The killer of Socrates: Coniine and Related Alkaloids in the Plant Kingdom

Abstract

Coniine, a polyketide-derived alkaloid, is poisonous to humans and animals. It is a nicotinic acetylcholine receptor antagonist, which leads to inhibition of the nervous system, eventually causing death by suffocation in mammals. Coniine's most famous victim is Socrates who was sentenced to death by poison chalice containing poison hemlock in 399 BC. In chemistry, coniine holds two historical records: It is the first alkaloid the chemical structure of which was established (in 1881), and that was chemically synthesized (in 1886). In plants, coniine and twelve closely related alkaloids are known from poison hemlock (Conium maculatum L.), and several Sarracenia and Aloe species. Recent work confirmed its biosynthetic polyketide origin. Biosynthesis commences by carbon backbone formation from butyryl-CoA and two malonyl-CoA building blocks catalyzed by polyketide synthase. A transamination reaction incorporates nitrogen from l-alanine and non-enzymatic cyclization leads to γ-coniceine, the first hemlock alkaloid in the pathway. Ultimately, reduction of γ-coniceine to coniine is facilitated by NADPH-dependent γ-coniceine reductase. Although coniine is notorious for its toxicity, there is no consensus on its ecological roles, especially in the carnivorous pitcher plants where it occurs. Lately there has been renewed interest in coniine's medical uses particularly for pain relief without an addictive side effect.

Keywords: Aloe; Sarracenia; Socrates; alkaloids; coniine; poison hemlock (Conium maculatum L.); polyketides; secondary metabolism.

Figure 1

Classification of hemlock alkaloids naturally occurring in poison hemlock (Conium maculatum L.), Sarracenia spp. and Aloe spp. according to their carbon number. Theoretical hemlock alkaloids are N-methylconhydrine [12] and 5-hydroxy-γ-coniceine [13]. Reproduced from [14].

Figure 2

Distribution map of plants containing hemlock alkaloids. Aloe in green, Conium in blue and Sarracenia in red. C for poison hemlock as an introduced weed.

Figure 3

Poison hemlock (Conium maculatum L.).

Figure 4

Alkaloids of Semnostachya menglaensis Tsui [79].

Figure 5

Poison hemlock plants were fed sodium [1-¹⁴C]-acetate and the radioactive carbon (blue dots) was found in the even-numbered carbons of coniine [87,89].

Figure 6

An alternative explanation of how the labeling pattern of ¹⁴C described by Leete [8,87] could be explained. Blue dots present the labeled carbon and FAS is fatty acid synthase.

Figure 7

Biosynthetic pathway scheme of coniine in poison hemlock based on [12,14,30,52,87,89,91,92,95,96,100,101,102,103,104,105]. Hypothetical intermediates and alkaloids are shown in brackets. Abbreviations: AAT l-alanine:5-keto-octanal aminotransferase, CSAM S-Adenosyl-L-methionine:coniine methyltransferase, CR γ-coniceine reductase, CPKS5 Conium polyketide synthase 5.