Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme
5-Aminolevulinic acid synthase (ALAS) catalyzes the first step in heme biosynthesis. We present the crystal structure of a eukaryotic ALAS from Saccharomyces cerevisiae. In this homodimeric structure, one ALAS subunit contains covalently bound cofactor, pyridoxal 5′-phosphate (PLP), whereas the seco...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2020
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| Online Access: | https://hdl.handle.net/1721.1/125924 |
| _version_ | 1826216463699017728 |
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| author | Brown, Breann L. Kardon, Julia R. Sauer, Robert T Baker, Tania |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Brown, Breann L. Kardon, Julia R. Sauer, Robert T Baker, Tania |
| author_sort | Brown, Breann L. |
| collection | MIT |
| description | 5-Aminolevulinic acid synthase (ALAS) catalyzes the first step in heme biosynthesis. We present the crystal structure of a eukaryotic ALAS from Saccharomyces cerevisiae. In this homodimeric structure, one ALAS subunit contains covalently bound cofactor, pyridoxal 5′-phosphate (PLP), whereas the second is PLP free. Comparison between the subunits reveals PLP-coupled reordering of the active site and of additional regions to achieve the active conformation of the enzyme. The eukaryotic C-terminal extension, a region altered in multiple human disease alleles, wraps around the dimer and contacts active-site-proximal residues. Mutational analysis demonstrates that this C-terminal region that engages the active site is important for ALAS activity. Our discovery of structural elements that change conformation upon PLP binding and of direct contact between the C-terminal extension and the active site thus provides a structural basis for investigation of disruptions in the first step of heme biosynthesis and resulting human disorders. Brown et al. determine structures of ALAS, a heme biosynthetic enzyme, that reveal how its PLP cofactor orders the active site. These structures also reveal the positioning of the eukaryote-specific C-terminal extension, providing a framework for understanding the mechanism of erythroid disease-causing mutations. |
| first_indexed | 2024-09-23T16:48:06Z |
| format | Article |
| id | mit-1721.1/125924 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:48:06Z |
| publishDate | 2020 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1259242022-10-03T08:25:05Z Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme Brown, Breann L. Kardon, Julia R. Sauer, Robert T Baker, Tania Massachusetts Institute of Technology. Department of Biology 5-Aminolevulinic acid synthase (ALAS) catalyzes the first step in heme biosynthesis. We present the crystal structure of a eukaryotic ALAS from Saccharomyces cerevisiae. In this homodimeric structure, one ALAS subunit contains covalently bound cofactor, pyridoxal 5′-phosphate (PLP), whereas the second is PLP free. Comparison between the subunits reveals PLP-coupled reordering of the active site and of additional regions to achieve the active conformation of the enzyme. The eukaryotic C-terminal extension, a region altered in multiple human disease alleles, wraps around the dimer and contacts active-site-proximal residues. Mutational analysis demonstrates that this C-terminal region that engages the active site is important for ALAS activity. Our discovery of structural elements that change conformation upon PLP binding and of direct contact between the C-terminal extension and the active site thus provides a structural basis for investigation of disruptions in the first step of heme biosynthesis and resulting human disorders. Brown et al. determine structures of ALAS, a heme biosynthetic enzyme, that reveal how its PLP cofactor orders the active site. These structures also reveal the positioning of the eukaryote-specific C-terminal extension, providing a framework for understanding the mechanism of erythroid disease-causing mutations. Burroughs Wellcome Postdoctoral Enrichment Program (Award 1015092) National Institutes of Health (Award F32DK095726) National Institutes of Health (Grant R01 DK115558) 2020-06-22T20:21:20Z 2020-06-22T20:21:20Z 2018-04 2017-11 2019-11-26T17:03:09Z Article http://purl.org/eprint/type/JournalArticle 0969-2126 https://hdl.handle.net/1721.1/125924 Brown, Breann L. et al. "Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme." Structure 26, 4 (April 2018): 580-589 © 2018 Elsevier Ltd en http://dx.doi.org/10.1016/j.str.2018.02.012 Structure Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Brown, Breann L. Kardon, Julia R. Sauer, Robert T Baker, Tania Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme |
| title | Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme |
| title_full | Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme |
| title_fullStr | Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme |
| title_full_unstemmed | Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme |
| title_short | Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme |
| title_sort | structure of the mitochondrial aminolevulinic acid synthase a key heme biosynthetic enzyme |
| url | https://hdl.handle.net/1721.1/125924 |
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