One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse
Abstract The increasing availability of experimental and computational protein structures entices their use for function prediction. Here we develop an automated procedure to identify enzymes involved in metabolic reactions by assessing substrate conformations docked to a library of protein structur...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47466-3 |
| _version_ | 1797209185678524416 |
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| author | Marco Malatesta Emanuele Fornasier Martino Luigi Di Salvo Angela Tramonti Erika Zangelmi Alessio Peracchi Andrea Secchi Eugenia Polverini Gabriele Giachin Roberto Battistutta Roberto Contestabile Riccardo Percudani |
| author_facet | Marco Malatesta Emanuele Fornasier Martino Luigi Di Salvo Angela Tramonti Erika Zangelmi Alessio Peracchi Andrea Secchi Eugenia Polverini Gabriele Giachin Roberto Battistutta Roberto Contestabile Riccardo Percudani |
| author_sort | Marco Malatesta |
| collection | DOAJ |
| description | Abstract The increasing availability of experimental and computational protein structures entices their use for function prediction. Here we develop an automated procedure to identify enzymes involved in metabolic reactions by assessing substrate conformations docked to a library of protein structures. By screening AlphaFold-modeled vitamin B6-dependent enzymes, we find that a metric based on catalytically favorable conformations at the enzyme active site performs best (AUROC Score=0.84) in identifying genes associated with known reactions. Applying this procedure, we identify the mammalian gene encoding hydroxytrimethyllysine aldolase (HTMLA), the second enzyme of carnitine biosynthesis. Upon experimental validation, we find that the top-ranked candidates, serine hydroxymethyl transferase (SHMT) 1 and 2, catalyze the HTMLA reaction. However, a mouse protein absent in humans (threonine aldolase; Tha1) catalyzes the reaction more efficiently. Tha1 did not rank highest based on the AlphaFold model, but its rank improved to second place using the experimental crystal structure we determined at 2.26 Å resolution. Our findings suggest that humans have lost a gene involved in carnitine biosynthesis, with HTMLA activity of SHMT partially compensating for its function. |
| first_indexed | 2024-04-24T09:50:41Z |
| format | Article |
| id | doaj.art-14c67f718fbf493085d50d336b285301 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T09:50:41Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-14c67f718fbf493085d50d336b2853012024-04-14T11:22:03ZengNature PortfolioNature Communications2041-17232024-04-0115111610.1038/s41467-024-47466-3One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouseMarco Malatesta0Emanuele Fornasier1Martino Luigi Di Salvo2Angela Tramonti3Erika Zangelmi4Alessio Peracchi5Andrea Secchi6Eugenia Polverini7Gabriele Giachin8Roberto Battistutta9Roberto Contestabile10Riccardo Percudani11Department of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaDepartment of Chemical Sciences, University of PaduaIstituto Pasteur Italia-Fondazione Cenci Bolognetti and Department of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of RomeInstitute of Molecular Biology and Pathology, Italian National Research CouncilDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaDepartment of Mathematical, Physical and Computer Sciences, University of ParmaDepartment of Chemical Sciences, University of PaduaDepartment of Chemical Sciences, University of PaduaIstituto Pasteur Italia-Fondazione Cenci Bolognetti and Department of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of RomeDepartment of Chemistry, Life Sciences and Environmental Sustainability, University of ParmaAbstract The increasing availability of experimental and computational protein structures entices their use for function prediction. Here we develop an automated procedure to identify enzymes involved in metabolic reactions by assessing substrate conformations docked to a library of protein structures. By screening AlphaFold-modeled vitamin B6-dependent enzymes, we find that a metric based on catalytically favorable conformations at the enzyme active site performs best (AUROC Score=0.84) in identifying genes associated with known reactions. Applying this procedure, we identify the mammalian gene encoding hydroxytrimethyllysine aldolase (HTMLA), the second enzyme of carnitine biosynthesis. Upon experimental validation, we find that the top-ranked candidates, serine hydroxymethyl transferase (SHMT) 1 and 2, catalyze the HTMLA reaction. However, a mouse protein absent in humans (threonine aldolase; Tha1) catalyzes the reaction more efficiently. Tha1 did not rank highest based on the AlphaFold model, but its rank improved to second place using the experimental crystal structure we determined at 2.26 Å resolution. Our findings suggest that humans have lost a gene involved in carnitine biosynthesis, with HTMLA activity of SHMT partially compensating for its function.https://doi.org/10.1038/s41467-024-47466-3 |
| spellingShingle | Marco Malatesta Emanuele Fornasier Martino Luigi Di Salvo Angela Tramonti Erika Zangelmi Alessio Peracchi Andrea Secchi Eugenia Polverini Gabriele Giachin Roberto Battistutta Roberto Contestabile Riccardo Percudani One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse Nature Communications |
| title | One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse |
| title_full | One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse |
| title_fullStr | One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse |
| title_full_unstemmed | One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse |
| title_short | One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse |
| title_sort | one substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse |
| url | https://doi.org/10.1038/s41467-024-47466-3 |
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