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

Abstract

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.

Growth-uncoupled propanediol production in a Thermoanaerobacterium thermosaccharolyticum strain engineered for high ethanol yield

“…Since ATP is known to chelate magnesium 32 , it is possible that the observed inhibition is due to chelation of magnesium present in the cell extracts. Whether such chelation could happen following a spike in ATP levels in vivo is unknown, though a recent structural study of ATP inhibition of a human aldehyde dehydrogenase showed a complex interplay of ATP and magnesium binding 33 .…”

Quantitative Proteomic Analysis of Zearalenone-Induced Intestinal Damage in Weaned Piglets

“…In addition, the ALDH-NAD + from the three pathways mentioned above was suppressed in the ZEN-treated piglets. The ALDH-NAD + was the one of ALDH [ 65 ], and its deficiency enhanced the ethanol-induced disruption of intestinal epithelial tight junctions and barrier dysfunction [ 66 ]. Therefore, we hypothesized that ZEN could cause damage to the intestine by regulating amino acid metabolic processes via inhibiting ALDH expression in weaned piglets.…”

Adipose precursor cell-associated markgene combined with single-cell sequencing with machine learning to build an obesity prediction model

“…The aldehyde dehydrogenase (ALDH) superfamily contains 19 enzyme isoforms that catalyze the irreversible oxidation of NAD (P) -dependent aldehydes to the corresponding carboxylic acid. ALDHs act on a wide variety of aldehyde substrates, some of which are derived from lipids, for example, retinoids, steroids, and lipid peroxidation products [19]. They play important roles in several biological processes, including the oxidative stress response, lipid hormone metabolism, and cell differentiation [20].…”