7MER

Structure of ALDH4A1 complexed with trans-4-Hydroxy-L-proline

7MER の概要

• エントリーDOI: 10.2210/pdb7mer/pdb
• 分子名称: Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial, 4-HYDROXYPROLINE, PENTAETHYLENE GLYCOL, ... (6 entities in total)
• 機能のキーワード: aldehyde dehydrogenase, rossmann fold, nucleotide binding, acting on aldehyde or oxo group of donors, nad or nadp as acceptor, mitochondria, oxidoreductase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 124945.49

構造登録者

Bogner, A.N.,Stiers, K.M.,Tanner, J.J. (登録日: 2021-04-07, 公開日: 2021-06-09, 最終更新日: 2023-10-18)

主引用文献

Bogner, A.N.,Stiers, K.M.,McKay, C.M.,Becker, D.F.,Tanner, J.J.
Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans-4-hydroxy-L-proline.
Protein Sci., 30:1714-1722, 2021

PubMed Abstract: Aldehyde dehydrogenase 4A1 (ALDH4A1) catalyzes the final steps of both proline and hydroxyproline catabolism. It is a dual substrate enzyme that catalyzes the NAD -dependent oxidations of L-glutamate-γ-semialdehyde to L-glutamate (proline metabolism), and 4-hydroxy-L-glutamate-γ-semialdehyde to 4-erythro-hydroxy-L-glutamate (hydroxyproline metabolism). Here we investigated the inhibition of mouse ALDH4A1 by the six stereoisomers of proline and 4-hydroxyproline using steady-state kinetics and X-ray crystallography. Trans-4-hydroxy-L-proline is the strongest of the inhibitors studied, characterized by a competitive inhibition constant of 0.7 mM, followed by L-proline (1.9 mM). The other compounds are very weak inhibitors (approximately 10 mM or greater). Insight into the selectivity for L-stereoisomers was obtained by solving crystal structures of ALDH4A1 complexed with trans-4-hydroxy-L-proline and trans-4-hydroxy-D-proline. The structures suggest that the 10-fold greater preference for the L-stereoisomer is due to a serine residue that hydrogen bonds to the amine group of trans-4-hydroxy-L-proline. In contrast, the amine group of the D-stereoisomer lacks a direct interaction with the enzyme due to a different orientation of the pyrrolidine ring. These results suggest that hydroxyproline catabolism is subject to substrate inhibition by trans-4-hydroxy-L-proline, analogous to the known inhibition of proline catabolism by L-proline. Also, drugs targeting the first enzyme of hydroxyproline catabolism, by elevating the level of trans-4-hydroxy-L-proline, may inadvertently impair proline catabolism by the inhibition of ALDH4A1.

PubMed: 34048122
DOI: 10.1002/pro.4131

実験手法

X-RAY DIFFRACTION (1.74 Å)