1987). "Remarks on the biological activity of aspergillomarasmine A Fe3+ chelate and other iron transporting phytotoxins with reference to their role in the photodegradation of aromatic amino-acids in infected plant leaves". Journal of Phytopathology 120 (4): 365–368. doi:10.1111/j.1439-0434.1987.tb00500.x. ISSN 0931-1785.
  8. ↑ Huggins, John P.; Pelton, John T. (1996-12-23). Endothelins in Biology and Medicine. CRC Press. p. 121. ISBN 9780849369759. Retrieved 27 June 2014.