Aspergillomarasmine A

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]

Aspergillomarasmine A
Names
IUPAC name
(R-(R*,R*))-N-(2-((2-Amino-2-carboxyethyl)amino)-2-carboxyethyl)-L-aspartic acid
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
UNII
  • InChI=1S/C10H17N3O8/c11-4(8(16)17)2-12-6(10(20)21)3-13-5(9(18)19)1-7(14)15/h4-6,12-13H,1-3,11H2,(H,14,15)(H,16,17)(H,18,19)(H,20,21)/t4-,5+,6-/m1/s1
    Key: XFTWUNOVBCHBJR-NGJCXOISSA-N
  • C(C(C(=O)O)NCC(C(=O)O)NCC(C(=O)O)N)C(=O)O
Properties
C10H17N3O8
Molar mass 307.257
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

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 by substituting a hydrogen on the methyl group with a link to the amine group. Aspergillomarasmine B differs in that the last alanine is replaced by glycine.

The crystalline substance was first isolated in 1956, but its name was given until 1965.[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 P. teres, a biosynthetic precursor of aspergillomarasmine A, L,L-N-(2-amino-2-carboxyethyl)-aspartic acid has also been isolated and found to contribute to the phytotoxic properties of this microbe.[4] This precursor, aspergillomarasmine A itself, and a lactam form (anhydroaspergillomarasmine A) are together termed the marasmines.[2]

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]

Properties

Aspergillomarasmine A takes the form of colourless crystals. The chemical is insoluble in common organic solvents, but can dissolve in water under either basic or strongly acidic conditions.[3]

Anhydroaspergillomarasmine A, a lactam of aspergillomarasmine A, chemically called [1-(2-amino-2carboxyethyl)-6-carboxy-3-carboxymethyl-3-piperazinone], can also be found in Pyrenophora teres. The relative amount of these two toxins is dependent upon the pH of the growth medium, with lower pH favouring the lactam form.[2] The lactam can be hydrolyzed to aspergillomarasmine A by treating it with trifluoroacetic acid.[2]

Aspergillomarasmine A functions as a chelating agent, sequestering 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-diaminopropionic acid. Even though the precursor component is chiral, 2,3-diaminopropionic acid easily racemizes in acid.[3]

Aspergillomarasmine A has [α]20°D at pH 7 of -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, Andrew M.; Sarah A. Reid-Yu; Wenliang Wang; Dustin T. King; Gianfranco De Pascale; Natalie C. Strynadka; Timothy R. Walsh; Brian K. Coombes; Gerard D. Wright (2014). "Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance". Nature. 510 (7506): 503–506. Bibcode:2014Natur.510..503K. doi:10.1038/nature13445. ISSN 0028-0836. PMC 4981499. PMID 24965651.
  2. 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. Haenni, A. L.; M. Robert; W. Vetter; L. Roux; M. Barbier; E. Lederer (1965). "Structure chimique des aspergillomarasmines A et B" [Chemical structure of aspergellomarasmines A and B]. Helvetica Chimica Acta (in French). 48 (4): 729–750. doi:10.1002/hlca.19650480409. ISSN 0018-019X. PMID 14321962.
  4. Friis, P; Olsen C.E.; Møller B.L. (15 July 1991). "Toxin production in Pyrenophora teres, the ascomycete causing the net-spot blotch disease of barley (Hordeum vulgare L.)". The Journal of Biological Chemistry. 266 (20): 13329–13335. doi:10.1016/S0021-9258(18)98843-5. PMID 2071605.
  5. 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, Akihiro; Hiroshi Okumura; Rieko Asakura; Naoki Ashizawa; Mayumi Takahashi; Fujio Kobayashi; Nami Ashikawa; Koshi Arai (1993). "Pharmacological profiles of aspergillomarasmines as endothelin converting enzyme inhibitors". The Japanese Journal of Pharmacology. 63 (2): 187–193. 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.
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