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News & Updates


The Pharmaceutical Industry - Product Development and Safety Assessment of Pharmaceuticals
Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity.
Aldehyde dehydrogenase 1B1 (ALDH1B1) is a potential biomarker for human colon cancer.
Importance of inverse correlation between ALDH3A1 and PPARγ in tumor cells and tissue regeneration.
Structural and functional modifications of corneal crystallin ALDH3A1 by UVB light.
Molecular characterization, expression analysis, and role of ALDH3B1 in the cellular protection against oxidative stress.
The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1.
Aldehyde dehydrogenase 1B1: molecular cloning and characterization of a novel mitochondrial acetaldehyde-metabolizing enzyme.
Aldehyde dehydrogenase 3B1 (ALDH3B1): immunohistochemical tissue distribution and cellular-specific localization in normal and cancerous human tissues.
Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress.
Aldehyde Dehydrogenase 3B1 (ALDH3B1): Immunohistochemical Tissue Distribution and Cellular-specific Localization in Normal and Cancerous Human Tissues.
Corneal aldehyde dehydrogenases: multiple functions and novel nuclear localization.
Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart.
Human aldehyde dehydrogenase genes: alternatively spliced transcriptional variants and their suggested nomenclature.
The aldehyde dehydrogenase gene superfamily resource center.
Exon Duplication in Rattus norvegicus ALDH3B2.
ALDH Servers Back Online!
The Missing Link Found! Rattus norvegicus ALDH4A1
New Record Feature Added : Alternative Splice Variants
Aldehyde Dehydrogenase Enzyme Kinetics for Substrates and Inhibitors Section Incorporated
ALDH Molecular Features Section Revised
Aldehyde Dehydrogenase, Alcohol Use, and Flushing / Hives
ALDH.ORG Version 3 Released!
ALDH Database Revision - Murine Aldh1a7 and Aldh1a4
Welcome to WWW.ALDH.ORG. This site is hosted and curated by Dr. Vasilis Vasiliou's laboratory at the University of Colorado's Health Sciences Center. ALDH.ORG is dedicated to providing a detailed resource for the aldehyde dehydrogenase gene superfamily.

Genus species (Common Name) Superfamily Records Record Status
Bos taurus (Domestic cow) 4 (In Progress)
Homo sapiens (Human) 20 (Complete)
Mus musculus (House mouse) 21 (Complete)
Rattus norvegicus (Norway rat) 20 (Complete)
Vitis vinifera (Wine Grape) 17 (In Progress)
 
 

The Pharmaceutical Industry - Product Development and Safety Assessment of Pharmaceuticals

(Posted by William Black, 2012-10-16)
I have received a number of requests for our slide presentation, The Pharmaceutical Industry Product Development and Safety Assessment of Pharmaceuticals, from this years 2012 Society of Toxicologic Pathologists (STP) conference. It is now available online at Hugh E. Black & Associates, Inc., Consultants in Preclinical Drug Safety and Metabolism.

Please feel free to contact me if you need this presentation in another format. I apologize for any confusion.

Best regards, William J. Black, Ph.D.
Click to Enlarge
Figure 1. 2012 Society of Toxicologic Pathologists, The Pharmaceutical Industry - Product Development and Safety Assessment of Pharmaceuticals
 
 
 

Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity.

(Posted by William Black, 2011-03-01)
Mammalian aldehyde dehydrogenase 7A1 (ALDH7A1) is homologous to plant ALDH7B1 which protects against various forms of stress such as increased salinity, dehydration and treatment with oxidants or pesticides. Deleterious mutations in human ALDH7A1 are responsible for pyridoxine-dependent and folinic acid-responsive seizures. In previous studies, we have shown that human ALDH7A1 protects against hyperosmotic stress presumably through the generation of betaine, an important cellular osmolyte, formed from betaine aldehyde. Hyperosmotic stress is coupled to an increase in oxidative stress and lipid peroxidation (LPO). In this study, cell viability assays revealed that stable expression of mitochondrial ALDH7A1 in Chinese hamster ovary (CHO) cells provides significant protection against treatment with the LPO-derived aldehydes hexanal and 4-hydroxy-2-nonenal (4HNE) implicating a protective function for the enzyme during oxidative stress. A significant increase in cell survival was also observed in CHO cells expressing either mitochondrial or cytosolic ALDH7A1 treated with increasing concentrations of hydrogen peroxide (H(2)O(2)) or 4HNE, providing further evidence for anti-oxidant activity. In vitro enzyme activity assays indicate that human ALDH7A1 is sensitive to oxidation and that efficiency can be at least partially restored by incubating recombinant protein with the thiol reducing agent -mercaptoethanol (BME). We also show that after reactivation with BME, recombinant ALDH7A1 is capable of metabolizing the reactive aldehyde 4HNE. In conclusion, ALDH7A1 mechanistically appears to provide cells protection through multiple pathways including the removal of toxic LPO-derived aldehydes in addition to osmolyte generation.

Reference:

Brocker C, Cantore M, Failli P, Vasiliou V.
Chem Biol Interact. 2011 Feb 19.

PMID:  21338592
 
 
 

Aldehyde dehydrogenase 1B1 (ALDH1B1) is a potential biomarker for human colon cancer.

(Posted by William Black, 2011-02-15)
Aldehyde dehydrogenases (ALDHs) belong to a superfamily of NAD(P)(+)-dependent enzymes, which catalyze the oxidation of endogenous and exogenous aldehydes to their corresponding acids. Increased expression and/or activity of ALDHs, particularly ALDH1A1, have been reported to occur in human cancers. It is proposed that the metabolic function of ALDH1A1 confers the stemness properties to normal and cancer stem cells. Nevertheless, the identity of ALDH isozymes that contribute to the enhanced ALDH activity in specific types of human cancers remains to be elucidated. ALDH1B1 is a mitochondrial ALDH that metabolizes a wide range of aldehyde substrates including acetaldehyde and products of lipid peroxidation (LPO). In this study, we immunohistochemically examined the expression profile of ALDH1A1 and ALDH1B1 in human adenocarcinomas of colon (N=40), lung (N=30), breast (N=33) and ovary (N=33) using an NIH tissue array. The immunohistochemical expression of ALDH1A1 or ALDH1B1 in tumor tissues was scored by their intensity (scale=1-3) and extensiveness (% of total cancer cells). Herein we report a 5.6-fold higher expression score for ALDH1B1 in cancerous tissues than that for ALDH1A1. Remarkably, 39 out of 40 colonic cancer specimens were positive for ALDH1B1 with a staining intensity of 2.80.5. Our study demonstrates that ALDH1B1 is more profoundly expressed in the adenocarcinomas examined in this study relative to ALDH1A1 and that ALDH1B1 is dramatically upregulated in human colonic adenocarcinoma, making it a potential biomarker for human colon cancer.

Reference:

Chen Y, Orlicky DJ, Matsumoto A, Singh S, Thompson DC, Vasiliou V.
Biochem Biophys Res Commun. 2011 Feb 11;405(2):173-9.

PMID:  21216231
 
 
 

Importance of inverse correlation between ALDH3A1 and PPARγ in tumor cells and tissue regeneration.

(Posted by William Black, 2011-02-15)
Aldehyde dehydrogenase (ALDH) enzymes are involved in maintaining cellular homeostasis by metabolizing both endogenous and exogenous reactive aldehydes. They modulate several cell functions including proliferation, differentiation, survival as well as cellular response to oxidative stress. We previously reported that ALDH3A1 expression is inversely correlated with the activation of PPARs (Peroxisome Proliferators-Activated Receptors), a category of orphan nuclear hormone receptors, in both rat and human cells. PPARγ is involved in cell proliferation. In this study, we have used PPARγ transfection and inhibition to examine the relationship between ALDH3A1 and PPARγ and their role as regulators of cell proliferation. Induction of PPARγ in A549 and NCTC 2544 cells by transfection caused a decrease in ALDH3A1 and inhibition of cell proliferation, a result we obtained previously using ligands that induce PPARγ. A reduction of PPARγ expression using siRNA increased ALDH3A1 expression and cell proliferation. In cells induced to proliferate in a model of tissue regeneration, ALDH3A1 expression increased during the period of proliferation, whereas PPARγ expression decreased. In conclusion, through modulation of PPARγ or ALDH3A1, it may be possible to reduce cell proliferation in tumor cells or stimulate cell proliferation in normal cells during tissue regeneration.

Reference:

Oraldi M, Saracino S, Maggiora M, Chiaravalloti A, Buemi C, Martinasso G, Paiuzzi E, Thompson D, Vasiliou V, Canuto RA.
Chem Biol Interact. 2011 Jan 18.

PMID:  21251908
 
 
 

Structural and functional modifications of corneal crystallin ALDH3A1 by UVB light.

(Posted by William Black, 2011-02-10)
As one of the most abundantly expressed proteins in the mammalian corneal epithelium, aldehyde dehydrogenase 3A1 (ALDH3A1) plays critical and multifaceted roles in protecting the cornea from oxidative stress. Recent studies have demonstrated that one protective mechanism of ALDH3A1 is the direct absorption of UV-energy, which reduces damage to other corneal proteins such as glucose-6-phosphate dehydrogenase through a competition mechanism. UV-exposure, however, leads to the inactivation of ALDH3A1 in such cases. In the current study, we demonstrate that UV-light caused soluble, non-native aggregation of ALDH3A1 due to both covalent and non-covalent interactions, and that the formation of the aggregates was responsible for the loss of ALDH3A1 enzymatic activity. Spectroscopic studies revealed that as a result of aggregation, the secondary and tertiary structure of ALDH3A1 were perturbed. LysC peptide mapping using MALDI-TOF mass spectrometry shows that UV-induced damage to ALDH3A1 also includes chemical modifications to Trp, Met, and Cys residues. Surprisingly, the conserved active site Cys of ALDH3A1 does not appear to be affected by UV-exposure; this residue remained intact after exposure to UV-light that rendered the enzyme completely inactive. Collectively, our data suggest that the UV-induced inactivation of ALDH3A1 is a result of non-native aggregation and associated structural changes rather than specific damage to the active site Cys.

Reference:

Estey T, Chen Y, Carpenter JF, Vasiliou V.
PLoS One. 2010 Dec 21;5(12):e15218.

PMID:  21203538
 
 
 

Molecular characterization, expression analysis, and role of ALDH3B1 in the cellular protection against oxidative stress.

(Posted by William Black, 2011-01-15)
Aldehyde dehydrogenase (ALDH) enzymes are critical in the detoxification of aldehydes. The human genome contains 19 ALDH genes, mutations in which are the basis of several diseases. The expression, subcellular localization, enzyme kinetics, and role of ALDH3B1 in aldehyde- and oxidant-induced cytotoxicity were investigated. ALDH3B1 was purified from Sf9 cells using chromatographic methods, and enzyme kinetics were determined spectrophotometrically. ALDH3B1 demonstrated high affinity for hexanal (K(m)=62 M), octanal (K(m)=8 μM), 4-hydroxy-2-nonenal (4HNE; K(m)=52 μM), and benzaldehyde (K(m)=46 μM). Low affinity was seen toward acetaldehyde (K(m)=23.3 mM), malondialdehyde (K(m)=152 mM), and the ester p-nitrophenyl acetate (K(m)=3.6 mM). ALDH3B1 mRNA was abundant in testis, lung, kidney, and ovary. ALDH3B1 protein was highly expressed in these tissues and the liver. Immunofluorescence microscopy of ALDH3B1-transfected human embryonic kidney (HEK293) cells and subcellular fractionation of mouse kidney and liver revealed a cytosolic protein localization. ALDH3B1-transfected HEK293 cells were significantly protected from the lipid peroxidation-derived aldehydes trans-2-octenal, 4HNE, and hexanal and the oxidants H(2)O(2) and menadione. In addition, ALDH3B1 protein expression was up-regulated by 4HNE in ARPE-19 cells. The results detailed in this study support a pathophysiological role for ALDH3B1 in protecting cells from the damaging effects of oxidative stress.

Reference:

Marchitti SA, Brocker C, Orlicky DJ, Vasiliou V.
Free Radic Biol Med. 2010 Nov 15;49(9):1432-43.

PMID:  20699116
 
 
 

The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1.

(Posted by William Black, 2010-12-15)
Pyridoxine-dependent epilepsy is a disorder associated with severe seizures that may be caused by deficient activity of -aminoadipic semialdehyde dehydrogenase, encoded by the ALDH7A1 gene, with accumulation of -aminoadipic semialdehyde and piperideine-6-carboxylic acid. The latter reacts with pyridoxal-phosphate, explaining the effective treatment with pyridoxine. We report the clinical phenotype of three patients, their mutations and those of 12 additional patients identified in our clinical molecular laboratory. There were six missense, one nonsense, and five splice-site mutations, and two small deletions. Mutations c.1217_1218delAT, I431F, IVS-1(+2)T > G, IVS-2(+1)G > A, and IVS-12(+1)G > A are novel. Some disease alleles were recurring: E399Q (eight times), G477R (six times), R82X (two times), and c.1217_1218delAT (two times). A systematic review of mutations from the literature indicates that missense mutations cluster around exons 14, 15, and 16. Nine mutations represent 61% of alleles. Molecular modeling of missense mutations allows classification into three groups: those that affect NAD+ binding or catalysis, those that affect the substrate binding site, and those that affect multimerization. There are three clinical phenotypes: patients with complete seizure control with pyridoxine and normal developmental outcome (group 1) including our first patient; patients with complete seizure control with pyridoxine but with developmental delay (group 2), including our other two patients; and patients with persistent seizures despite pyridoxine treatment and with developmental delay (group 3). There is preliminary evidence for a genotype-phenotype correlation with patients from group 1 having mutations with residual activity. There is evidence from patients with similar genotypes for nongenetic factors contributing to the phenotypic spectrum.

Reference:

Scharer G, Brocker C, Vasiliou V, Creadon-Swindell G, Gallagher RC, Spector E, Van Hove JL.
J Inherit Metab Dis. 2010 Oct;33(5):571-81.

PMID:  20814824
 
 
 

Aldehyde dehydrogenase 1B1: molecular cloning and characterization of a novel mitochondrial acetaldehyde-metabolizing enzyme.

(Posted by William Black, 2010-12-01)
Ethanol-induced damage is largely attributed to its toxic metabolite, acetaldehyde. Clearance of acetaldehyde is achieved by its oxidation, primarily catalyzed by the mitochondrial class II aldehyde dehydrogenase (ALDH2). ALDH1B1 is another mitochondrial aldehyde dehydrogenase (ALDH) that shares 75% peptide sequence homology with ALDH2. Recent population studies in whites suggest a role for ALDH1B1 in ethanol metabolism. However, to date, no formal documentation of the biochemical properties of ALDH1B1 has been forthcoming. In this current study, we cloned and expressed human recombinant ALDH1B1 in Sf9 insect cells. The resultant enzyme was purified by affinity chromatography to homogeneity. The kinetic properties of purified human ALDH1B1 were assessed using a wide range of aldehyde substrates. Human ALDH1B1 had an exclusive preference for NAD(+) as the cofactor and was catalytically active toward short- and medium-chain aliphatic aldehydes, aromatic aldehydes, and the products of lipid peroxidation, 4-hydroxynonenal and malondialdehyde. Most importantly, human ALDH1B1 exhibited an apparent K(m) of 55 M for acetaldehyde, making it the second low K(m) ALDH for metabolism of this substrate. The dehydrogenase activity of ALDH1B1 was sensitive to disulfiram inhibition, a feature also shared with ALDH2. The tissue distribution of ALDH1B1 in C57BL/6J mice and humans was examined by quantitative polymerase chain reaction, Western blotting, and immunohistochemical analysis. The highest expression occurred in the liver, followed by the intestinal tract, implying a potential physiological role for ALDH1B1 in these tissues. The current study is the first report on the expression, purification, and biochemical characterization of human ALDH1B1 protein.

Reference:

Stagos D, Chen Y, Brocker C, Donald E, Jackson BC, Orlicky DJ, Thompson DC, Vasiliou V.
Drug Metab Dispos. 2010 Oct;38(10):1679-87.

PMID:  20616185
 
 
 

Aldehyde dehydrogenase 3B1 (ALDH3B1): immunohistochemical tissue distribution and cellular-specific localization in normal and cancerous human tissues.

(Posted by William Black, 2010-11-01)
Aldehyde dehydrogenase (ALDH) enzymes are critical in the detoxification of endogenous and exogenous aldehydes. Our previous findings indicate that the ALDH3B1 enzyme is expressed in several mouse tissues and is catalytically active toward aldehydes derived from lipid peroxidation, suggesting a potential role against oxidative stress. The aim of this study was to elucidate by immunohistochemistry the tissue, cellular, and subcellular distribution of ALDH3B1 in normal human tissues and in tumors of human lung, colon, breast, and ovary. Our results indicate that ALDH3B1 is expressed in a tissue-specific manner and in a limited number of cell types, including hepatocytes, proximal convoluted tubule cells, cerebellar astrocytes, bronchiole ciliated cells, testis efferent ductule ciliated cells, and histiocytes. ALDH3B1 expression was upregulated in a high percentage of human tumors (lung > breast = ovarian > colon). Increased ALDH3B1 expression in tumor cells may confer a growth advantage or be the result of an induction mechanism mediated by increased oxidative stress. Subcellular localization of ALDH3B1 was predominantly cytosolic in tissues, with the exception of normal human lung and testis, in which localization appeared membrane-bound or membrane-associated. The specificity of ALDH3B1 distribution may prove to be directly related to the functional role of this enzyme in human tissues.

Reference:

Marchitti SA, Orlicky DJ, Brocker C, Vasiliou V.
J Histochem Cytochem. 2010 Sep;58(9):765-83.

PMID:  20729348
 
 
 

Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress.

(Posted by William Black, 2010-08-01)
Mammalian ALDH7A1 is homologous to plant ALDH7B1, an enzyme that protects against various forms of stress, such as salinity, dehydration, and osmotic stress. It is known that mutations in the human ALDH7A1 gene cause pyridoxine-dependent and folic acid-responsive seizures. Herein, we show for the first time that human ALDH7A1 protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes. Human ALDH7A1 expression in Chinese hamster ovary cells attenuated osmotic stress-induced apoptosis caused by increased extracellular concentrations of sucrose or sodium chloride. Purified recombinant ALDH7A1 efficiently metabolized a number of aldehyde substrates, including the osmolyte precursor, betaine aldehyde, lipid peroxidation-derived aldehydes, and the intermediate lysine degradation product, alpha-aminoadipic semialdehyde. The crystal structure for ALDH7A1 supports the enzyme's substrate specificities. Tissue distribution studies in mice showed the highest expression of ALDH7A1 protein in liver, kidney, and brain, followed by pancreas and testes. ALDH7A1 protein was found in the cytosol, nucleus, and mitochondria, making it unique among the aldehyde dehydrogenase enzymes. Analysis of human and mouse cDNA sequences revealed mitochondrial and cytosolic transcripts that are differentially expressed in a tissue-specific manner in mice. In conclusion, ALDH7A1 is a novel aldehyde dehydrogenase expressed in multiple subcellular compartments that protects against hyperosmotic stress by generating osmolytes and metabolizing toxic aldehydes.

Reference:

Brocker C, Lassen N, Estey T, Pappa A, Cantore M, Orlova VV, Chavakis T, Kavanagh KL, Oppermann U, Vasiliou V.
J Biol Chem. 2010 Jun 11;285(24):18452-63.

PMID:  20207735
 
 
 

Aldehyde Dehydrogenase 3B1 (ALDH3B1): Immunohistochemical Tissue Distribution and Cellular-specific Localization in Normal and Cancerous Human Tissues.

(Posted by William Black, 2010-07-15)
Aldehyde dehydrogenase (ALDH) enzymes are critical in the detoxification of endogenous and exogenous aldehydes. Our previous findings indicate that the ALDH3B1 enzyme is expressed in several mouse tissues and is catalytically active towards aldehydes derived from lipid peroxidation, suggesting a potential role against oxidative stress. The aim of this study was to elucidate by immunohistochemistry the tissue, cellular and subcellular distribution of ALDH3B1 in normal human tissues and in tumors of human lung, colon, breast, and ovary. Our results indicate that ALDH3B1 is expressed in a tissue-specific manner and in a limited number of cell types, including hepatocytes, proximal convoluted tubule cells, cerebellar astrocytes, bronchiole ciliated cells, testis efferent ductule ciliated cells, and histiocytes. ALDH3B1 expression was up-regulated in a high percentage of human tumors (lung > breast = ovarian > colon). Increased ALDH3B1 expression in tumor cells may confer a growth advantage or be the result of an induction mechanism mediated by increased oxidative stress. Subcellular localization of ALDH3B1 was predominantly cytosolic with the exception of normal human lung and testis in which localization appeared membrane-bound or membrane-associated. The specificity of ALDH3B1 distribution may prove to be directly related to the functional role of this enzyme in human tissues.

Reference:

Marchitti SA, Orlicky DJ, Brocker C, Vasiliou V.
J Histochem Cytochem. 2010 May 24.

PMID:  20729348
 
 
 

Corneal aldehyde dehydrogenases: multiple functions and novel nuclear localization.

(Posted by William Black, 2010-04-15)
Aldehyde dehydrogenases (ALDHs) represent a superfamily of NAD(P)(+)-dependent enzymes which catalyze the oxidation of a wide variety of endogenous and exogenous aldehydes to their corresponding acids. Some ALDHs have been identified as corneal crystallins and thereby contribute to the protective and refractive properties of the cornea. ALDH3A1 is highly expressed in the cornea of most mammals with the exception of rabbit that abundantly expresses ALDH1A1 in the cornea instead of ALDH3A1. In this study, we examined the gene expression of other ALDHs and found high messenger levels of ALDH1B1, ALDH2 and ALDH7A1 in mouse cornea and lens. Substantial evidence supports a protective role for ALDH3A1 and ALDH1A1 against ultraviolet radiation (UVR)-induced oxidative damage to ocular tissues. The mechanism by which this protection occurs includes UVR filtering, detoxification of reactive aldehydes generated by UVR exposure and antioxidant activity. We recently have identified ALDH3A1 as a nuclear protein in corneal epithelium. Herein, we show that ALDH3A1 is also found in the nucleus of rabbit keratocytes. The nuclear presence of ALDH3A1 may be involved in cell cycle regulation.

Reference:

Stagos D, Chen Y, Cantore M, Jester JV, Vasiliou V.
Brain Res Bull. 2010 Feb 15;81(2-3):211-8. Epub 2009 Aug 29.

PMID:  19720116
 
 
 

Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart.

(Posted by William Black, 2010-01-15)
RATIONALE: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease.

OBJECTIVE: We investigated how the heart compensates for the accelerated accumulation of aldehydes.

METHODS AND RESULTS: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2alpha phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.)

CONCLUSIONS: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.

Reference:

Endo J, Sano M, Katayama T, Hishiki T, Shinmura K, Morizane S, Matsuhashi T, Katsumata Y, Zhang Y, Ito H, Nagahata Y, Marchitti S, Nishimaki K, Wolf AM, Nakanishi H, Hattori F, Vasiliou V, Adachi T, Ohsawa I, Taguchi R, Hirabayashi Y, Ohta S, Suematsu M, Ogawa S, Fukuda K.
Circ Res. 2009 Nov 20;105(11):1118-27

PMID:  19815821
 
 
 

Human aldehyde dehydrogenase genes: alternatively spliced transcriptional variants and their suggested nomenclature.

(Posted by William Black, 2010-01-15)
OBJECTIVE: The human aldehyde dehydrogenase (ALDH) gene superfamily consists of 19 genes encoding enzymes critical for NAD(P)-dependent oxidation of endogenous and exogenous aldehydes, including drugs and environmental toxicants. Mutations in ALDH genes are the molecular basis of several disease states (e.g. Sjgren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia) and may contribute to the etiology of complex diseases such as cancer and Alzheimer's disease. The aim of this nomenclature update was to identify splice transcriptional variants principally for the human ALDH genes.

METHODS: Data-mining methods were used to retrieve all human ALDH sequences. Alternatively spliced transcriptional variants were determined based on (i) criteria for sequence integrity and genomic alignment; (ii) evidence of multiple independent cDNA sequences corresponding to a variant sequence; and (iii) if available, empirical evidence of variants from the literature.

RESULTS AND CONCLUSION: Alternatively spliced transcriptional variants and their encoded proteins exist for most of the human ALDH genes; however, their function and significance remain to be established. When compared with the human genome, rat and mouse include an additional gene, Aldh1a7, in the ALDH1A subfamily. To avoid confusion when identifying splice variants in various genomes, nomenclature guidelines for the naming of such alternative transcriptional variants and proteins are recommended herein. In addition, a web database (www.aldh.org) has been developed to provide up-to-date information and nomenclature guidelines for the ALDH superfamily.

Reference:

Black WJ, Stagos D, Marchitti SA, Nebert DW, Tipton KF, Bairoch A, Vasiliou V.
Pharmacogenet Genomics. 2009 Nov;19(11):893-902.

PMID:  19823103
 
 
 

The aldehyde dehydrogenase gene superfamily resource center.

(Posted by William Black, 2010-01-15)
The website www.aldh.org is a publicly available database for nomenclature and functional and molecular sequence information for members of the aldehyde dehydrogenase (ALDH) gene superfamily for animals, plants, fungi and bacteria. The site has organised gene-specific records. It provides synopses of ALDH gene records, marries trivial terms to correct nomenclature and links global accession identifiers with source data. Server-side alignment software characterises the integrity of each sequence relative to the latest genomic assembly and provides identifier-specific detail reports, including a graphical presentation of the transcript's exon-intron structure, its size, coding sequence, genomic strand and locus. Also included are a summary of substrates, inhibitors and enzyme kinetics. The site provides reference lists and is designed to facilitate data mining by interested investigators.

Reference:

Black W, Vasiliou V.
Hum Genomics. 2009 Dec;4(2):136-42.

PMID:  20038501
 
 
 

Exon Duplication in Rattus norvegicus ALDH3B2.

(Posted by William Black, 2009-05-31)
The GSRC SAST software identified Rat ALDH3B2 exons 2, 3, 4, 5, and 6 are duplicated ~47000 bases upstream to this gene. This may be due to either a sequencing error in the genomic assembly (NC_005100) or possibly evidence for retroviral involvment in gene duplication. Translation of these five exons yield the bulk of the ALDH peptide domain (Aldeh) according to Pfam analysis. Data are currently being analyzed as to whether or not these exons are transcriptionally supported within cDNA libraries.
 
 
 

ALDH Servers Back Online!

(Posted by William Black, 2009-05-30)
The ALDH servers have been unavailable due to extensive hardware and software upgrades in order to improve their performance.

Currently, we are making ongoing improvements to several of the sequence alignment algorithms as a result from your reportings. Thank you! Keep them coming!

If you happen to find any error reports within the site please feel free to send them to william.black@aldh.org so that they can be rectified. Also, any comments or suggestions to improve the site are welcomed!
 
 
 

The Missing Link Found! Rattus norvegicus ALDH4A1

(Posted by William Black, 2009-01-10)
Well maybe not that missing link ... however, Reference Sequences for Rat ALDH4A1 are missing from the NCBI and EBI databases.

Here we have partly identified exons for ALDH4A1 (Figure 1. highlighted in red) as part of a potential fusion gene in Rat. This may be yet another error in the NCBI and EBI databases and is under investigation. Stay tuned!
Click to Enlarge
Figure 1. Rattus norvegicus ALDH4A1? Highlighted as red exons are orthologous exons between Rat, Mouse and Human.
 
 
 

New Record Feature Added : Alternative Splice Variants

(Posted by William Black, 2008-10-15)
Our laboratory continues to compile data for the aldehyde dehydrogenase (ALDH) gene superfamily to provide a cohesive informational resource regarding this enzyme family.

One area of interest has been defining the alternative splice variants for each ALDH within the superfamily. Alternative splicing is the RNA splicing variation mechanism in which the exons of the primary gene transcript (pre-mRNA) are spliced to produce alternative RNA arrangements yielding a variety of altered peptide products for the same gene. The functional roles for these arrangements remain to be determined and are under current investigation in a number of laboratories.

Prior to our compilations, alternative splice variants in the ALDH superfamily like most other genes remained very much in the gray area. Basic questions such as,
How many alternative splice variants are there for my gene product? or
How many exons are in my transcript? or
Which part of the sequence belongs to which exon?,
can become a matter of dispute depending on which database you visit and occasionally the time of day you visit that particular site.

The National Center for Biotechnology Information (NCBI) webserver AceView, provides one of the better screenings for alternative splice variants for a given gene but not without its share of weaknesses. Screening numerous cDNA sequences for a given gene, AceView breaks down the possible splice variants and gives each variant its own accession identification number (yet another accession identification number to chalk up on a yellow Post-It). However, we caution that you check and recheck the splice variants for your gene as they may often not be a variant at all.

As an example of this we left human ALDH1A3 variant 3 (ALDH1A3_v3) in our database to demonstrate graphically that just because it is reported in AceView, GenBank, RefSeq, Ensembl TransView etc. as an alternative splice variant does not necessarily mean it is actually an alternative splice variant for your gene.

This kind of thing is ubiquitous throughout the major sequence databases and is just one of many. Another example is ALDH8A1_v3.

Our goal is to catalog the existing accession identification numbers available from the major databases to the corresponding alternative splice variant based upon that accession's reported sequence using our proprietary alignment software.

These sequences are continually aligned to the latest genomic sequence assemblies released by NCBI for a given species (i.e. the current assembly for Homo sapiens is NCBI Build 36.3, March 26, 2008 reference assembly). A catalog of alternative splice variants as well as a number of features are produced in both a graphical and tabular format available to the end-users for personal use or reproduction and include,
  • positional coordinates of transcript features (5'untranslated region, coding sequence, 3' untranslated region, polyA signal, polyA tail, etc.)
  • positional coordinates of exons on the transcripts,
  • positional coordinates of triplet codons and peptide translation of these transcripts,
  • positional coordinates of exons on the genomic sequence,
  • positional coordinates of introns on the genomic sequence as well as sequences for the introns
  • information regarding differences in the sequences between the transcripts and the genomic sequence assembly (insertions, deletions and single nucleotide polymorphisms).


We developed this system for several reasons.

We want to ensure that users have the latest available data based upon the latest sequence assemblies released to the community. This isn't always the case when sifting thru other databases.

For example a number of GenBank accessions provide sequence coordinates for coding sequences, UTR's and exon positions according to SPLIGN or some other alignment software on a very dated genomic sequence assembly. However, more recent assemblies do not necessarily reflect those coordinates and may be misleading. We have also noted software errors in EBI's Ensembl curation engine that on occasion does not appropriately translate the transcript sequence or may report a 2-base deletion in the transcript sequence as an actual intron thereby inaccurately recording the number of exons and potentially the number of alternative splice variants for a given gene.

Therefore it is the goal of our curation system to provide users a degree of confidence with the details provided for the latest transcript and genome assemblies and the coordinates derived in a simplified graphical and tabular user interface.

To view this information, select a Gene Record from the 'ALDH Gene Superfamily' menu and click on 'Click Here for Graphical and Tabular Details' found under the Molecular Features Section.

We hope you find this useful and we welcome all input to help make this system a friendlier and useful tool for all. Let us know what you think!

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Figure 1. Graphical representation of aligned alternative splice variants now available for Aldehyde Dehydrogenases. Easily distinguish the similarities and differences of ALDH splice variants for a given gene.
 
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Figure 2. Detailed graphical representation for each accession ID that has been determined to have valid exon and intron structural integrity. SNPs, Insertions or Deletions found within these sequences are reported and easily viewable for the sequence.
 
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Figure 3. Primary peptide sequences are available and sequence anomalies are visually presented.
 
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Figure 4. A detailed report of alternative splice variants with hotlinks to source information and details regarding the accession number.
 
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Figure 5. Tabular report for each accession ID with sequence information and positional coordinates for the transcript sequence and corresponding genomic sequence.
 
 
 

Aldehyde Dehydrogenase Enzyme Kinetics for Substrates and Inhibitors Section Incorporated

(Posted by William Black, 2007-10-23)
We have added the Enzyme Kinetics for Substrates and Inhibitors section under each ALDH Gene record. This is a compilation of data derived from the literature available from Pubmed and under certain circumstances some data from unpublished studies. We are in a constant state of adding data to this section and would be greatly appreciative for any manuscripts our users recommend for incorpation into the website.
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Figure 1.
 
 
 

ALDH Molecular Features Section Revised

(Posted by William Black, 2007-09-30)
The Molecular Features section for each ALDH was revised to reflect proper references for data presented. Each entry is detailed with the Accession Numbers or links to where the data are derived. Also, a number of accession numbers from the various databases were updated and/or retired due to the latest builds from NCBI / EBI, accordingly.
 
 
 

Aldehyde Dehydrogenase, Alcohol Use, and Flushing / Hives

(Posted by William Black, 2007-07-06)
Over the years we have received an enormous number of e-mails regarding questions about facial flushing that may occur following consumption of an alcoholic beverage. As so often is the case, their doctor fails to provide a detailed reason for such an incidence but may mention aldehyde dehydrogenase which leads them to us!

To be frank, we were not exactly prepared for these kind of questions as we were more focused on the molecular biology and chemistry of this gene superfamily. However the web is a wonderful tool that brings users with a vast range of scientific backgrounds together. As a result, I am preparing a Section within the ALDH Overview detailing the role of aldehyde dehydrogenases in the flushing syndrome experienced by so many.
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Figure 1.
 
 
 

ALDH.ORG Version 3 Released!

(Posted by William Black, 2007-07-05)
The site is being significantly revised in hopes of providing users with an easier access system to data sought.

At this time, we are releasing the human, mouse and rat ALDH records as a beta test to work out the growing pains as well as obtain valuable feedback from users. Several sections for each ALDH will not be immediately available (polymorphisms, alternative splicing, and substrates specificities) but will be released in the coming weeks.

Please feel free to contact us if you have any questions or comments with the site.
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ALDH Database Revision - Murine Aldh1a7 and Aldh1a4

(Posted by William Black, 2007-04-04)
Mus musculus (mouse) Aldh1a7 and Rattus norvegicus (Norway rat) Aldh1a4 pairwise alignments of their gene products demonstrate 92% sequence homology using ClustalW (version 1.83). Under the nomenclature guidelines for aldehyde dehydrogenases, this homology is indicative that these sequences are in fact orthologs. As a result, these two ALDH's were submitted to the major databases for revision, accordingly, and are annotated under Aldh1a7.
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Figure 1. Pairwise alignment of Mouse Aldh1a7 (NCBI Entrez Protein: NP_058968) and Rat Aldh1a4 (NCBI Entrez Protein: NP_058968) demonstrates 92% sequence homology using ClustalW (version 1.83).
 
 

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