Structural and biochemical evidence that ATP inhibits the cancer biomarker human aldehyde dehydrogenase 1A3

Albert Castellví, Raquel Pequerul, Vito Barracco, Judith Juanhuix, Xavier Parés, Jaime Farres Vicen

Producció científica: Contribució a una revistaArticleRecercaAvaluat per experts

7 Cites (Scopus)

Resum

Human aldehyde dehydrogenase (ALDH) participates in the oxidative stress response and retinoid metabolism, being involved in several diseases, including cancer, diabetes and obesity. The ALDH1A3 isoform has recently elicited wide interest because of its potential use as a cancer stem cell biomarker and drug target. We report high-resolution three-dimensional ALDH1A3 structures for the apo-enzyme, the NAD+ complex and a binary complex with ATP. Each subunit of the ALDH1A3-ATP complex contains one ATP molecule bound to the adenosine-binding pocket of the cofactor-binding site. The ATP complex also shows a molecule, putatively identified as a polyethylene glycol aldehyde, covalently bound to the active-site cysteine. This mimics the thioacyl-enzyme catalytic intermediate, which is trapped in a dead enzyme lacking an active cofactor. At physiological concentrations, ATP inhibits the dehydrogenase activity of ALDH1A3 and other isoforms, with a Ki value of 0.48 mM for ALDH1A3, showing a mixed inhibition type against NAD+. ATP also inhibits esterase activity in a concentration-dependent manner. The current ALDH1A3 structures at higher resolution will facilitate the rational design of potent and selective inhibitors. ATP binding to ALDH1A3 enables activity modulation by the energy status of the cell and metabolic reprogramming, which may be relevant in several disease conditions.

Idioma originalEnglish
Número d’article354
Pàgines (de-a)354
RevistaCommunications Biology
Volum5
Número1
DOIs
Estat de la publicacióPublicada - 13 d’abr. 2022

Fingerprint

Navegar pels temes de recerca de 'Structural and biochemical evidence that ATP inhibits the cancer biomarker human aldehyde dehydrogenase 1A3'. Junts formen un fingerprint únic.

Com citar-ho