Lethal synthesis, or suicide metabolism, [1] is the biosynthesis of a toxin from a precursor which is not itself toxic, such as the synthesis of fluorocitrate from fluoroacetate or the synthesis of methylglyoxal from glycerol. [2] [3] [4]
The term was first publicised by Rudolph Peters in his Croonian Lecture of 1951. [5] [3] [6]
A 1971 study published by the Harvard Medical School identified methylglyoxal, a form of glycerol, as a product of lethal synthesis in a specific E.coli mutant. [4] In E.coli, the synthesis of triose phosphate from glycerol is a reaction regulated by the synthesis rate of glycerol kinase and by feedback inhibition by fructose-1,6-bisphosphate. [4] The study demonstrated that, in E.coli mutants that had lost both control mechanisms, glycerol kinase no longer reacted to feedback regulation and instead produced the cytotoxic methylglyoxal. [4] A more recent review of research done on methylglyoxal metabolism concluded that the compound's cytotoxic nature is dependent on its ability to form advanced glycation end products (AGEs). [7] These compounds, which are thought to be factors in ageing and in the progression of degenerative diseases, have been shown to hinder the functions of the proteins they target. [7]