Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism
A growing number of inborn errors of metabolism (IEM) have been identified that manifest 3-methylglutaconic (3MGC) aciduria as a phenotypic feature. In primary 3MGC aciduria, IEM-dependent deficiencies in leucine pathway enzymes prevent catabolism of <i>trans</i>-3MGC CoA. Consequently,...
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MDPI AG
2022-04-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/12/5/377 |
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| author | Dylan E. Jones Elizabeth A. Jennings Robert O. Ryan |
| author_facet | Dylan E. Jones Elizabeth A. Jennings Robert O. Ryan |
| author_sort | Dylan E. Jones |
| collection | DOAJ |
| description | A growing number of inborn errors of metabolism (IEM) have been identified that manifest 3-methylglutaconic (3MGC) aciduria as a phenotypic feature. In primary 3MGC aciduria, IEM-dependent deficiencies in leucine pathway enzymes prevent catabolism of <i>trans</i>-3MGC CoA. Consequently, this metabolite is converted to 3MGC acid and excreted in urine. In secondary 3MGC aciduria, however, no leucine metabolism pathway enzyme deficiencies exist. These IEMs affect mitochondrial membrane structure, electron transport chain function or ATP synthase subunits. As a result, acetyl CoA oxidation via the TCA cycle slows and acetyl CoA is diverted to <i>trans</i>-3MGC CoA, and then to 3MGC acid. Whereas the <i>trans</i> diastereomer of 3MGC CoA is the only biologically relevant diastereomer, the urine of affected subjects contains both <i>cis</i>- and <i>trans</i>-3MGC acids. Studies have revealed that <i>trans</i>-3MGC CoA is susceptible to isomerization to <i>cis</i>-3MGC CoA. Once formed, <i>cis</i>-3MGC CoA undergoes intramolecular cyclization, forming an anhydride that, upon hydrolysis, yields <i>cis</i>-3MGC acid. Alternatively, <i>cis</i>-3MGC anhydride can acylate protein lysine side chains. Once formed, <i>cis</i>-3MGCylated proteins can be deacylated by the NAD<sup>+</sup>-dependent enzyme, sirtuin 4. Taken together, the excretion of 3MGC acid in secondary 3MGC aciduria represents a barometer of defective mitochondrial function. |
| first_indexed | 2024-03-10T03:27:01Z |
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| id | doaj.art-6ece9a47f93f40bdadcb394c65a62039 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T03:27:01Z |
| publishDate | 2022-04-01 |
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| series | Metabolites |
| spelling | doaj.art-6ece9a47f93f40bdadcb394c65a620392023-11-23T12:06:30ZengMDPI AGMetabolites2218-19892022-04-0112537710.3390/metabo12050377Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of MetabolismDylan E. Jones0Elizabeth A. Jennings1Robert O. Ryan2Department of Biochemistry & Molecular Biology, University of Nevada Reno, Reno, NV 89557, USADepartment of Biochemistry & Molecular Biology, University of Nevada Reno, Reno, NV 89557, USADepartment of Biochemistry & Molecular Biology, University of Nevada Reno, Reno, NV 89557, USAA growing number of inborn errors of metabolism (IEM) have been identified that manifest 3-methylglutaconic (3MGC) aciduria as a phenotypic feature. In primary 3MGC aciduria, IEM-dependent deficiencies in leucine pathway enzymes prevent catabolism of <i>trans</i>-3MGC CoA. Consequently, this metabolite is converted to 3MGC acid and excreted in urine. In secondary 3MGC aciduria, however, no leucine metabolism pathway enzyme deficiencies exist. These IEMs affect mitochondrial membrane structure, electron transport chain function or ATP synthase subunits. As a result, acetyl CoA oxidation via the TCA cycle slows and acetyl CoA is diverted to <i>trans</i>-3MGC CoA, and then to 3MGC acid. Whereas the <i>trans</i> diastereomer of 3MGC CoA is the only biologically relevant diastereomer, the urine of affected subjects contains both <i>cis</i>- and <i>trans</i>-3MGC acids. Studies have revealed that <i>trans</i>-3MGC CoA is susceptible to isomerization to <i>cis</i>-3MGC CoA. Once formed, <i>cis</i>-3MGC CoA undergoes intramolecular cyclization, forming an anhydride that, upon hydrolysis, yields <i>cis</i>-3MGC acid. Alternatively, <i>cis</i>-3MGC anhydride can acylate protein lysine side chains. Once formed, <i>cis</i>-3MGCylated proteins can be deacylated by the NAD<sup>+</sup>-dependent enzyme, sirtuin 4. Taken together, the excretion of 3MGC acid in secondary 3MGC aciduria represents a barometer of defective mitochondrial function.https://www.mdpi.com/2218-1989/12/5/377organic acidurialeucineacetyl CoAsirtuin 43-methylglutaconic acidmitochondria |
| spellingShingle | Dylan E. Jones Elizabeth A. Jennings Robert O. Ryan Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism Metabolites organic aciduria leucine acetyl CoA sirtuin 4 3-methylglutaconic acid mitochondria |
| title | Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism |
| title_full | Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism |
| title_fullStr | Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism |
| title_full_unstemmed | Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism |
| title_short | Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism |
| title_sort | diversion of acetyl coa to 3 methylglutaconic acid caused by discrete inborn errors of metabolism |
| topic | organic aciduria leucine acetyl CoA sirtuin 4 3-methylglutaconic acid mitochondria |
| url | https://www.mdpi.com/2218-1989/12/5/377 |
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