Plant cytosolic aldehyde dehydrogenases from family 2 (ALDH2s, EC 1.2.1.3) are non-specific enzymes and participate for example in the metabolism of acetaldehyde or biosynthesis of phenylpropanoids. Plant aminoaldehyde dehydrogenases (AMADHs, ALDH10 family, EC 1.2.1.19) are broadly specific and play an important role in polyamine degradation or production of osmoprotectants. We have tested imidazole and pyrazole carbaldehydes and their alkyl-, allyl-, benzyl-, phenyl-, pyrimidinyl- or thienyl-derivatives as possible substrates of plant ALDH2 and ALDH10 enzymes. Imidazole represents a building block of histidine, histamine as well as certain alkaloids. It also appears in synthetic pharmaceuticals such as imidazole antifungals. Biological compounds containing pyrazole are rare (e.g. pyrazole-1-alanine and pyrazofurin antibiotics) but the ring is often found as a constituent of many synthetic drugs and pesticides. The aim was to evaluate whether aldehyde compounds based on azole heterocycles are oxidized by the enzymes, which would further support their expected role as detoxifying aldehyde scavengers. The analyzed imidazole and pyrazole carbaldehydes were only slowly converted by ALDH10s but well oxidized by cytosolic maize ALDH2 isoforms (particularly by ALDH2C1). In the latter case, the respective Km values were in the range of 10-2000 μmol l-1; the kcat values appeared mostly between 0.1 and 1.0 s-1. The carbaldehyde group at the position 4 of imidazole was oxidized faster than that at the position 2. Such a difference was not observed for pyrazole carbaldehydes. Aldehydes with an aromatic substituent on their heterocyclic ring were oxidized faster than those with an aliphatic substituent. The most efficient of the tested substrates were comparable to benzaldehyde and p-anisaldehyde known as the best aromatic aldehyde substrates of plant cytosolic ALDH2s in vitro.

• Klíčová slova
• Aldehyde dehydrogenase, Aminoaldehyde dehydrogenase, Imidazole, Isoenzyme, Pyrazole, Substrate,
• MeSH
• aldehyddehydrogenasa metabolismus   MeSH
• aldehydy chemie   metabolismus   MeSH
• hrách setý enzymologie   MeSH
• imidazoly chemie   metabolismus   MeSH
• kukuřice setá enzymologie   MeSH
• molekulární struktura MeSH
• oxidace-redukce MeSH
• pyrazoly chemie   metabolismus   MeSH
• Solanum lycopersicum enzymologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aldehyddehydrogenasa MeSH
• aldehydy MeSH
• imidazole MeSH Prohlížeč
• imidazoly MeSH
• pyrazole MeSH Prohlížeč
• pyrazoly MeSH

A Streptomyces aureofaciens gene, gap, encoding glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was previously identified. Hybridization studies suggested the presence of a second gap gene in S. aureofaciens. To clone the gene, S. aureofaciens subgenomic library was screened with an oligonucleotide probe encoding a peptide motif conserved in all GAPDH. 3352 bp positive BamHI fragment was identified, the length of which correlated with the hybridization signal. The nucleotide sequence of the fragment was determined, and analysis of the sequence revealed the presence of three open reading frames (ORF). However, none of the genes coded for GAPDH. All three genes formed an operon, consisting of gene orf251, with a high homology to a conserved gene present only in archaeabacteria, and the aldA and adhA genes homologous to various eukaryotic and prokaryotic aldehyde- and alcohol-dehydrogenases, with maximum homology to the phenylacetaldehyde dehydrogenases and arylalcohol dehydrogenases, respectively.

• MeSH
• aldehyddehydrogenasa chemie   genetika   metabolismus   MeSH
• klonování DNA * MeSH
• molekulární sekvence - údaje MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA MeSH
• sekvenční seřazení MeSH
• Streptomyces aureofaciens enzymologie   genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehyddehydrogenasa MeSH

Aldehyde dehydrogenase (ALDH) is a proposed biomarker and possible target to eradicate cancer stem cells. ALDH inhibition as a treatment approach is supported by anti-cancer effects of the alcohol-abuse drug disulfiram (DSF, Antabuse). Given that metabolic products of DSF, rather than DSF itself inhibit ALDH in vivo, and that DSF's anti-cancer activity is potentiated by copper led us to investigate the relevance of ALDH as the suggested molecular cancer-relevant target of DSF. Here we show that DSF does not directly inhibit ALDH activity in diverse human cell types, while DSF's in vivo metabolite, S-methyl-N,N-diethylthiocarbamate-sulfoxide inhibits ALDH activity yet does not impair cancer cell viability. Our data indicate that the anti-cancer activity of DSF does not involve ALDH inhibition, and rather reflects the impact of DSF's copper-containing metabolite (CuET), that forms spontaneously in vivo and in cell culture media, and kills cells through aggregation of NPL4, a subunit of the p97/VCP segregase. We also show that the CuET-mediated, rather than any ALDH-inhibitory activity of DSF underlies the preferential cytotoxicity of DSF towards BRCA1- and BRCA2-deficient cells. These findings provide evidence clarifying the confusing literature about the anti-cancer mechanism of DSF, a drug currently tested in clinical trials for repositioning in oncology.

• MeSH
• aldehyddehydrogenasa antagonisté a inhibitory   MeSH
• antitumorózní látky metabolismus   farmakologie   MeSH
• buňky A549 MeSH
• buňky K562 MeSH
• disulfiram metabolismus   farmakologie   MeSH
• inhibitory acetaldehyd dehydrogenasy metabolismus   farmakologie   MeSH
• jaderné proteiny metabolismus   MeSH
• kultivační média MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehyddehydrogenasa MeSH
• antitumorózní látky MeSH
• disulfiram MeSH
• inhibitory acetaldehyd dehydrogenasy MeSH
• jaderné proteiny MeSH
• kultivační média MeSH
• NPLOC4 protein, human MeSH Prohlížeč

Heterokonts, Alveolata protists, green algae from Charophyta and Chlorophyta divisions, and all Embryophyta plants possess an aldehyde dehydrogenase (ALDH) gene named ALDH12. Here, we provide a biochemical characterization of two ALDH12 family members from the lower plant Physcomitrella patens and higher plant Zea mays. We show that ALDH12 encodes an NAD+-dependent glutamate γ-semialdehyde dehydrogenase (GSALDH), which irreversibly converts glutamate γ-semialdehyde (GSAL), a mitochondrial intermediate of the proline and arginine catabolism, to glutamate. Sedimentation equilibrium and small-angle X-ray scattering analyses reveal that in solution both plant GSALDHs exist as equilibrium between a domain-swapped dimer and the dimer-of-dimers tetramer. Plant GSALDHs share very low-sequence identity with bacterial, fungal, and animal GSALDHs (classified as ALDH4), which are the closest related ALDH superfamily members. Nevertheless, the crystal structure of ZmALDH12 at 2.2-Å resolution shows that nearly all key residues involved in the recognition of GSAL are identical to those in ALDH4, indicating a close functional relationship with ALDH4. Phylogenetic analysis suggests that the transition from ALDH4 to ALDH12 occurred during the evolution of the endosymbiotic plant ancestor, prior to the evolution of green algae and land plants. Finally, ALDH12 expression in maize and moss is downregulated in response to salt and drought stresses, possibly to maintain proline levels. Taken together, these results provide molecular insight into the biological roles of the plant ALDH12 family.

• Klíčová slova
• ALDH12, Physcomitrella patens, Zea mays, glutamate γ-semialdehyde, proline,
• MeSH
• aldehyddehydrogenasa chemie   MeSH
• fylogeneze MeSH
• krystalografie rentgenová metody   MeSH
• prolin chemie   MeSH
• rostliny chemie   MeSH
• substrátová specifita MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• aldehyddehydrogenasa MeSH
• prolin MeSH

Aldehyde dehydrogenases (ALDHs) represent a superfamily of enzymes, which oxidize aldehydes to the corresponding acids. Certain families, namely ALDH9 and ALDH10, are best active with ω-aminoaldehydes arising from the metabolism of polyamines such as 3-aminopropionaldehyde and 4-aminobutyraldehyde. Plant ALDH10s show broad specificity and accept many different aldehydes (aliphatic, aromatic and heterocyclic) as substrates. This work involved the above-mentioned aminoaldehydes acylated with dicarboxylic acids, phenylalanine, and tyrosine. The resulting products were then examined with native ALDH10 from pea and recombinant ALDH7s from pea and maize. This investigation aimed to find a common efficient substrate for the two plant ALDH families. One of the best natural substrates of ALDH7s is aminoadipic semialdehyde carrying a carboxylic group opposite the aldehyde group. The substrate properties of the new compounds were demonstrated by mass spectrometry of the reaction mixtures, spectrophotometric assays and molecular docking. The N-carboxyacyl derivatives were good substrates of pea ALDH10 but were only weakly oxidized by the two plant ALDH7s. The N-phenylalanyl and N-tyrosyl derivatives of 3-aminopropionaldehyde were good substrates of pea and maize ALDH7. Particularly the former compound was converted very efficiently (based on the kcat/Km ratio), but it was only weakly oxidized by pea ALDH10. Although no compound exhibited the same level of substrate properties for both ALDH families, we show that these enzymes may possess more common substrates than expected.

• Klíčová slova
• Acylation, Aldehyde dehydrogenase, Aminoaldehyde, Docking, Enzyme, Substrate,
• MeSH
• aldehyddehydrogenasa * metabolismus   chemie   genetika   MeSH
• aldehydy * metabolismus   chemie   MeSH
• hrách setý * enzymologie   MeSH
• kinetika MeSH
• kukuřice setá * enzymologie   MeSH
• oxidace-redukce MeSH
• rostlinné proteiny metabolismus   chemie   genetika   MeSH
• simulace molekulového dockingu * MeSH
• substrátová specifita MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aldehyddehydrogenasa * MeSH
• aldehydy * MeSH
• rostlinné proteiny MeSH

BACKGROUND: Aldehyde dehydrogenase (ALDH) is highly active in physiological stem cells as well as in tumor-initiating cells of some malignancies including multiple myeloma (MM). Finding higher activity of ALDH in some cell subsets in monoclonal gammopathies (MG) could identify potential source of myeloma-initiating cells (MICs). METHODS: Bone marrow of 12 MM, 9 monoclonal gammopathy of undetermined significance (MGUS), and 10 healthy donors (HD) were analyzed by flow cytometry. ALDH activity of B-cells and plasma cells (PC) was analyzed using Aldefluor. RESULTS: Similar changes of ALDH activity were found during B-cell development in HD and MG. Decreasing of ALDH activity from immature to naïve B-cells was found. In postgerminal stages, the activity started to increase, and in PCs, the ALDH activity was the same as in immature B-cells. Increased ALDH activity of all PC subsets compared to naïve B-cells was found in MM as well as in HD, while in MGUS, only CD19- PCs have higher ALDH activity. In HD, ALDH activity was higher in CD19+ PCs compared with MG. CONCLUSIONS: Our results indicate that changes of ALDH activity are the natural phenomenon in B-cell development; thus, high ALDH activity as a single marker is not appropriate for MICs identification.

• Klíčová slova
• B-cell, aldehyde dehydrogenase, multiple myeloma, plasma cell,
• MeSH
• aktivace enzymů MeSH
• aldehyddehydrogenasa metabolismus   MeSH
• antigeny povrchové metabolismus   MeSH
• B-lymfocyty enzymologie   patologie   MeSH
• biologické markery MeSH
• dospělí MeSH
• imunofenotypizace MeSH
• kostní dřeň patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom diagnóza   enzymologie   MeSH
• monoklonální gamapatie nejasného významu diagnóza   enzymologie   MeSH
• paraproteinemie diagnóza   enzymologie   MeSH
• plazmatické buňky enzymologie   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aldehyddehydrogenasa MeSH
• antigeny povrchové MeSH
• biologické markery MeSH

BACKGROUND: ALDH-2 has been considered an important molecular target for the treatment of drug addiction due to its involvement in the metabolism of the neurotransmitter dopamine: however, the molecular basis for the selective inhibition of ALDH-2 versus ALDH-1 should be better investigated to enable a more pragmatic approach to the design of novel ALDH-2 selective inhibitors. OBJECTIVE: In the present study, we investigated the molecular basis for the selective inhibition of ALDH-2 by the antioxidant isoflavonoid daidzin (IC50 = 0.15 μM) compared to isoform 1 of ALDH through molecular dynamics studies and semiempirical calculations of the enthalpy of interaction. METHODS: The applied methodology consisted of performing the molecular docking of daidzin in the structures of ALDH-1 and ALDH-2 and submitting the lower energy complexes obtained to semiempirical calculations and dynamic molecular simulations. RESULTS: Daidzin in complex with ALDH-2 presented directed and more specific interactions, resulting in stronger bonds in energetic terms and, therefore, in enthalpic gain. Moreover, the hydrophobic subunits of daidzin, in a conformationally more restricted environment (such as the catalytic site of ALDH-2), promote the better organization of the water molecules when immersed in the solvent, also resulting in an entropic gain. CONCLUSION: The molecular basis of selective inhibition of ALDH-2 by isoflavonoids and related compounds could be related to a more favorable equilibrium relationship between enthalpic and entropic features. The results described herein expand the available knowledge regarding the physiopathological and therapeutic mechanisms associated with drug addiction.

• Klíčová slova
• ALDH-2, daidzin, isoflavonoids, molecular dynamics, nucleus accumbens, selective inhibition,
• MeSH
• aldehyddehydrogenasa metabolismus   MeSH
• dopamin metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• isoflavony farmakologie   MeSH
• poruchy spojené s užíváním psychoaktivních látek farmakoterapie   MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehyddehydrogenasa MeSH
• daidzin MeSH Prohlížeč
• dopamin MeSH
• inhibitory enzymů MeSH
• isoflavony MeSH

It is becoming increasingly evident that a high degree of regulation is involved in the protein synthesis machinery entailing more interacting regulatory factors. A multitude of proteins have been identified recently which show regulatory function upon binding to the ribosome. Here, we identify tight association of a metabolic protein aldehyde-alcohol dehydrogenase E (AdhE) with the E. coli 70S ribosome isolated from cell extract under low salt wash conditions. Cryo-EM reconstruction of the ribosome sample allows us to localize its position on the head of the small subunit, near the mRNA entrance. Our study demonstrates substantial RNA unwinding activity of AdhE which can account for the ability of ribosome to translate through downstream of at least certain mRNA helices. Thus far, in E. coli, no ribosome-associated factor has been identified that shows downstream mRNA helicase activity. Additionally, the cryo-EM map reveals interaction of another extracellular protein, outer membrane protein C (OmpC), with the ribosome at the peripheral solvent side of the 50S subunit. Our result also provides important insight into plausible functional role of OmpC upon ribosome binding. Visualization of the ribosome purified directly from the cell lysate unveils for the first time interactions of additional regulatory proteins with the ribosome.

• MeSH
• aldehydoxidoreduktasy chemie   metabolismus   MeSH
• alkoholdehydrogenasa chemie   metabolismus   MeSH
• Escherichia coli metabolismus   MeSH
• konformace proteinů MeSH
• molekulární modely MeSH
• poriny chemie   metabolismus   MeSH
• proteiny z Escherichia coli chemie   metabolismus   MeSH
• ribozomy chemie   genetika   metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adhE protein, E coli MeSH Prohlížeč
• aldehydoxidoreduktasy MeSH
• alkoholdehydrogenasa MeSH
• OmpC protein MeSH Prohlížeč
• poriny MeSH
• proteiny z Escherichia coli MeSH

Increased oxidative stress is indisputably an important mechanism of doxorubicin side effects, especially its cardiotoxicity. To prevent impairment of non-tumorous tissue and to improve the specificity in targeting the tumor tissue, new drug nanotransporters are developed. In many cases preclinical therapeutic advantage has been shown when compared with the administration of conventional drug solution. Three forms of doxorubicin--conventional (DOX), encapsulated in liposomes (lipoDOX) and in apoferritin (apoDOX) were applied to Wistar rats. After 24 h exposition, the plasma level of 4-hydroxy-2-nonenal (4-HNE) as a marker of lipoperoxidation and tissue gene expression of thioredoxin reductase 2 (TXNRD2) and aldehyde dehydrogenase 3A1 (ALDH3A1) as an important part of antioxidative system were determined. Only conventional DOX significantly increases the level of 4-HNE; encapsulated forms on the other hand show significant decrease in plasma levels of 4-HNE in comparison with DOX. They also cause significant decrease in gene expression of ALDH3A1 and TXNRD2 in liver as a main detoxification organ, and a mild influence on the expression of these enzymes in left heart ventricle as a potential target of toxicity. Thus, 4-HNE seems to be a good potential biomarker of oxidative stress induced by various forms of doxorubicin.

• MeSH
• aldehyddehydrogenasa genetika   metabolismus   MeSH
• aldehydy krev   MeSH
• antibiotika antitumorózní aplikace a dávkování   chemie   toxicita   MeSH
• apoferritiny aplikace a dávkování   chemie   toxicita   MeSH
• biologické markery krev   MeSH
• chemie farmaceutická MeSH
• down regulace MeSH
• doxorubicin aplikace a dávkování   analogy a deriváty   chemie   toxicita   MeSH
• játra účinky léků   enzymologie   MeSH
• oxidační stres účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• polyethylenglykoly aplikace a dávkování   chemie   toxicita   MeSH
• potkani Wistar MeSH
• regulace genové exprese enzymů MeSH
• thioredoxinreduktasa 2 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 4-hydroxy-2-nonenal MeSH Prohlížeč
• aldehyddehydrogenasa MeSH
• aldehydy MeSH
• antibiotika antitumorózní MeSH
• apoferritin doxorubicin MeSH Prohlížeč
• apoferritiny MeSH
• biologické markery MeSH
• doxorubicin MeSH
• liposomal doxorubicin MeSH Prohlížeč
• polyethylenglykoly MeSH
• thioredoxinreduktasa 2 MeSH
• Txnrd2 protein, rat MeSH Prohlížeč

Plant NAD(+)-dependent aminoaldehyde dehydrogenases (AMADHs, EC 1.2.1.19) belong to the family 10 of aldehyde dehydrogenases. They participate in the metabolism of polyamines or osmoprotectants. The enzymes are characterized by their broad substrate specificity covering ω-aminoaldehydes, aliphatic and aromatic aldehydes as well as nitrogen-containing heterocyclic aldehydes. The isoenzyme 1 from tomato (Solanum lycopersicum; SlAMADH1) oxidizes aliphatic aldehydes very efficiently and converts also furfural, its derivatives or benzaldehyde, which are present at low concentrations in alcoholic distillates such as fruit brandy. In this work, SlAMADH1 was examined as a bioanalytical tool for their detection. These aldehydes arise from fermentation processes or thermal degradation of sugars and their presence is related to health complications after consumption including nausea, emesis, sweating, decrease in blood pressure, hangover headache, among others. Sixteen samples of slivovitz (plum brandy) from local producers in Moravia, Czech Republic, were analyzed for their aldehyde content using a spectrophotometric activity assay with SlAMADH1. In all cases, there were oxidative responses observed when monitoring NADH production in the enzymatic reaction. Aldehydes in the distillate samples were also subjected to a standard determination using reversed-phase HPLC with spectrophotometric and tandem mass spectrometric detection after a derivatization with 2,4-dinitrophenylhydrazine. Results obtained by both methods were found to correlate well for a majority of the analyzed samples. The possible applicability of SlAMADH1 for the evaluation of aldehyde content in food and beverages has now been demonstrated.

• MeSH
• aldehydy škodlivé účinky   analýza   MeSH
• alkoholické nápoje škodlivé účinky   analýza   MeSH
• biotechnologie MeSH
• destilace MeSH
• izoenzymy metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• ovoce chemie   MeSH
• retinaldehydrogenasa metabolismus   MeSH
• rodina enzymů aldehyddehydrogenasy 1 MeSH
• rostlinné proteiny metabolismus   MeSH
• slivoň švestka chemie   MeSH
• Solanum lycopersicum enzymologie   MeSH
• tandemová hmotnostní spektrometrie MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aldehydy MeSH
• ALDH1A1 protein, human MeSH Prohlížeč
• izoenzymy MeSH
• retinaldehydrogenasa MeSH
• rodina enzymů aldehyddehydrogenasy 1 MeSH
• rostlinné proteiny MeSH