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Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex
The pyruvate dehydrogenase multienzyme assembly (PDH) generates acetyl coenzyme A and reducing equivalents from pyruvate in a multiple-step process that is a nexus of central metabolism. We report crystal structures of the Geobacillus stearothermophilus PDH E1p subunit with ligands that mimic the pr...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663715/ https://www.ncbi.nlm.nih.gov/pubmed/19081062 http://dx.doi.org/10.1016/j.str.2008.10.009 |
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author | Pei, Xue Yuan Titman, Christopher M. Frank, René A.W. Leeper, Finian J. Luisi, Ben F. |
author_facet | Pei, Xue Yuan Titman, Christopher M. Frank, René A.W. Leeper, Finian J. Luisi, Ben F. |
author_sort | Pei, Xue Yuan |
collection | PubMed |
description | The pyruvate dehydrogenase multienzyme assembly (PDH) generates acetyl coenzyme A and reducing equivalents from pyruvate in a multiple-step process that is a nexus of central metabolism. We report crystal structures of the Geobacillus stearothermophilus PDH E1p subunit with ligands that mimic the prereaction complex and the postdecarboxylation product. The structures implicate residues that help to orient substrates, nurture intermediates, and organize surface loops so that they can engage a mobile lipoyl domain that receives the acetyl group and shuttles it to the next active site. The structural and enzymatic data suggest that H128β performs a dual role: first, as electrostatic catalyst of the reaction of pyruvate with the thiamine cofactor; and second, as a proton donor in the second reaction of acetyl group with the lipoate. We also identify I206α as a key residue in mediating the conformation of active-site loops. We propose that a simple conformational flip of the H271α side chain assists transfer of the acetyl group from thiamine cofactor to lipoyl domain in synchrony with reduction of the dithiolane ring. |
format | Text |
id | pubmed-2663715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-26637152009-04-17 Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex Pei, Xue Yuan Titman, Christopher M. Frank, René A.W. Leeper, Finian J. Luisi, Ben F. Structure Article The pyruvate dehydrogenase multienzyme assembly (PDH) generates acetyl coenzyme A and reducing equivalents from pyruvate in a multiple-step process that is a nexus of central metabolism. We report crystal structures of the Geobacillus stearothermophilus PDH E1p subunit with ligands that mimic the prereaction complex and the postdecarboxylation product. The structures implicate residues that help to orient substrates, nurture intermediates, and organize surface loops so that they can engage a mobile lipoyl domain that receives the acetyl group and shuttles it to the next active site. The structural and enzymatic data suggest that H128β performs a dual role: first, as electrostatic catalyst of the reaction of pyruvate with the thiamine cofactor; and second, as a proton donor in the second reaction of acetyl group with the lipoate. We also identify I206α as a key residue in mediating the conformation of active-site loops. We propose that a simple conformational flip of the H271α side chain assists transfer of the acetyl group from thiamine cofactor to lipoyl domain in synchrony with reduction of the dithiolane ring. Cell Press 2008-12-12 /pmc/articles/PMC2663715/ /pubmed/19081062 http://dx.doi.org/10.1016/j.str.2008.10.009 Text en © 2008 ELL & Excerpta Medica. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license |
spellingShingle | Article Pei, Xue Yuan Titman, Christopher M. Frank, René A.W. Leeper, Finian J. Luisi, Ben F. Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex |
title | Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex |
title_full | Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex |
title_fullStr | Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex |
title_full_unstemmed | Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex |
title_short | Snapshots of Catalysis in the E1 Subunit of the Pyruvate Dehydrogenase Multienzyme Complex |
title_sort | snapshots of catalysis in the e1 subunit of the pyruvate dehydrogenase multienzyme complex |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663715/ https://www.ncbi.nlm.nih.gov/pubmed/19081062 http://dx.doi.org/10.1016/j.str.2008.10.009 |
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