ost in promiscuity? An evolutionary and biochemical evaluation of HSD10 function in cardiolipin metabolism.

Autor: Wohlfarter Y; Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Str. 1/1.OG, 6020, Innsbruck, Austria., Eidelpes R; Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Yu RD; Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany.; Research Group Structure and Function of Molecular Machines, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany., Sailer S; Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Str. 1/1.OG, 6020, Innsbruck, Austria., Koch J; Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Str. 1/1.OG, 6020, Innsbruck, Austria., Karall D; Department of Paediatrics I (Inherited Metabolic Disorders), Medical University of Innsbruck, Innsbruck, Austria., Scholl-Bürgi S; Department of Paediatrics I (Inherited Metabolic Disorders), Medical University of Innsbruck, Innsbruck, Austria., Amberger A; Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Str. 1/1.OG, 6020, Innsbruck, Austria., Hillen HS; Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany.; Research Group Structure and Function of Molecular Machines, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Zschocke J; Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Str. 1/1.OG, 6020, Innsbruck, Austria., Keller MA; Institute of Human Genetics, Medical University of Innsbruck, Peter-Mayr-Str. 1/1.OG, 6020, Innsbruck, Austria. markus.keller@i-med.ac.at.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2022 Oct 22; Vol. 79 (11), pp. 562. Date of Electronic Publication: 2022 Oct 22.
DOI: 10.1007/s00018-022-04579-6
Abstrakt: Multifunctional proteins are challenging as it can be difficult to confirm pathomechanisms associated with disease-causing genetic variants. The human 17β-hydroxysteroid dehydrogenase 10 (HSD10) is a moonlighting enzyme with at least two structurally and catalytically unrelated functions. HSD10 disease was originally described as a disorder of isoleucine metabolism, but the clinical manifestations were subsequently shown to be linked to impaired mtDNA transcript processing due to deficient function of HSD10 in the mtRNase P complex. A surprisingly large number of other, mostly enzymatic and potentially clinically relevant functions have been attributed to HSD10. Recently, HSD10 was reported to exhibit phospholipase C-like activity towards cardiolipins (CL), important mitochondrial phospholipids. To assess the physiological role of the proposed CL-cleaving function, we studied CL architectures in living cells and patient fibroblasts in different genetic backgrounds and lipid environments using our well-established LC-MS/MS cardiolipidomic pipeline. These experiments revealed no measurable effect on CLs, indicating that HSD10 does not have a physiologically relevant function towards CL metabolism. Evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro. The combination of an essential structural with a non-essential enzymatic function in the same protein could direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket, which is consistent with the results presented here.
(© 2022. The Author(s).)
Databáze: MEDLINE
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