Background and Significance

We study in particular enzymes of lipid metabolism which are CoA dependent and which catalyse reactions in which thioester chemistry plays a key role. Some of these enzymes are large complexes like the human CoA-dependent, tetrameric trifunctional enzyme (TFE, 260kDa, a2b2), which is membrane associated. TFEs have three active sites, catalysing three subsequent reactions of the b-oxidation pathway. For the mammalian TFE substrate channelling between the active sites has been established experimentally using 2-trans-hexadecanoyl-CoA as the substrate (Yao and Schulz, 1996). Monofunctional CoA dependent enzymes that we study are isovaleryl-CoA dehydrogenase, enoyl-CoA isomerase and thiolase.  We also study human and rat MFE1 (multifunctional enzyme, type 1), which has two active sites that catalyse the hydratase and the dehydrogenase reactions of the b-oxidation pathway, respectively.

Another set of enzymes that we study in depth are the collagen prolyl 4-hydroxylases (Myllyharju, 2006), in particular tetrameric collagen prolyl 4-hydroxylases (C-P4H, 240kDa, a2b2). The latter enzyme is equipped with a peptide substrate binding domain (the PSB domain), separately from the catalytic domain. The substrate of C-P4H is procollagen and it is believed that the function of the PSB domain is related to capturing this polymeric substrate. The interplay between the PSB-domain and the catalytic domain is an intriguing mystery, providing the enzyme most likely with processivity properties. We aim to understand the enzyme mechanistic properties of C-P4H by structural enzymology approaches. In human there are three isoenzymes, C-P4H-I,-II and-III, and the PSB domain may also provide these isoenzymes effectively with different in vivo substrate specificity properties and therefore different functions.

Viimeksi päivitetty: 28.10.2016