np9b01094_si_003.pdf (8.52 MB)
Algal Toxin Goniodomin A Binds Potassium Ion Selectively to Yield a Conformationally Altered Complex with Potential Biological Consequences
journal contribution
posted on 2020-02-21, 19:34 authored by Craig J. Tainter, Nathan D. Schley, Constance M. Harris, Donald F. Stec, Anna K. Song, Andrzej Balinski, Jody C. May, John A. McLean, Kimberly S. Reece, Thomas M. HarrisThe marine toxin goniodomin A (GDA)
is a polycyclic macrolide containing
a spiroacetal and three cyclic ethers as part of the macrocycle backbone.
GDA is produced by three species of the Alexandrium genus of dinoflagellates, blooms of which are associated with “red
tides”, which are widely dispersed and can cause significant
harm to marine life. The toxicity of GDA has been attributed to stabilization
of the filamentous form of the actin group of structural proteins,
but the structural basis for its binding is not known. Japanese workers,
capitalizing on the assumed rigidity of the heavily substituted macrolide
ring, assigned the relative configuration and conformation by relying
on NMR coupling constants and NOEs; the absolute configuration was
assigned by degradation to a fragment that was compared with synthetic
material. We have confirmed the absolute structure and broad features
of the conformation by X-ray crystallography but have found GDA to
complex with alkali metal ions in spite of two of the heterocyclic
rings facing outward. Such an arrangement would have been expected
to impair the ability of GDA to form a crown-ether-type multidentate
complex. GDA shows preference for K+, Rb+, and
Cs+ over Li+ and Na+ in determinations
of relative affinities by TLC on metal-ion-impregnated silica gel
plates and by electrospray mass spectrometry. NMR studies employing
the K+ complex of GDA, formed from potassium tetrakis[pentafluorophenyl]borate
(KBArF20), reveal a major alteration of the conformation
of the macrolide ring. These observations argue against the prior
assumption of rigidity of the ring. Alterations in chemical shifts,
coupling constants, and NOEs indicate the involvement of most of the
molecule other than ring F. Molecular mechanics simulations suggest
K+ forms a heptacoordinate complex involving OA, OB, OC, OD, OE, and
the C-26 and C-27 hydroxy groups. We speculate that complexation of
K+ with GDA electrostatically stabilizes the complex of
GDA with filamentous actin in marine animals due to the protein being
negatively charged at physiological pH. GDA may also cause potassium
leakage through cell membranes. This study provides insight into the
structural features and chemistry of GDA that may be responsible for
significant ecological damage associated with the GDA-producing algal
blooms.