Abstract
The first lecture addresses the issue of suicide enzymes, defined as enzymes that become inactive after a single catalytic cycle because they consume a cofactor or transform an amino acid, in a form of cannibalization of the system. This concept is obviously intriguing and counter-intuitive, since to ensure this activity on an ongoing basis, the cell is obliged to discard the degraded enzymes and synthesize the enzyme system again, each time producing an equivalent product. This is not what we expect from a perfectly mastered cellular economy. It's for this reason that reported examples of suicidal enzymes are regularly re-examined, with the aim of confirming or refuting this very particular character. The first historical example is that of O6-methylguanine-DNA methyltransferase (Ada), an enzyme involved in DNA repair (demethylation of methylated nucleic bases). To carry out its activity, Ada irreversibly transfers the methyl group of the base to a cysteine in the active site. Thus methylated, the cysteine is no longer active and the enzyme is unable to demethylate other nucleic bases. Interestingly, examples of suicidal enzymes can be found in sulfuration reactions. This is the case of thiamine thiazole synthase (THI4p), which consumes the sulfur of a protein cysteine, transforming it into dehydroalanine and then rendering it inactive, to synthesize thiazole, a precursor of the vitamin thiamine. The same type of mechanism (use of the sulphur atom of a cysteine in the enzyme) is put forward for the biosynthesis of nicotinic acid adenine dinucleotide, the organic cofactor of lactate racemase. Another mechanism is involved in the case of several iron-sulfur enzymes that degrade their own essential iron-sulfur cluster, rendered inactive after a catalytic cycle, using the sulfur atoms of this cluster in the biosynthesis of biotin(biotin synthase) and lipoic acid(lipoate synthase).
