Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

E487K-Induced Disorder in Functionally Relevant Dynamics of Mitochondrial Aldehyde Dehydrogenase 2.

ABSTRACT: Mitochondrial aldehyde dehydrogenase 2 (ALDH2), which is a homotetramer assembled by two equivalent dimers, is an important enzyme that metabolizes ethanol-derived acetaldehyde to acetate in a coenzyme-dependent manner. The highly reactive acetaldehyde exhibits a toxic effect, indicating that the proper functioning of ALDH2 is essential to counteract aldehyde-associated diseases. It is known that the catalytic activity of ALDH2 is drastically impaired by a frequently observed mutation, E487K, in a dominant fashion. However, the molecular basis of the inactivation mechanism is elusive because of the complex nature of the dynamic behavior. Here, we performed microsecond-timescale molecular dynamics simulations of the proteins complexed with coenzymes. The E487K mutation elevated the conformational heterogeneity of the dimer interfaces, which are relatively distal from the substituted residue. Dynamic network analyses showed that Glu487 and the dimer interface were dynamically communicated, and the dynamic community further spanned throughout all of the subunits in the wild-type; however, this network was completely rearranged by the E487K mutation. The perturbation of the dynamic properties led to alterations of the global conformational motions and destabilization of the coenzyme binding required for receiving a proton from the catalytic nucleophile. The insights into the dynamic behavior of the dominant negative mutant in this work will provide clues to restore its function.

SUBMITTER: Matsumoto S

PROVIDER: S-EPMC7399495 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Characterizing the dynamics of functionally relevant complexes of formate dehydrogenase.

Project description:The potential for femtosecond to picosecond time-scale motions to influence the rate of the intrinsic chemical step in enzyme-catalyzed reactions is a source of significant controversy. Among the central challenges in resolving this controversy is the difficulty of experimentally characterizing thermally activated motions at this time scale in functionally relevant enzyme complexes. We report a series of measurements to address this problem using two-dimensional infrared spectroscopy to characterize the time scales of active-site motions in complexes of formate dehydrogenase with the transition-state-analog inhibitor azide (N(3)(-)). We observe that the frequency-frequency time correlation functions (FFCF) for the ternary complexes with NAD(+) and NADH decay completely with slow time constants of 3.2 ps and 4.6 ps, respectively. This result suggests that in the vicinity of the transition state, the active-site enzyme structure samples a narrow and relatively rigid conformational distribution indicating that the transition-state structure is well organized for the reaction. In contrast, for the binary complex, we observe a significant static contribution to the FFCF similar to what is seen in other enzymes, indicating the presence of the slow motions that occur on time scales longer than our measurement window.

| S-EPMC2964212 | biostudies-literature

Extramitochondrial Assembly of Mitochondrial Targeting Signal Disrupted Mitochondrial Enzyme Aldehyde Dehydrogenase.

Project description:Supramolecular assembly of metabolic enzymes has been studied both in vivo and in vitro for nearly a decade. Experimental evidence has suggested a close relationship between enzymatic activity and enzyme assembly/disassembly. However, most cases were studied with the cytosolic enzymes. Here, I report the evidence for a mitochondrial enzyme with its ability in forming visible intracellular structures. By removing the mitochondrial targeting sequence, yeast mitochondrial enzyme aldehyde dehydrogenase (Ald4p) exhibits reversible supramolecular assembly in the cytoplasm, thus creating a useful system for further characterization of the regulatory factors that modulate the assembly/disassembly of this mitochondrial enzyme.

| S-EPMC5906672 | biostudies-literature

The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis.

Project description:High aldehyde dehydrogenase (ALDH) activity can be used to identify tumor-initiating and metastasis-initiating cells in various human carcinomas, including prostate cancer. To date, the functional importance of ALDH enzymes in prostate carcinogenesis, progression and metastasis has remained elusive. Previously we identified strong expression of ALDH7A1 in human prostate cancer cell lines, primary tumors and matched bone metastases. In this study, we evaluated whether ALDH7A1 is required for the acquisition of a metastatic stem/progenitor cell phenotype in human prostate cancer. Knockdown of ALDH7A1 expression resulted in a decrease of the ?2(hi)/?v(hi)/CD44(+) stem/progenitor cell subpopulation in the human prostate cancer cell line PC-3M-Pro4. In addition, ALDH7A1 knockdown significantly inhibited the clonogenic and migratory ability of human prostate cancer cells in vitro. Furthermore, a number of genes/factors involved in migration, invasion and metastasis were affected including transcription factors (snail, snail2, and twist) and osteopontin, an ECM molecule involved in metastasis. Knockdown of ALDH7A1 resulted in decreased intra-bone growth and inhibited experimentally induced (bone) metastasis, while intra-prostatic growth was not affected. In line with these observations, evidence is presented that TGF-?, a key player in cancer invasiveness and bone metastasis, strongly induced ALDH activity while BMP7 (an antagonist of TGF-? signaling) down-regulated ALDH activity. Our findings show, for the first time, that the ALDH7A1 enzyme is functionally involved in the formation of bone metastases and that the effect appeared dependent on the microenvironment, i.e., bone versus prostate.

| S-EPMC3198191 | biostudies-literature

Partially irreversible inactivation of mitochondrial aldehyde dehydrogenase by nitroglycerin.

Project description:Mitochondrial aldehyde dehydrogenase (ALDH2) may be involved in the biotransformation of glyceryl trinitrate (GTN), and the inactivation of ALDH2 by GTN may contribute to the phenomenon of nitrate tolerance. We studied the GTN-induced inactivation of ALDH2 by UV/visible absorption spectroscopy. Dehydrogenation of acetaldehyde and hydrolysis of p-nitrophenylacetate (p-NPA) were both inhibited by GTN. The rate of inhibition increased with the GTN concentration and decreased with the substrate concentration, indicative of competition between GTN and the substrates. Inactivation of p-NPA hydrolysis was greatly enhanced in the presence of NAD(+), and, to a lesser extent, in the presence of NADH. In the presence of dithiothreitol (DTT) inactivation of ALDH2 was much slower. Dihydrolipoic acid (LPA-H(2)) was less effective than DTT, whereas glutathione, cysteine, and ascorbate did not protect against inactivation. When DTT was added after complete inactivation, dehydrogenase reactivation was quite modest (< or =16%). The restored dehydrogenase activity correlated inversely with the GTN concentration but was hardly affected by the concentrations of acetaldehyde or DTT. Partial reactivation of dehydrogenation was also accomplished by LPA-H(2) but not by GSH. We conclude that, in addition to the previously documented reversible inhibition by GTN that can be ascribed to the oxidation of the active site thiol, there is an irreversible component to ALDH inactivation. Importantly, ALDH2-catalyzed GTN reduction was partly inactivated by preincubation with GTN, suggesting that the inactivation of GTN reduction is also partly irreversible. These observations are consistent with a significant role for irreversible inactivation of ALDH2 in the development of nitrate tolerance.

| S-EPMC2576553 | biostudies-literature

Mitochondrial aldehyde dehydrogenase obliterates endoplasmic reticulum stress-induced cardiac contractile dysfunction via correction of autophagy.

Project description:ER stress triggers myocardial contractile dysfunction while effective therapeutic regimen is still lacking. Mitochondrial aldehyde dehydrogenase (ALDH2), an essential mitochondrial enzyme governing mitochondrial and cardiac function, displays distinct beneficial effect on the heart. This study was designed to evaluate the effect of ALDH2 on ER stress-induced cardiac anomalies and the underlying mechanism involved with a special focus on autophagy. WT and ALDH2 transgenic mice were subjected to the ER stress inducer thapsigargin (1mg/kg, i.p., 48h). Echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties as well as myocardial histology, autophagy and autophagy regulatory proteins were evaluated. ER stress led to compromised echocardiographic indices (elevated LVESD, reduced fractional shortening and cardiac output), cardiomyocyte contractile and intracellular Ca(2+) properties and cell survival, associated with upregulated autophagy, dampened phosphorylation of Akt and its downstream signal molecules TSC2 and mTOR, the effects of which were alleviated or mitigated by ALDH2. Thapsigargin promoted ER stress proteins Gadd153 and GRP78 without altering cardiomyocyte size and interstitial fibrosis, the effects of which were unaffected by ALDH2. Treatment with thapsigargin in vitro mimicked in vivo ER stress-induced cardiomyocyte contractile anomalies including depressed peak shortening and maximal velocity of shortening/relengthening as well as prolonged relengthening duration, the effect of which was abrogated by the autophagy inhibitor 3-methyladenine and the ALDH2 activator Alda-1. Interestingly, Alda-1-induced beneficial effect against ER stress was obliterated by autophagy inducer rapamycin, Akt inhibitor AktI and mTOR inhibitor RAD001. These data suggest a beneficial role of ALDH2 against ER stress-induced cardiac anomalies possibly through autophagy reduction.

| S-EPMC3578096 | biostudies-literature

Empagliflozin Ameliorates Aldehyde Dehydrogenase 2 Deficiency-induced Endothelial Dysfunction

Project description:We conducted RNA sequcing of the homozygous and heterozygous of ALDH2*2 by using human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs)

2023-03-30 | GSE184419 | GEO

Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications.

Project description:Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+-dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low Km enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated.

| S-EPMC3177986 | biostudies-literature

The mitochondrial aldehyde dehydrogenase OsALDH2b negatively regulates tapetum degeneration in rice.

Project description:Timely degradation of anther tapetal cells is a prerequisite for normal pollen development in flowering plants. Although several genes involved in tapetum development have been identified, the molecular basis of tapetum degeneration regulation remains poorly understood. In this study, we identified and characterized the nucleus-encoded, conserved mitochondrial aldehyde dehydrogenase OsALDH2b as a key regulator of tapetum degeneration in rice (Oryza sativa). OsALDH2b was highly expressed in anthers from meiosis to the early microspore stage. Mutation of OsALDH2b resulted in excess malonaldehyde accumulation and earlier programmed cell death in the tapetum, leading to premature tapetum degeneration and abnormal microspore development. These results demonstrate that OsALDH2b negatively regulates tapetal programmed cell death and is required for male reproductive development, providing insights into the regulation of tapetum development in plants.

| S-EPMC7210758 | biostudies-literature

Aldehyde dehydrogenase homologous folate enzymes: Evolutionary switch between cytoplasmic and mitochondrial localization.

Project description:Cytosolic and mitochondrial 10-formyltetrahydrofolate dehydrogenases are products of separate genes in vertebrates but only one such gene is present in invertebrates. There is a significant degree of sequence similarity between the two enzymes due to an apparent origin of the gene for the mitochondrial enzyme (ALDH1L2) from the duplication of the gene for the cytosolic enzyme (ALDH1L1). The primordial ALDH1L gene originated from a natural fusion of three unrelated genes, one of which was an aldehyde dehydrogenase. Such structural organization defined the catalytic mechanism of these enzymes, which is similar to that of aldehyde dehydrogenases. Here we report the analysis of ALDH1L1 and ALDH1L2 genes from different species and their phylogeny and evolution. We also performed sequence and structure comparison of ALDH1L enzymes possessing aldehyde dehydrogenase catalysis to those lacking this feature in an attempt to explain mechanistic differences between cytoplasmic ALDH1L1 and mitochondrial ALDH1L2 enzymes and to better understand their functional roles.

| S-EPMC4414694 | biostudies-literature

Dynamics and interactions of AAC3 in DPC are not functionally relevant.

Project description: Not available

| S-EPMC6150436 | biostudies-literature