ArticleNature communications2024
One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 9 citations in OpenAlex.
- ALDH1B1 promotes mitochondrial γ-butyrobetaine biosynthesis and fatty acid oxidation in colorectal cancer.bioRxiv : the preprint server for biology · 2026Article
- Enzymes for Synthesis and Degradation of Bio-Based Polyesters: Automatic In Silico Screening and Experimental Validation.ChemSusChem · 2026Article
- A novel DCSTAMP antagonist impedes preosteoclast fusion via modulation of RAP1B-RAC1-mediated cytoskeletal remodeling.Experimental & molecular medicine · 2025Article
- Computational approaches to enzymatic reaction assignment: a review of methods, validations, and future directions.Briefings in bioinformatics · 2025Review
- C11orf54 catalyzes L-xylulose formation in human metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Predicting Protein Function in the AI and Big Data Era.Biochemistry · 2025Review
- Comprehensive review of the expanding roles of the carnitine pool in metabolic physiology: beyond fatty acid oxidation.Journal of translational medicine · 2025Review
- Comprehensive analysis of peripheral blood free amino acids in MASLD: the impact of glycine-serine-threonine metabolism.Amino acids · 2024Article
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
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.
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