J. Nat. Prod. doi:10.1021/np401097n

Marine animals use a diversity of potent neurotoxins to disable their prey. One such neurotoxin, tetrodotoxin, acts by blocking voltage-gated sodium channels with high affinity and specificity. As these channels are associated with chronic pain, tetrodotoxin and its analogs show promise as potential analgesics. However, the molecular determinants of activity, such as whether all six hydroxyl groups contribute to function, remain unclear. In a search for more information, Kudo et al. now report the discovery of 6-deoxytetrodotoxin, which lacks a hydroxyl group at the C6 position, from pufferfish. A unique HPLC retention time as compared to other deoxy analogs along with NMR data allowed the authors to assign the compound's structure, which is a dynamic equilibrium of the hemilactal and lactone conformations. Profiling of five animal samples indicated that the new analog was present at similar concentrations as other analogs, with particularly high concentrations found in the posterior salivary gland of the Australian blue-ringed octopus. Activity assays indicated that 6-deoxytetrodotoxin was only threefold less effective than the parent compound, whereas the loss of the neighboring C11 hydroxyl group (from either 6-deoxytetrodotoxin or tetrodotoxin) leads to a ∼60-fold drop in activity, indicating that the C6 group is not critical for function. This study provides the first direct test of the C6 modification and raises new questions about the biosynthetic pathway to this highly decorated molecule.