6bgn

Publication Abstract from PubMed

5-Halo-2-hydroxy-2,4-pentadienoates (5-halo-HPDs) are reportedly generated in the bacterial catabolism of halogenated aromatic hydrocarbons by the meta-fission pathway. The 5-halo-HPDs, where the halogen can be bromide, chloride, or fluoride, result in the irreversible inactivation of 4-oxalocrotonate tautomerase (4-OT), which precedes the enzyme that generates them. The loss of activity is due to the covalent modification of the nucleophilic amino-terminal proline. Mass spectral and crystallographic analysis of the modified enzymes indicates that inactivation of 4-OT by 5-chloro- and 5-bromo-2-hydroxy-2,4-pentadienoate follows a mechanism different from that for the inactivation of 4-OT by 5-fluoro-2-hydroxy-2,4-pentadienoate. The 5-chloro and 5-bromo derivatives undergo 4-OT-catalyzed tautomerization to their respective alpha,beta-unsaturated ketones followed by attack at C5 (by the prolyl nitrogen) with concomitant loss of the halide. For the 5-fluoro species, the presence of a small amount of the alpha,beta-unsaturated ketone could result in a Michael addition of the prolyl nitrogen to C4 followed by protonation at C3. The fluoride is not eliminated. These observations suggest that the inactivation of 4-OT by a downstream metabolite could hamper the efficacy of the pathway, which is the first time that such a bottleneck has been reported for the meta-fission pathway.

Inactivation of 4-Oxalocrotonate Tautomerase by 5-Halo-2-hydroxy-2,4-pentadienoates.,Stack TMM, Li W, Johnson WH Jr., Zhang YJ, Whitman CP Biochemistry. 2018 Feb 13;57(6):1012-1021. doi: 10.1021/acs.biochem.7b00899. Epub, 2018 Jan 24. PMID:29303557^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.