8PUM

Tha1 L-threonine aldolase (mouse), monoclinic form (C2)

8PUM の概要

• エントリーDOI: 10.2210/pdb8pum/pdb
• 分子名称: L-threonine aldolase, SODIUM ION (3 entities in total)
• 機能のキーワード: amino acid metabolic process, threonine aldolase, hydroxy trimethyl-lysine aldolase, carnitine biosynthesis, plp-dependent enzyme, lyase
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 83608.77

構造登録者

Battistutta, R.,Fornasier, E.,Giachin, G. (登録日: 2023-07-17, 公開日: 2024-03-20, 最終更新日: 2024-10-02)

主引用文献

Malatesta, M.,Fornasier, E.,Di Salvo, M.L.,Tramonti, A.,Zangelmi, E.,Peracchi, A.,Secchi, A.,Polverini, E.,Giachin, G.,Battistutta, R.,Contestabile, R.,Percudani, R.
One substrate many enzymes virtual screening uncovers missing genes of carnitine biosynthesis in human and mouse.
Nat Commun, 15:3199-3199, 2024

PubMed 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.

PubMed: 38615009
DOI: 10.1038/s41467-024-47466-3

実験手法

X-RAY DIFFRACTION (2.6 Å)