Abstract
Domoic acid (DA, 1), a potent neurotoxin that causes amnesic shellfish poisoning, has been found in diatoms and red algae. While biosynthetic pathway towards DA from geranyl diphosphate and l-glutamate has been previously proposed, its late stage is still unclear. Here, six novel DA related compounds, 7′-methyl-isodomoic acid A (2) and B (3), N-geranyl-l-glutamic acid (4), 7′-hydroxymethyl-isodomoic acid A (5) and B (6), and N-geranyl-3(R)-hydroxy-l-glutamic acid (7), were isolated from the red alga, Chondria armata, and their structures were determined. The compounds 4 and 7, linear compounds, are predictable as the precursors to form the DA pyrrolidine ring. The compounds 2 and 3 are thought as the cyclized products of 7; therefore, dehydration and electron transfer from the internal olefin of 7 is a possible mechanism for the pyrrolidine ring formation. One terminal methyl group of the side chain of 2 and 3 is predicted to be oxidized to hydroxymethyl (5, 6), and then to carboxylic acids, forming isodomoic acids A and B. Finally, the terminal olefin of isodomoic acid A would be isomerized to form DA. In addition, [15N, D]-labeled 4 was incorporated into DA using the diatom, Pseudo-nitzschia multiseries, demonstrating that 4 is the genuine precursor of DA.
Highlights
Domoic acid (DA, 1, Fig. 1), a neuroexcitatory amino acid, is the toxic principle of amnesic shellfish poisoning (ASP) that first occurred in Prince Edward Island, Canada, in 19871,2
DA has attracted the attention of chemists, even though it is a small molecule, due to its characteristic structure that is composed of three carboxylic acids, a pyrrolidine ring, and a (Z, E)-conjugated diene side chain
Small amounts of isodomoic acids A, B18, and C19 have been identified in DA-producing diatoms, and isodomoic acid D, E, F, and 5-epi-domoic acid have been isolated from DA-contaminated shellfish[20]
Summary
The lyophilized extract from the red alga, C. armata collected in Kagoshima prefecture, Japan, was desalted using a reversed phase column, and used for screening of new DA-related compounds having the molecular formula C15HxNOy using high-resolution (HR)-LC-MS (see methods). Other NOEs around the pyrrolidine rings of 5 and 6 were not clearly detected, probably due to the small sample amount, the stereochemistry of the pyrrolidine rings of 5 and 6 was assumed to be identical to that of DA, based on the almost identical chemical shifts of 1H of H2-H5 of 6 and 3 (Δ < 0.05 ppm; Table 1), and those of 13C of C2-C6 of 5 and DA (Δ < 0.7 ppm; Table 2) These data suggested that 5 and 6 are 7′-hydroxymethyl-isodomoic acids A and B, respectively (Fig. 1B). In the isotope pattern of DA from the culture administered 4′ (Fig. 5B), the ion at m/z 314.1490 corresponding to 1′ was clearly detected, while that of DA from control almost agreed to the theoretical isotope pattern of DA (Fig. 5A) This result suggested that 4′ was partially incorporated into DA produced by P. multiseries, even in the low labeling rate (approximately 14%, based on the intensity of the isotope ions), demonstrating that 4 is the genuine precursor of DA for the first time. The biological activities of 2–7 should be examined in future
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
