Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

Marchitti, Satori A.; Brocker, Chad; Stagos, Dimitrios; Vasiliou, Vasilis

doi:10.1517/17425255.4.6.697

Cited by 696 publications

(515 citation statements)

References 238 publications

(277 reference statements)

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“…GST can bind free hemin, presumably reducing damage to the RBC membrane [ 4 , 6 , 7 ] . ALDH1 is indirectly involved in the protection against the eff ects of oxidative stress, oxidizing 4-HNE and MDA, the concentration of which increases as a result of lipid peroxidation [ 17 ] . The metastable aldehydes react with macromolecules such as proteins, lipids, phospholipids and DNA, which results in cytotoxic eff ects [ 18 ] .…”

mentioning

confidence: 99%

Blood ALDH1 and GST Activity in Diabetes Type 2 and its Correlation with Glycated Hemoglobin

Giebułtowicz

Sołobodowska

Bobilewicz

et al. 2014

Exp Clin Endocrinol Diabetes

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tive stress-associated pathologies. Excessive levels of LDAs are decreased by several enzyme systems that are able to oxidize them to acids like aldehyde dehydrogenase (ALDH) or catalyze their conjugation with endogenous ligands like glutathione-S-transferase (GST) [ 5 ] . There are only a few studies on erythrocyte glutathione S-transferase (GST) activity in DM, the results of which are ambiguous. Jerntorp et al. tried to fi nd an association between ALDH activity and DM and its complications such as large vessel disease, but the method they used did not lead to any valid conclusions [ 6 , 7 ] . Therefore, the aim of our studies was to compare the ALDH1 and GST activity in whole blood of DM patients and healthy control and analyze the relation of those enzymes activity with HbA1c. Materials and Methods ▼ Patients64 DM type 2 patients of the Warsaw Medical University Hospital (Group 1) and 60 healthy controls from the out-patients clinic (Control group) were enrolled in this study. Introduction ▼The number of patients with diabetes mellitus (DM), a metabolic disorder, is rapidly increasing worldwide due to several factors: population growth, aging, urbanization, increasing prevalence of obesity and reduced physical activity [ 1 ] . Increased oxidative stress (OS) may have an important causal role in β-cell failure and the development of insulin resistance, it is believed to be related with the onset and progression of diabetes. Moreover, OS also results from hyperglycemia associated with diabetes. Therefore, it is considered as a factor related to diabetes complications [ 2 ] . It is highly probable that not only reactive oxygen species (ROS) themselves but also secondary by-products of lipid peroxidation (LP) contribute to the deleterious consequences of OS e. g. insulin resistance [ 3 ] . Lipid peroxidationderived aldehydes (LDAs) may also increase the incidence of DM complications by the modifi cation of the collagen of the cardiovascular system causing its stiff ening and changes in the charge profi le [ 4 ] . This emphasizes the importance of the cellular protective mechanisms against LADs as they can prevent the development of some oxida-

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confidence: 99%

Blood ALDH1 and GST Activity in Diabetes Type 2 and its Correlation with Glycated Hemoglobin

Giebułtowicz

Sołobodowska

Bobilewicz

et al. 2014

Exp Clin Endocrinol Diabetes

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“…Enzymes belonging to the family of aldehyde dehydrogenases (ALDH) 3 are involved in conversions of a broad variety of aliphatic and aromatic aldehydes to their respective carboxylic acids (1)(2)(3). These enzymes are either dimers or tetramers of identical subunits (1).…”

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confidence: 99%

“…Two members of the family, cytosolic ALDH1 and mitochondrial ALDH2, are essential components of the pathway metabolizing ethanol (2,11). ALDH2 is also involved in mediating the vasodilator activity of nitroglycerine (12).…”

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confidence: 99%

Conserved Catalytic Residues of the ALDH1L1 Aldehyde Dehydrogenase Domain Control Binding and Discharging of the Coenzyme

Tsybovsky¹,

Krupenko

2011

Journal of Biological Chemistry

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The C-terminal domain (C t -FDH) of 10-formyltetrahydrofolate dehydrogenase (FDH, ALDH1L1) is an NADP ؉ -dependent oxidoreductase and a structural and functional homolog of aldehyde dehydrogenases. Here we report the crystal structures of several C t -FDH mutants in which two essential catalytic residues adjacent to the nicotinamide ring of bound NADP ؉ , Cys-707 and Glu-673, were replaced separately or simultaneously. The replacement of the glutamate with an alanine causes irreversible binding of the coenzyme without any noticeable conformational changes in the vicinity of the nicotinamide ring. Additional replacement of cysteine 707 with an alanine (E673A/ C707A double mutant) did not affect this irreversible binding indicating that the lack of the glutamate is solely responsible for the enhanced interaction between the enzyme and the coenzyme. The substitution of the cysteine with an alanine did not affect binding of NADP ؉ but resulted in the enzyme lacking the ability to differentiate between the oxidized and reduced coenzyme: unlike the wild-type C t -FDH/NADPH complex, in the C707A mutant the position of NADPH is identical to the position of NADP ؉ with the nicotinamide ring well ordered within the catalytic center. Thus, whereas the glutamate restricts the affinity for the coenzyme, the cysteine is the sensor of the coenzyme redox state. These conclusions were confirmed by coenzyme binding experiments. Our study further suggests that the binding of the coenzyme is additionally controlled by a longrange communication between the catalytic center and the coenzyme-binding domain and points toward an ␣-helix involved in the adenine moiety binding as a participant of this communication.Enzymes belonging to the family of aldehyde dehydrogenases (ALDH) 3 are involved in conversions of a broad variety of aliphatic and aromatic aldehydes to their respective carboxylic acids (1-3). These enzymes are either dimers or tetramers of identical subunits (1). Numerous crystal structures showed that subunits of different ALDHs have very similar fold with each composed of catalytic, nucleotide binding, and oligomerization domains (4 -10).Two members of the family, cytosolic ALDH1 and mitochondrial ALDH2, are essential components of the pathway metabolizing ethanol (2, 11). ALDH2 is also involved in mediating the vasodilator activity of nitroglycerine (12). Furthermore, activation of this enzyme correlates with reduced ischemic heart damage in rodent models (13). The polymorphism in the ALDH2 gene found in about 40% of the Asian population causes decreased tolerance to alcohol in heterozygous and homozygous individuals (14). This ALDH2 genetic variant, ALDH2 * 2, has a lysine instead of a glutamate at position 487 within the oligomerization domain of the tetrameric enzyme. This substitution induces conformational changes at the subunit interface, which are reflected by structural alterations within the catalytic center and the coenzyme binding site (5, 15, 16). The final outcome is a strong decrease in the affinity for NAD ...

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“…ALDHs are responsible for the detoxification of aldehyde molecules by oxidizing them to carboxylic acids [1]. Lipids are one source of cellular aldehydes; these lipid-derived aldehydes are generated via the normal metabolism of several lipids as well as the oxidation of unsaturated fatty acids due to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…The many aldehyde molecules present in living organisms are either absorbed from external sources such as diet, drugs, and environmental pollutants or endogenously produced via metabolism of lipids, amino acids, and neurotransmitters or through oxidation of biomolecules [1]. Aldehyde molecules are reactive in nature.…”

Section: Introductionmentioning

confidence: 99%

Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification

Kitamura

Takagi

Naganuma

et al. 2014

Biochemical Journal

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Short title: Lipid droplet localization of ALDH3B2Summary statement: The mouse aldehyde dehydrogenases ALDH3B2 and ALDH3B3 exhibit similar substrate specificity but distinct intracellular localization (ALDH3B2, lipid droplets; ALDH3B3, plasma membrane). The C-terminal prenylation and two Trp residues are important for the lipid droplet localization of ALDH3B2.2 ABSTRACT Aldehyde dehydrogenases (ALDHs) catalyze the conversion of toxic aldehydes to non-toxic carboxylic acids. Of the 21 ALDHs in mice, it is the ALDH3 family members (ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, and ALDH3B3) that are responsible for the removal of lipid-derived aldehydes. However, ALDH3B2 and ALDH3B3 have yet to be characterized.Here, we examined the enzyme activity, tissue distribution, and subcellular localization of ALDH3B2 and ALDH3B3. Both were found to exhibit broad substrate preferences from medium-chain to long-chain aldehydes, resembling ALDH3A2 and ALDH3B1. Although ALDH3B2 and ALDH3B3 share extremely high sequence similarity, their localizations differed, with ALDH3B2 found in lipid droplets and ALDH3B3 localized to the plasma membrane. Both ALDH3B2 and ALDH3B3 were modified by prenylation at their C-termini; this modification greatly influenced their membrane localization and enzymatic activity toward hexadecanal. We found that their C-terminal regions, particularly the two Trp residues (Trp462 and Trp469) of ALDH3B2 and the two Arg residues (Arg462 and Arg463) of ALDH3B3, were important for the determination of their specific localization. Abnormal quantity and perhaps quality of lipid droplets are implicated in several metabolic diseases. We speculate that ALDH3B2 acts to remove lipid-derived aldehydes in lipid droplets generated via oxidative stress as a quality control mechanism.

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Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

Cited by 696 publications

References 238 publications

Blood ALDH1 and GST Activity in Diabetes Type 2 and its Correlation with Glycated Hemoglobin

Blood ALDH1 and GST Activity in Diabetes Type 2 and its Correlation with Glycated Hemoglobin

Conserved Catalytic Residues of the ALDH1L1 Aldehyde Dehydrogenase Domain Control Binding and Discharging of the Coenzyme

Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification

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