Structural basis for catalysis by human lipoyl synthase
Abstract Lipoic acid is an essential cofactor in five mitochondrial multiprotein complexes. In each complex, it is tethered in an amide linkage to the side chain of a conserved lysyl residue on a lipoyl carrier protein or lipoyl domain to afford the lipoyl cofactor. Lipoyl synthase catalyzes the las...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61393-x |
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| _version_ | 1849343156161609728 |
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| author | Olga A. Esakova Douglas M. Warui Syam Sundar Neti John N. Alumasa Squire J. Booker |
| author_facet | Olga A. Esakova Douglas M. Warui Syam Sundar Neti John N. Alumasa Squire J. Booker |
| author_sort | Olga A. Esakova |
| collection | DOAJ |
| description | Abstract Lipoic acid is an essential cofactor in five mitochondrial multiprotein complexes. In each complex, it is tethered in an amide linkage to the side chain of a conserved lysyl residue on a lipoyl carrier protein or lipoyl domain to afford the lipoyl cofactor. Lipoyl synthase catalyzes the last step in the biosynthesis of the lipoyl cofactor, the addition of two sulfur atoms to carbons 6 and 8 of an octanoyllysyl residue of the H protein, the lipoyl carrier protein of the glycine cleavage system. Lipoyl synthase, a member of the radical S-adenosylmethionine superfamily, contains two [Fe4S4] clusters, one of which is sacrificed during catalysis to supply the appended sulfur atoms. Herein, we use X-ray crystallography to characterize several stages in lipoyl synthase catalysis and present a structure of an intermediate wherein the enzyme is cross-linked to the H protein substrate through a 6-mercaptooctanoyl ligand to a [Fe3S4] cluster. |
| format | Article |
| id | doaj-art-3c483ea04efd4cd6b07d760d1cd2d1f3 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3c483ea04efd4cd6b07d760d1cd2d1f32025-08-20T03:43:10ZengNature PortfolioNature Communications2041-17232025-07-0116111210.1038/s41467-025-61393-xStructural basis for catalysis by human lipoyl synthaseOlga A. Esakova0Douglas M. Warui1Syam Sundar Neti2John N. Alumasa3Squire J. Booker4Department of Chemistry, The Pennsylvania State UniversityDepartment of Chemistry, The Pennsylvania State UniversityDepartment of Chemistry, The Pennsylvania State UniversityDepartment of Chemistry, The Pennsylvania State UniversityDepartment of Chemistry, The Pennsylvania State UniversityAbstract Lipoic acid is an essential cofactor in five mitochondrial multiprotein complexes. In each complex, it is tethered in an amide linkage to the side chain of a conserved lysyl residue on a lipoyl carrier protein or lipoyl domain to afford the lipoyl cofactor. Lipoyl synthase catalyzes the last step in the biosynthesis of the lipoyl cofactor, the addition of two sulfur atoms to carbons 6 and 8 of an octanoyllysyl residue of the H protein, the lipoyl carrier protein of the glycine cleavage system. Lipoyl synthase, a member of the radical S-adenosylmethionine superfamily, contains two [Fe4S4] clusters, one of which is sacrificed during catalysis to supply the appended sulfur atoms. Herein, we use X-ray crystallography to characterize several stages in lipoyl synthase catalysis and present a structure of an intermediate wherein the enzyme is cross-linked to the H protein substrate through a 6-mercaptooctanoyl ligand to a [Fe3S4] cluster.https://doi.org/10.1038/s41467-025-61393-x |
| spellingShingle | Olga A. Esakova Douglas M. Warui Syam Sundar Neti John N. Alumasa Squire J. Booker Structural basis for catalysis by human lipoyl synthase Nature Communications |
| title | Structural basis for catalysis by human lipoyl synthase |
| title_full | Structural basis for catalysis by human lipoyl synthase |
| title_fullStr | Structural basis for catalysis by human lipoyl synthase |
| title_full_unstemmed | Structural basis for catalysis by human lipoyl synthase |
| title_short | Structural basis for catalysis by human lipoyl synthase |
| title_sort | structural basis for catalysis by human lipoyl synthase |
| url | https://doi.org/10.1038/s41467-025-61393-x |
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