9AYI

Human malic enzyme 2 cofactor complex at 1.89 Angstrom.

9AYI の概要

• エントリーDOI: 10.2210/pdb9ayi/pdb
• 関連するPDBエントリー: 8W24
• 分子名称: NAD-dependent malic enzyme, mitochondrial, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 1,2-ETHANEDIOL, ... (7 entities in total)
• 機能のキーワード: malic enzyme 2, nad+, co-factor complex, me2, mitochondrial localisation, m-nad-me, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 265233.75

構造登録者

Krinkel, B.A.,Squire, C.J.,Loomes, K.M. (登録日: 2024-03-07, 公開日: 2025-03-12, 最終更新日: 2025-10-29)

主引用文献

Jeon, J.H.,Slayton, M.D.,Krinkel, B.,Animasahun, O.,Shankaran, A.,Wuchu, F.,Nenwani, M.,Farah, Z.,Burke, J.,Achreja, A.,Nilaj, B.,Kohagen, K.,Eu, Y.H.,Rosenfeld, A.,Collard, M.,Bao, L.,Cheng, X.,Kleer, C.,Squire, C.,Loomes, K.,Nagrath, D.,Merajver, S.D.
Interplay between malic enzyme 2, de novo serine synthesis, and the malate-aspartate shuttle drives metabolic adaptation in triple-negative breast cancer.
Cancer Metab, 13:42-42, 2025

PubMed Abstract: Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer with poor clinical outcomes. Malic enzyme 2 (ME2) is a mitochondrial enzyme that catalyzes the conversion of malate to pyruvate and has been proposed as a therapeutic target. ME2 is highly expressed in many cell types including TNBC cells. We sought to define the molecular and cellular consequences of ME2 inhibition to facilitate its clinical translation. Here, we systematically evaluated the cellular and molecular effects of ME2 knockdown (ME2kd) in multiple TNBC models. ME2kd had heterogeneous effects on proliferation, migration, and metabolic flexibility in TNBC cell lines. ME2kd MDA-MB-468 xenografts in nude mice grew significantly slower and conferred prolonged host survival. ME2kd caused distinct shifts in mitochondrial respiration and glycolysis, whereas metabolomic and transcriptomic analyses revealed altered tricarboxylic acid (TCA) cycle flux, glutamine consumption, and serine/glycine metabolism, partly through changes in malate-aspartate shuttle (MAS) activity. The interplay between ME2, the serine synthesis pathway and the MAS was investigated with metabolite deprivation and co-knockdown assays. Importantly, we determined the crystal structure of ME2 bound to the small-molecule inhibitor NPD-389 and identified the binding interactions that drive the inhibitory response. These findings help to clarify the role of ME2 in TNBC phenotypes and highlight the therapeutic potential of ME2 inhibition in precision oncology.

PubMed: 41088330
DOI: 10.1186/s40170-025-00410-5

実験手法

X-RAY DIFFRACTION (1.89 Å)