Structural enzymological studies of multifunctional enzyme, type-1 (MFE1) with the 2E-decenoyl-CoA and 2E,4E-decadienoyl-CoA substrates: The regeneration of the dehydrogenase catalytic site is the rate limiting step of its combined reactionsShow others and affiliations
2026 (English)In: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 218, no 3, article id 108346Article in journal (Refereed) Published
Abstract [en]
The rat peroxisomal multifunctional enzyme, type-1 (RnMFE1) is a monomeric enzyme with two active sites, which catalyze the second and third reaction of the beta-oxidation cycle, being the 2E-enoyl-CoA hydratase (ECH) and the 3S-hydroxyacyl-CoA dehydrogenase (HAD) reaction, respectively. Previous enzyme kinetic studies of MFE1 have shown that MFE1 also degrades 2E,4E-decadienoyl-CoA using a substrate channeling mechanism for transferring the hydrated intermediate between the two active sites. In the current studies, the Michaelis-Menten parameters for the substrate 2E-decenoyl-CoA for the hydratase and dehydrogenase reactions are reported and compared with the corresponding values for 2E,4E-decadienoyl-CoA and 2E-butenoyl-CoA. Also, pre-steady state kinetic data for the dehydrogenase activity for 2E-decenoyl-CoA and 2E,4E-decadienoyl-CoA have been obtained. The kinetic data suggest that the rate determining step of the combined hydratase and dehydrogenase reactions, characterized by the respective kcat-values of the overall reaction of the studied substrates, concerns the regeneration of the HAD active site, after the dehydrogenation step. It is discussed that this kinetic behavior could be related to the dynamical properties of the enzyme. The crystallographic binding studies of RnMFE1 with 2E,4E-decadienoyl-CoA have captured its mode of binding in the ECH active site as a competent enzyme product complex but also as an incompetent enzyme substrate complex. Structural analysis shows that positively charged patches on the enzyme surface between the ECH and HAD active sites would facilitate the channeling of the hydrated intermediate of 2E,4E-decadienoyl-CoA between these sites by electrostatic steering, without being released into the bulk solvent.
Place, publisher, year, edition, pages
Elsevier, 2026. Vol. 218, no 3, article id 108346
Keywords [en]
beta-Oxidation, Enoyl-CoA hydratase, Enzyme dynamics, Peroxisome, Substrate channeling, Trans fatty acids
National Category
Molecular Biology Structural Biology
Identifiers
URN: urn:nbn:se:uu:diva-594944DOI: 10.1016/j.jsb.2026.108346ISI: 001825539500001PubMedID: 42435994Scopus ID: 2-s2.0-105044467935OAI: oai:DiVA.org:uu-594944DiVA, id: diva2:2094781
2026-08-242026-08-242026-08-24Bibliographically approved