Lethal synthesis

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]

Lethal Synthesis of Methylglyoxal

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]

References
  1. "Lethal synthesis". Compendium of Chemical Terminology (the "Gold Book"). IUPAC. 2014. doi:10.1351/goldbook.L03501. Retrieved 2018-03-13.
  2. "Lethal synthesis". Oxford Reference. Oxford University Press. Retrieved 2018-03-12.
  3. van der Kamp, Marc W.; McGeagh, John D.; Mulholland, Adrian J. (24 October 2011). ""Lethal Synthesis" of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling". Angewandte Chemie International Edition. 50 (44): 10349–10351. doi:10.1002/anie.201103260. PMID 21922613.
  4. Freedberg, W. B.; Kistler, W. S.; Lin, E. C. (October 1971). "Lethal synthesis of methylglyoxal by Escherichia coli during unregulated glycerol metabolism". Journal of Bacteriology. 108 (1): 137–144. doi:10.1128/JB.108.1.137-144.1971. ISSN 0021-9193. PMC 247042. PMID 4941552.
  5. Peters, R. A. (28 February 1952). "Croonian Lecture: Lethal Synthesis". Proceedings of the Royal Society B: Biological Sciences. 139 (895): 143–170. Bibcode:1952RSPSB.139..143P. doi:10.1098/rspb.1952.0001. PMID 14911820. S2CID 84782137.
  6. Anon (1982). "Obituary". BMJ. 284 (6315): 589–590. doi:10.1136/bmj.284.6315.589. S2CID 220197192.
  7. Chakraborty, Sangeeta; Karmakar, Kapudeep; Chakravortty, Dipshikha (2014). "Cells producing their own nemesis: Understanding methylglyoxal metabolism". IUBMB Life. 66 (10): 667–678. doi:10.1002/iub.1324. ISSN 1521-6551. PMID 25380137.


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