Anatoxin-A and Analogues

Emanuela Testai

Anatoxin-a (ATX) was isolated from strains of Dolichospermum {Anabaena) flosaquae originating from Canada (Carmichael etal., 1975). At the time, several types of toxins (anatoxins a-d) were suspected (Carmichael & Gorham, 1978), of which, however, only one eventually led to the elucidation of the absolute structure (Devlin et al., 1977) for which the suffix “-a” was kept.

Besides ATX, the following also includes information on its variant homoanatoxin-a (HTX), where available. The genetics and biosynthesis of ATX and other neurotoxic substances with a high structural variability produced by some marine cyanobacteria (Araoz et al., 2010) have been reviewed by Pearson et al. (2016) and Bruno et al. (2017).

Chemical Structures

Anatoxins are secondary amine alkaloids (Devlin et al., 1977; Figure 2.3a). The first synthesis of ATX yielded a racemic mixture of stereoisomers with optically positive and negative activity (Campbell et al., 1979). Homoanatoxin-a is a structural variant (differing from ATX by an ethyl-group at the carbonyl-C; Figure 2.3b). It was first synthesised by Wonnacott et al. (1992) just before Skulberg et al. (1992) isolated it from a sample of Kamptonema (Oscillatoria) formosum. Due to its structural similarity to ATX, HTX is most probably produced by the same biosynthetic pathway, with the additional carbon deriving from L-methionine via S-adenosyl-methionine (Namikoshi et al., 2004).

Further natural analogues of ATX are dihydroATX (dhATX; Figure 2.3c) and dihydroHTX reduced on C7 and C8, respectively (Smith & Lewis, 1987; Wonnacott et al., 1991).

Chemical structure of anatoxin-a (a), homoanatoxin (b) and dihydroana- toxin-a (c). Anatoxin-a

Figure 2.3 Chemical structure of anatoxin-a (a), homoanatoxin (b) and dihydroana- toxin-a (c). Anatoxin-a: molecular mass (monoisotopic): 165.115 Da; molecular weight (average): 165.237 g/mol. Homoanatoxin-a: molecular mass (monoisotopic) 179.131 Da; molecular weight (average): 179.264 g/mol. Dihydroanatoxin-a: molecular mass (monoisotopic) 167.131 Da; molecular weight (average): 167.252 g/mol.

Toxicity: Mode of Action

The toxic effects of anatoxin-a, summarised in the following, are described in detail in the WHO Background Document on Anatoxin-a (WHO, 2020); see there for further information and references). In summary, ATX is rapidly and passively absorbed after ingestion and widely distributed to different tissues, including the brain. No information about its biotransformation is available but, overall, a low bioaccumulating potential can be anticipated. Anatoxin-a acts as a potent pre- and postsynaptic depolarising agent; it efficiently competes with acetylcholine for nicotinic receptors in neuromuscular junctions and the central nervous system, triggering neurotransmitter release with an increased stimulation of postsynaptic receptors. The cardiovascular system has also been indicated as a target organ. Death through the administration of a lethal ATX dose is due to muscular paralysis and respiratory failure (i.v. LD50 = 85 pg/kg bw; i.p. LDJ0 = 260-315 pg/kg bw; oral LDso>5000 pg/kg bw). Acute studies in animals led to deaths within minutes of gavage administration. After the administration of a sublethal single dose, mice readily recovered. Additional effects attributed to ATX in cell cultures include cytotoxic effects, caspase activation, apoptosis, induction of oxidative stress and formation of reactive oxygen species. Diagnosis of ATX and HTX poisoning in dogs and livestock has been reported due to neurotoxic effects after drinking and bathing in waters with ATX-producing cyanobacteria, such as species of the genera Pbormidium, Oscillatoria and Tycbonema.

On a weight of evidence basis, it can be concluded that ATX has no developmental or teratogenicity potential and is not mutagenic in bacteria. No in vivo carcinogenicity studies have been carried out. Regarding effects in humans, neurological symptoms (e.g., headache and confusion/ visual disturbance) were reported in 3 of 11 outbreaks associated with cyanobacteria in the USA in 2009-2010 (Hilborn et al., 2014), in which ATX was found in a concentration range of 0.05-15 pg/L, while none of these symptoms were reported in the other 8 outbreaks, where ATX was not detected.

Homoanatoxin-a shows a mode of action and toxicological properties almost identical to its analogue ATX. Dihydro-anatoxin has been suggested as the congener most likely responsible for some dog deaths (Wood et al., 2017). Furthermore, a study indicates that dhATX is about fourfold more toxic than ATX when administered by gavage (Puddick et al., 2021).

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