The glycine N-acyltransferases, GLYAT and GLYATL1, contribute to the detoxification of isovaleryl-CoA - an in-silico and in vitro validation
- Isovaleric acidemia (IVA), due to isovaleryl-CoA dehydrogenase (IVD) deficiency, results in the accumulation of isovaleryl-CoA, isovaleric acid and secondary metabolites. The increase in these metabolites decreases mitochondrial energy production and increases oxidative stress. This contributes to the neuropathological features of IVA. A general assumption in the literature exists that glycine N-acyltransferase (GLYAT) plays a role in alleviating the symptoms experienced by IVA patients through the formation of N-isovalerylglycine. GLYAT forms part of the phase II glycine conjugation pathway in the liver and detoxifies excess acyl-CoA’s namely benzoyl-CoA. However, very few studies support GLYAT as the enzyme that conjugates isovaleryl-CoA to glycine. Furthermore, GLYATL1, a paralogue of GLYAT, conjugates phenylacetyl-CoA to glutamine. Therefore, GLYATL1 might also be a candidate for the formation of N-isovalerylglycine. Based on the findings from the literature review, we proposed that GLYAT or GLYATL1 can form N-isovalerylglycine in IVA patients. To test this hypothesis, we performed an in-silico analysis to determine which enzyme is more likely to conjugate isovaleryl-CoA with glycine using AutoDock Vina. Thereafter, we performed in vitro validation using purified enzyme preparations. The in-silico and in vitro findings suggested that both enzymes could form N-isovaleryglycine albeit at lower affinities than their preferred substrates. Furthermore, an increase in glycine concentration does not result in an increase in N-isovalerylglycine formation. The results from the critical literature appraisal, in-silico, and in vitro validation, suggest the importance of further investigating the reaction kinetics and binding behaviors between these substrates and enzymes in understanding the pathophysiology of IVA.
Document Type: | Article |
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Language: | English |
Author: | Stefan Kühn, Monray E. Williams, Marli Dercksen, Jörn Oliver Sass, Rencia van der Sluis |
Parent Title (English): | Computational and Structural Biotechnology Journal |
Volume: | 21 |
Number of pages: | 13 |
First Page: | 1236 |
Last Page: | 1248 |
ISSN: | 2001-0370 |
URN: | urn:nbn:de:hbz:1044-opus-66037 |
DOI: | https://doi.org/10.1016/j.csbj.2023.01.041 |
PMID: | https://pubmed.ncbi.nlm.nih.gov/36817957 |
Publisher: | Elsevier |
Publishing Institution: | Hochschule Bonn-Rhein-Sieg |
Date of first publication: | 2023/02/03 |
Copyright: | © 2023 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license. |
Funding: | Research support by Heinz und Heide Dürr Stiftung (Berlin, Germany) to J.O. Sass is gratefully acknowledged. MW was funded by DSI-NRF Research Development Grants for new Generation of Academics Programme (nGAP) Scholars. |
Keyword: | Glycine N-acyltransferase; Glycine conjugation; Isovaleric acidemia; N-isovalerylglycine |
Departments, institutes and facilities: | Fachbereich Angewandte Naturwissenschaften |
Institut für funktionale Gen-Analytik (IFGA) | |
Dewey Decimal Classification (DDC): | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Entry in this database: | 2023/02/09 |
Licence (German): | Creative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International |