Endogenous Aldehydes Research Articles

Metabolic engineering of Escherichia coli for upcycling of polyethylene terephthalate waste to vanillin.

Polyethylene terephthalate (PET) waste presents a significant environmental challenge due to its durability and resistance to degradation. Innovative approaches for upcycling PET waste into high-value chemicals can mitigate these issues while contributing to a circular economy. In this study, we developed a multi-enzyme cascade system in E. coli to convert PET-derived monomer terephthalic acid (TPA) into vanillin (VAN). The metabolic engineering approach was then employed to increase VAN production, including 1) inhibition of VAN degradation by knocking out endogenous aldehyde reductases and alcohol dehydrogenases and 2) enhancement of TPA uptake by modifying membrane proteins to increase cell permeability. The engineered E. coli demonstrated a VAN production of 658.55 mg/L from 1992 mg/L of TPA with a molar conversion rate of 71.1 %, representing the highest production of VAN using TPA as the substrate. Additionally, the engineered E. coli effectively converted post-consumer PET waste into VAN under mild conditions, with the highest production of 259.2 mg/L in 20× diluted PET hydrolysates, highlighting its potential for application in PET waste upcycling. This approach not only provides an environmentally friendly alternative to traditional chemical synthesis but also offers substantial economic benefits by transforming low-value waste into high-value chemicals.

Suppression of aldehyde dehydrogenase 2 in kidney proximal tubules contributes to kidney fibrosis through Transforming Growth Factor-β signaling

Chronic kidney disease (CKD) is an increasingly prevalent disorder that poses a significant global health and socioeconomic burden. East Asian countries such as China, Taiwan, Japan, and South Korea have a higher incidence and prevalence of kidney failure when compared to Western nations, and the reasons for this discrepancy remain unclear. Aldehyde dehydrogenase 2 (ALDH2) is an essential detoxifying enzyme for exogenous and endogenous aldehyde metabolism in mitochondria. Inactivating mutations at E504K and E487K are found in 35-45% of East Asian populations and has been linked to a higher risk of various disorders, including cardiovascular diseases and cancer. However, little is known about the role of ALDH2 in CKD. Here, we characterized the expression pattern of ALDH2 in normal and CKD human and mouse kidneys and demonstrated that ALDH2 expression was significantly reduced, and that the protein level was inversely correlated with the degree of CKD and fibrosis. Further, we treated ALDH2*2 knock-in mice, a loss of ALDH2 function model, with aristolochic acid and found that these mice showed enhanced fibrosis. Moreover, ALDH2 deficiency was associated with kidney fibrosis involving epithelial cell differentiation process in vivo and in vitro. However, ALDH2 overexpression protected proximal tubule epithelial cells from transforming growth factor-β-induced dedifferentiation or partial epithelial-mesenchymal transdifferentiation in vitro. Thus, our findings yield important clinical information regarding the development and progression of CKD involving ALDH2, especially among East Asian populations.

Aldehydes alter TGF-β signaling and induce obesity and cancer

Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2-/- and Aldh2-/-Sptbn1+/- mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

MRI Probes for In Vivo Aldehyde Sensing

AbstractEndogenous aldehydes are produced via tightly regulated metabolic processes and are rapidly cleared by aldehyde dehydrogenases. However, dysregulation of these processes leads to accumulation of toxic aldehydes in affected tissues, resulting in electrophilic stress forming pathogenic DNA‐ and protein‐adducts. The highly reactive aldehydes contribute to numerous pathologies including traumatic brain injury, cancer, cardiovascular diseases, and fibrosis. Due to their transient nature and electrophilicity, the development of molecular imaging probes with the ability to trap and detect aldehydes in vivo remains a challenge. Herein, two classes of aldehyde‐mapping MRI probes are discussed: (1) gadolinium and manganese‐containing macrocyclic MRI agents targeting extracellular aldehydes produced during active tissue fibrosis, and (2) metal‐free hydrazoCEST‐MRI agents for total intracellular aldehyde detection. This comprehensive review outlines the development, mechanisms, and potential applications of diverse MRI probes targeting aldehydes, aiming to advance non‐invasive diagnostic tools, disease staging, and therapeutic interventions in multiple pathologies.

Research Progress on the Correlation between Acetaldehyde Dehydrogenase 2 and Hepatocellular Carcinoma Development.

Hepatocellular carcinoma (HCC) is the predominant pathologic type of primary liver cancer. It is a malignant tumor of liver epithelial cells. There are many ways to treat HCC, but the survival rate for HCC patients remains low. Therefore, understanding the underlying mechanisms by which HCC occurs and develops is critical to explore new therapeutic targets. Aldehyde dehydrogenase 2 (ALDH2) is an important player in the redox reaction of ethanol with endogenous aldehyde products released by lipid peroxidation. Increasing evidence suggests that ALDH2 is a crucial regulator of human tumor development, including HCC. Therefore, clarifying the relationship between ALDH2 and HCC is helpful for formulating rational treatment strategies. This review highlights the regulatory roles of ALDH2 in the development of HCC, elucidates the multiple potential mechanisms by which ALDH2 regulates the development of HCC, and summarizes the progress of research on ALDH2 gene polymorphisms and HCC susceptibility. Meanwhile, we envision viable strategies for targeting ALDH2 in the treatment of HCC SIGNIFICANCE STATEMENT: Numerous studies have aimed to explore novel therapeutic targets for HCC, and ALDH2 has been reported to be a critical regulator of HCC progression. This review discusses the functions, molecular mechanisms, and clinical significance of ALDH2 in the development of HCC and examines the prospects of ALDH2-based therapy for HCC.

ALDH2 deficiency exacerbates MCD-diet induced MASLD by modulating bile acid metabolism

Aldehyde dehydrogenase 2 (ALDH2), an acetaldehyde dehydrogenase in mitochondria, is primarily responsible for metabolizing alcohol-derived acetaldehyde and other endogenous aldehydes. Inactivating ALDH2 rs671 polymorphism is found in up to 8 % of the global population and 40 % of the East Asian population. Recent studies have shown that rs671 SNP mutation in the human ALDH2 gene is associated with an increased risk of metabolic dysfunction-associated steatotic liver diseases (MASLD), but the mechanism remains unclear. Here, we identify the role of ALDH2 in MASLD. Firstly, ALDH2 activity was lower in MASLD patients and the methionine-choline deficiency (MCD) diet induced MASLD model. Secondly, activation of ALDH2 activity with Alda-1 (ALDH2 agonist) attenuated MCD-diet induced hepatic triglyceride (TG) accumulation and steatosis, whereas the opposite result was observed with cyanamide (CYA, ALDH2 inhibitor). Furthermore, ALDH2 deficiency exacerbated hepatic steatosis, inflammation, and fibrosis in the MCD-diet induced mice. RNA sequencing (RNA-seq) revealed that oxysterol 7-α hydroxylase (Cyp7b1) and the related metabolic pathway significantly changed in the MCD-diet challenged ALDH2−/− mice. In ALDH2−/− mice, the expression of Cyp7b1 was downregulated and FXR/SHP signaling was inhibited, reducing the alternative bile acid (BA) synthetic pathway. In our in vitro experiments, knockdown of ALDH2 exacerbated TG accumulation in hepatocytes, whereas the opposite result was observed with overexpression of ALDH2. Moreover, chenodeoxycholic acid (CDCA) rescued ALDH2 downregulation induced TG accumulation in hepatocytes. Our study reveals that ALDH2 attenuates hepatocyte steatosis by regulating the alternative BA synthesis pathway, and ALDH2 may serve as a potential target for the treatment of MASLD.

Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis

BackgroundAldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear.MethodsHere, we...

Treatment of cardiomyocytes isolated from left ventricular myocardium of dogs with chronic heart failure with ALDA-1, an activator of aldehyde dehydrogenase-2, improves mitochondrial function

Abstract Background Reactive oxygen species (ROS) generated by dysfunctional mitochondria (MITO) of the failing heart plays an important role in lipid peroxidation of polyunsaturated fatty acids in cell and MITO membranes resulting in the production of aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). MITO aldehyde dehydrogenase-2 (mALDH2) is a key enzyme for the detoxification of endogenous aldehyde substrates through NAD dependent oxidation. ALDH2 catalyzes toxic 4HNE to nontoxic 4HNA in cardiac cells. We previously showed that mALDH2 expression and activity are markedly reduced in MITO of failing LV cardiomyocytes (CM), a maladaptation that can lead to considerable accumulation of 4-HNE in MITO and ultimately to progressive LV systolic and diastolic dysfunction. In this study, we tested the hypothesis that exposure of failing cardiomyocytes to ALDA-1, an activator of mALDH2, improves MITO function. Methods Freshly isolated CM from LV myocardium of dogs (n = 7) with heart failure (HF, LV ejection fraction ≤35%) and of normal (NL) dogs (n = 4) were incubated for 1 hour in absence (baseline) and presence of Alda-1 at concentration of 10 µM. After incubation, ADP-stimulated respiration (ADPresp) and maximal rate of ATP synthesis (ATPmax) were measured using Strathklein respirometer and bioluminescence ATP assay kit. Results Treatment of isolated CM from HF dogs with 10 µM Alda-1 significantly increased ADPresp (277 ± 18 vs. 189 ± 12 nAtom O/min/mg, p<0.05) and ATPmax (30 ± 3 vs. 16 ± 3 nmoles/min/mg, p<0.05) compared to untreated CM of HF dogs. Treatment of CM from NL dogs with 10 µM Alda-1 had no effect on ADPresp (488 ± 18 vs. 484 ± 19 nAtom O/min/mg) or ATPmax (54 ± 3 vs. 52 ± 2 nmoles/min/mg) compared to untreated NL CM. Conclusions Treatment of CM from HF dogs with Alda-1 improved overall MITO function. Activation of mALDH2 represents a potential viable therapeutic target for treating HF.

Abstract P3173: Exposure Of Mitochondria Isolated From Left Ventricular Myocardium Of Dogs With Moderate Heart Failure To 4-hydroxy-2-nonenal (4-hne) Worsens Existing Mitochondrial Dysfunction

Background: Reactive oxygen species (ROS) generated by dysfunction of mitochondria (MITO) of the failing heart plays an important role in lipid peroxidation of polyunsaturated fatty acids in cell and MITO membranes resulting in the production of aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE). MITO aldehyde dehydrogenase-2 (mALDH2) is a key enzyme for the detoxification of endogenous aldehyde substrates through NAD dependent oxidation. We previously showed that mALDH2 expression and activity are markedly reduced in MITO of failing LV cardiomyocytes, a maladaptation that can lead to considerable accumulation of 4-HNE in MITO. It is unclear whether such an accumulation of 4-HNE can further exacerbate MITO dysfunction resulting in further limitation to ATP formation via oxidative phosphorylation. Hypothesis: This study tested the hypothesis that exposure of MITO isolated from failing hearts to exogenous 4-HNE can result in further deterioration of MITO function. Methods: Freshly isolated MITO from LV myocardium of dogs with moderate heart failure (HF, LV ejection fraction ~40%) were incubated for 1 hour in absence (baseline) and presence of 4-HNE at concentrations of 3 and 30 μM. MITO energetic parameters namely ADP-stimulated respiration (ADPresp), maximal respiratory capacity (MRC) and ATP-linked respiration (ATPresp) were evaluated using an XFe96 analyzer (Seahorse Biosciences). Results: Compared to baseline, exposure of MITO to 3 μM 4-HNE has no significant effects on any of the MITO energetic measures. However, exposure of MITO to 30 μM 4-HNE resulted in significant reduction of ADPresp (490 ± 37 vs. 179 ± 7 OCR pmols/O 2 /min, p<0.05), significant reduction of MRC (334 ± 56 vs. 124 ± 18 OCR pmols/O 2 /min, p<0.05), and significant reduction of ATPresp (48 ± 10 vs. 20 ± 12 OCR pmols/O 2 /min, p<0.05). Conclusions: Exposure of MITO from failing myocardium to elevated levels of 4-HNE can lead to marked deterioration of MITO function that can result in a further reduction of ATP leading to progression of LV dysfunction. Limiting the accumulation of 4-HNE through pharmacologic normalization of ALDH2 activity can potentially represent a therapeutic target for retarding the progression of LV dysfunction toward intractable HF.

Determination of hexanal and heptanal in saliva samples by an adapted magnetic headspace adsorptive microextraction for diagnosis of lung cancer

In this work, an analytical method for the determination of two endogenous aldehydes (hexanal and heptanal) as lung cancer biomarkers in saliva samples is presented for the first time. The method is based on a modification of magnetic headspace adsorptive microextraction (M–HS–AME) followed by gas chromatography coupled to mass spectrometry (GC-MS). For this purpose, an external magnetic field generated by a neodymium magnet is used to hold the magnetic sorbent (i.e., CoFe2O4 magnetic nanoparticles embedded into a reversed-phase polymer) in the headspace of a microtube to extract the volatilized aldehydes. Subsequently, the analytes are desorbed in the appropriate solvent and the extract is injected into the GC-MS system for separation and determination. Under the optimized conditions, the method was validated and showed good analytical features in terms of linearity (at least up to 50 ng mL−1), limits of detection (0.22 and 0.26 ng mL−1 for hexanal and heptanal, respectively), and repeatability (RSD ≤12%). This new approach was successfully applied to saliva samples from healthy volunteers and those with lung cancer, obtaining notably differences between both groups. These results reveal the prospect of the method as potential diagnostic tool for lung cancer by saliva analysis. This work contributes to the Analytical Chemistry field presenting a double novelty: on the one hand, the use of M–HS–AME in bioanalysis is unprecedentedly proposed, thus expanding the analytical potential of this technique, and, on the other hand, the determination of hexanal and heptanal is carried out in saliva samples for the first time.

Isotope-coded derivatization with designed Girard-type reagent as charged isobaric mass tags for non-targeted profiling and discovery of natural aldehydes by liquid chromatography-tandem mass spectrometry

Aldehyde-containing metabolites are reactive electrophiles that have attracted extensive attention due to their widespread occurrence in organisms and natural foods. Herein we described a newly-designed Girard's reagent, 1-(4-hydrazinyl-4-oxobutyl)pyridin-1-ium bromide (HBP), as charged tandem mass (MS/MS) tags to facilitate selective capture, sensitive detection and semi-targeted discovery of aldehyde metabolites via hydrazone formation. After HBP labeling, the detection signals of the test aldehydes were increased by 21–2856 times, with the limits of detection were 2.5–7 nM. Upon isotope-coded derivatization with a pair of labeling reagents, HBP-d0 and its deuterium-labeled counterpart HBP-d5, the aldehyde analytes were converted to hydrazone derivatives, which generated characteristic neutral fragments of 79 Da and 84 Da, respectively. The isobaric HBP-d0/HBP-d5 labeling based LC-MS/MS method was validated by relative quantification of human urinary aldehydes (slope=0.999, R2 > 0.99, RSDs ≤ 8.5%) and discrimination analysis between diabetic and control samples. The unique isotopic doubles (Δm/z = 5 Da) by dual neutral loss scanning (dNLS) provided a generic reactivity-based screening strategy that allowed non-targeted profiling and identification of endogenous aldehydes even amidst noisy data. The LC-dNLS-MS/MS screening of cinnamon extracts led to finding 61 possible natural aldehydes and guided discovery of 10 previously undetected congeners in this medicinal plant.

The role of aldehyde dehydrogenase 2 in cardiovascular disease.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD whoharbour the ALDH2 rs671 polymorphism.

Significantly enhanced bioconversion of high titer biomass-derived furfural to furfuryl alcohol by robust endogenous aldehyde reductase in a sustainable way

This study developed an effective and sustainable process for the production of furfuryl alcohol from biomass in a tandem reaction with a biochar-based heterogeneous chemocatalyst and a robust reductase biocatalyst using an aqueous system.

Aldehyde dehydrogenase 1: Its key role in cell physiology and oral carcinogenesis.

Aldehyde dehydrogenase (ALDH), an aldehyde-metabolizing enzyme, is a cytosolic antioxidant. It performs many important physiological catalytic and non-catalytic functions in mammalian cells. Apart from physiological functions, like the biosynthesis of vital molecules, this NAD(P)+ substrate-dependent enzyme superfamily is primarily involved in catalyzing the oxidation of highly reactive exogenous and endogenous aldehydes to their respective carboxylic acids. Among ALDH isoenzymes, ALDH1 has gained much attention as a prominent stem cell marker, as it is associated with the maintenance of stemness and the differentiation of normal stem cells, in addition to involvement in oncogenic functions, like cell proliferation, anti-apoptosis and the reduction of oxidative stress in cancer stem cells (CSCs). In this context, the authors review the physiological functions of ALDH1 in normal cells, normal stem cells and CSCs, along with the discussion of the putative role of ALDH1 in oral carcinogenesis by commenting on its expression in normal oral mucosa cells, oral potentially malignant disorders (OPMDs), like leukoplakia and dysplastic lesions, and oral squamous cell carcinoma (OSCC).

Активність цитозольних ензимів катаболізму ендогенних альдегідів у печінці щурів за умов різної забезпеченості раціону нутрієнтами

The research was conducted to study the activity of aldehyde dehydrogenase (EC 1.2.1.3) and aldehyde reductase (EC 1.1.1.21), the levels of TBA reactive substances and protein carbonyl derivates in the cytosolic fraction of rat liver under the conditions of different dietary sucrose and protein content. The animals were distributed into the 4 experimental groups: group I — animals receiving full-value semi-synthetic feed (control group); group II — animals on a low-protein diet (LPD); III group — animals on a high-sucrose diet (HS); IV group — animals on a low-protein and high-sucrose diet (LPD/HS). It was found that in animals under conditions of dietary protein deficiency, there was a two-fold increase in the levels of TBA reactive substances and protein carbonyl derivates in the liver cytosolic fraction against the absence of changes in the aldehyde reductase and aldehyde dehydrogenase activity. At the same time, in animals on a high-sucrose diet, there was a significant accumulation of the TBA reactive substances and carbonyl derivatives in the liver cytosolic fraction along with a 2–2.5-fold increase in both aldehyde reductase and aldehyde dehydrogenase activity. The maximum accumulation of the products of oxidative damage to proteins and lipids along with the insufficient activation of the enzymes ensuring their catabolism can be considered as one of the possible mechanisms of liver cell damage under conditions of the low-protein/high-sucrose diet. The obtained results open new prospects for future studies of the mechanisms of endogenous aldehydes detoxification and further development of a strategy for the correction of metabolic liver disorders under the conditions of nutrient imbalance.

Utilizing Alcohol for Alkane Biosynthesis by Introducing a Fatty Alcohol Dehydrogenase.

Alkanes produced by microorganisms are expected to be an alternative to fossil fuels as an energy source. Microbial synthesis of alkanes involves the formation of fatty aldehydes via fatty acyl coenzyme A (acyl-CoA) intermediates derived from fatty acid metabolism, followed by aldehyde decarbonylation to generate alkanes. Advancements in metabolic engineering have enabled the construction of such pathways in various microorganisms, including Escherichia coli. However, endogenous aldehyde reductases in the host microorganisms are highly active in converting fatty aldehydes to fatty alcohols, limiting the substrate pool for alkane production. To reuse the alcohol by-product, a screening of fatty alcohol-assimilating microorganisms was conducted, and a bacterial strain, Pantoea sp. strain 7-4, was found to convert 1-tetradecanol to tetradecanal. From this strain, an alcohol dehydrogenase, PsADH, was purified and found to be involved in 1-tetradecanol-oxidizing reaction. Subsequent heterologous expression of the PsADH gene in E. coli was conducted, and recombinant PsADH was purified for a series of biochemical characterizations, including cofactors, optimal reaction conditions, and kinetic parameters. Furthermore, direct alkane production from alcohol was achieved in E. coli by coexpressing PsADH with a cyanobacterial aldehyde-deformylating oxygenase and a reducing system, including ferredoxin and ferredoxin reductase, from Nostoc punctiforme PCC73102. The alcohol-aldehyde-alkane synthetic route established in this study will provide a new approach to utilizing fatty alcohols for the production of alkane biofuel. IMPORTANCE Alcohol dehydrogenases are a group of enzymes found in many organisms. Unfortunately, studies on these enzymes mainly focus on their activities toward short-chain alcohols. In this study, we discovered an alcohol dehydrogenase, PsADH, from the bacterium Pantoea sp. 7-4, which can oxidize 1-tetradecanol to tetradecanal. The medium-chain aldehyde products generated by this enzyme can serve as the substrate of aldehyde-deformylating oxygenase to produce alkanes. The enzyme found in this study can be applied to the biosynthetic pathway involving the formation of medium-chain aldehydes to produce alkanes and other valuable compounds.

The Role of Oxidative Stress and Changes in the Composition of the Gut Microbiota in the Genesis of Adolescent Obesity

Studying the pathogenetic mechanisms in the formation and development of obesity in adolescence is essential due to its high prevalence. Obesity was found to be associated with chronic inflammation in adipose tissue, dyslipidemia, the development of oxidative stress (OS), microbiota composition disorder, and other factors. A consequence of the OS progression is the accumulation in the body of cytotoxic compounds, including endogenous aldehydes, acting as mediators of damage and provoking characteristic shifts in metabolism. Gut microbiota contributes significantly to the development of metabolic disorders and obesity by modeling the cascade of enzymatic reactions of the macroorganism, interacting with receptors directly and/or with its metabolites and signaling molecules. In this context, it may be relevant to investigate the significance of the interaction of these systems to substantiate personalized approaches to the prevention and treatment of adolescent obesity.

Aldehyde dehydrogenase 2 and arrhythmogenesis.

Cardiac arrhythmia is a common cardiovascular disease that leads to considerable economic burdens and significant global public health challenges. Despite the remarkable progress made in recent decades, antiarrhythmic therapy remains suboptimal. Aldehyde dehydrogenase 2 (ALDH2), a critical detoxifying enzyme, catalyzes toxic aldehydes and protects individuals from damage caused by oxidative stress. Accumulating evidence has demonstrated that ALDH2 activation has potential antiarrhythmic benefits. The correlation between ALDH2 deficiency and arrhythmogenesis has been widely recognized. In this review, we summarize recent research on the potential role of ALDH2 activation and antiarrhythmic protection, as well as the role played by the ALDH2∗2 polymorphism (rs671) in promoting arrhythmic risk. Additionally, we discuss important new findings illustrating the use of ALDH2 activators, which may prove to be promising antiarrhythmic therapy agents.

Production of retinoic acid by engineered Saccharomyces cerevisiae using an endogenous aldehyde dehydrogenase

Retinoic acid (RA), a vitamin A (retinol)-derived lipophilic compound, is involved in various physiological functions. The demand for RA is growing in the pharmaceutical industry, but RA biosynthesis is still in its infancy compared to other forms of retinoids such as retinol and retinal, largely due to the lack of efficient retinal dehydrogenases. To achieve effective biosynthesis of RA, the catalytic activities of exogenous retinal dehydrogenases were comparatively analyzed in a previously constructed retinoids-producing Saccharomyces cerevisiae strain, followed by mining of endogenous enzymes with higher retinal dehydrogenase activities using homology-based search. After confirming the retinal oxidation activity of the endogenous aldehyde dehydrogenase Hfd1 using in vivo and in vitro experiments, it was overexpressed in multiple copies, and the resulting strain produced 99.71 mg/L of RA in shake-flask cultures. Finally, 545.28 mg/L of RA was produced in fed-batch fermentation. This study suggests the yeast endogenous Hfd1 as a potent catalyst for RA biosynthesis, and demonstrates the potential of yeast as a platform for RA production.

Genetic mapping of a bioethanol yeast strain reveals new targets for hydroxymethylfurfural- and thermotolerance

Current technology that enables bioethanol production from agricultural biomass imposes harsh conditions for Saccharomyces cerevisiae’s metabolism. In this work, the genetic architecture of industrial bioethanol yeast strain SA-1 was evaluated. SA-1 segregant FMY097 was previously described as highly aldehyde resistant and here also as thermotolerant: two important traits for the second-generation industry. A Quantitative Trait Loci (QTL) mapping of 5-hydroxymethylfurfural (HMF) -resistant segregants of hybrid FMY097/BY4742 disclosed a region in chromosome II bearing alleles with uncommon non-synonymous (NS) single nucleotide polymorphisms (SNPs) in FMY097: MIX23, PKC1, SEA4, and SRO77. Allele swap to susceptible laboratory strain BY4742 revealed that SEA4FMY097 enhances robustness towards HMF, but the industrial fitness could not be fully recovered. The genetic network arising from the causative genes in the QTL window suggests that intracellular signaling TOR (Target of Rapamycin) and CWI (Cell Wall Integrity) pathways are regulators of this phenotype in FMY097. Because the QTL mapping did not result in one major allelic contribution to the evaluated trait, a background effect in FMY097′s HMF resistance is expected. Quantification of NADPH - cofactor implied in endogenous aldehyde detoxification reactions - supports the former hypothesis, given its high availability in FMY097. Regarding thermotolerance, SEA4FMY097 grants BY4742 ability to grow in temperatures as high as 38 ºC in liquid, while allele PKC1FMY097 allows growth up to 40 ºC in solid medium. Both SEA4FMY097 and PKC1FMY097 encode rare NS SNPs, not found in other > 1013S. cerevisiae. Altogether, these findings point towards crucial membrane and stress mediators for yeast robustness.