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1325  structures 8529  species 4  interactions 98431  sequences 508  architectures

Family: Aldedh (PF00171)

Summary: Aldehyde dehydrogenase family

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This is the Wikipedia entry entitled "Aldehyde dehydrogenase". More...

Aldehyde dehydrogenase Edit Wikipedia article

Aldehyde dehydrogenase (NAD+)
Monomer with an NAD (with surface).png
Monomer of human aldehyde dehydrogenase 2 (ALDH2) with a space-filling model of NAD+ in the active site.[1]
Identifiers
EC number 1.2.1.3
CAS number 9028-86-8
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO

Aldehyde dehydrogenases (EC 1.2.1.3) are a group of enzymes that catalyse the oxidation of aldehydes.[2] Despite the name "dehydrogenase", their mode of oxidation is by addition of oxygen rather than by removal of hydrogen – that is, they convert aldehydes (R–C(=O)–H) to carboxylic acids (R–C(=O)–O–H).[3] To date, nineteen ALDH genes have been identified within the human genome. These genes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes.

Function

Aldehyde dehydrogenase is a polymorphic enzyme[4] responsible for the oxidation of aldehydes to carboxylic acids, which leave the liver and are metabolized by the body’s muscle and heart.[4] There are three different classes of these enzymes in mammals: class 1 (low Km, cytosolic), class 2 (low Km, mitochondrial), and class 3 (high Km, such as those expressed in tumors, stomach, and cornea). In all three classes, constitutive and inducible forms exist. ALDH1 and ALDH2 are the most important enzymes for aldehyde oxidation, and both are tetrameric enzymes composed of 54 kDa subunits. These enzymes are found in many tissues of the body but are at the highest concentration in the liver.[4]

Active site

The active site of the aldehyde dehydrogenase enzyme is largely conserved throughout the different classes of the enzyme and, although the number of amino acids present in a subunit can change, the overall function of the site changes little. The active site binds to one molecule of an aldehyde and one of either NAD+ or NADP+ that functions as a cofactor. A cysteine and a glutamate will interact with the aldehyde substrate. Many other residues will interact with the NAD(P)+ to hold it in place. A magnesium may be used to help the enzyme function, although the amount it helps the enzyme can vary between different classes of aldehydes.

Tetramer of aldehyde dehydrogenase 2 with a space filling model of NAD+ in each active site.[1] 
The active site of a human mitochondrial aldehyde dehydrogenase 2. Cys302 and Glu268 interact with the aldehyde substrate. The NAD+ is held in place by multiple residues (shown as wires or sticks).[1] 
The active site of the K487E mutant aldehyde dehydrogenase 2 with a space filling model of NAD+ in the active site. The amino acid Glu349 is highlighted.[1] 

Mechanism

The overall reaction catalysed by the aldehyde dehydrogenases is:

In this NAD(P)+-dependent reaction, the aldehyde enters the active site through a channel extending from the surface of the enzyme. The active site contains a Rossman fold, and interactions between the cofactor and the fold allow for the action of the active site.[5]

Mechanism of Aldehyde Dehydrogenase

A sulfur from a cysteine in the active site makes a nucleophilic attack on the carbonyl carbon of the aldehyde. The hydrogen is kicked off as a hydride and attacks NAD(P)+ to make NAD(P)H. The enzyme's active site then goes through an isomorphic change whereby the NAD(P)H is moved, creating room for a water molecule to access the substrate. The water is primed by a glutamate in the active site, and the water makes a nucleophilic attack on the carbonyl carbon, kicking off the sulfur as a leaving group.

Pathology (aldehyde dehydrogenase deficiency)

Role of aldehyde dehydrogenase (shown in red box) in norepinephrine degradation, creating vanillylmandelic acid, the major catecholamine metabolite.[6]

ALDH2 plays a crucial role in maintaining low blood levels of acetaldehyde during alcohol oxidation. In this pathway, the intermediate structures can be toxic, and health problems arise when those intermediates cannot be cleared.[4] When high levels of acetaldehyde occur in the blood, facial flushing, lightheadedness, palpitations, nausea, and general “hangover” symptoms occur. These symptoms are indicative of a medical condition known as the alcohol flush reaction, also known as “Asian flush” or “Oriental flushing syndrome”.[7]

There is a mutant form of aldehyde dehydrogenase, termed ALDH2*2, wherein a lysine residue replaces a glutamate in the active site at position 487 of ALDH2.[8] Homozygous individuals with the mutant allele have almost no ALDH2 activity, and those heterozygous for the mutation have reduced activity. Thus, the mutation is partially dominant.[4] The ineffective homozygous allele works at a rate of about 8% of the normal allele, for it shows a higher Km for NAD+ and has a higher maximum velocity than the wild-type allele.[4] This mutation is common in Japan, where 41% of a non-alcoholic control group were ALDH2 deficient, where only 2–5% of an alcoholic group were ALDH2-deficient. In Taiwan, the numbers are similar, with 30% of the control group showing the deficiency and 6% of alcoholics displaying it.[4] The deficiency is manifested by slow acetaldehyde removal, with low alcohol tolerance perhaps leading to a lower frequency of alcoholism.[4][7]

These symptoms are the same as those observed in people who drink while being treated by the drug disulfiram, which is why it is used to treat alcoholism. The patients show higher blood levels of acetaldehyde, and become violently ill upon consumption of even small amounts of alcohol.[4] Several drugs (e.g., metronidazole) cause a similar reaction known as "disulfiram-like reaction."

Yokoyama et al. found that decreased enzyme activity of aldehyde dehydrogenase-2, caused by the mutated ALDH2 allele, contributes to a higher chance of esophageal and oropharyngolaryngeal cancers. The metabolized acetaldehyde in the blood, which is six times higher than in individuals without the mutation, has shown to be a carcinogen in lab animals. ALDH2*2 is associated with increased odds of oropharyngolaryngeal, esophageal, gastric, colon, and lung cancer. However, they found no connection between increased levels of ALDH2*2 in the blood and an increased risk of liver cancer.[9]

Some case-control studies claimed that carriage of ALDH2*2 allele was a risk of late-onset Alzheimer’s disease independent of the apolipoprotein E gene (the odds for LOAD in carriers of ALDH2*2 allele almost twice that of non-carriers).[10] Moreover, ALDH gene, protein expression and activity are substantially decreased in the substantia nigra of Parkinson’s disease patients.[11] These reports are in line with findings implementing toxic lipid oxidation-derived aldehydes in these diseases and in neurodegeneration in general.[12]

Fitzmaurice et al. explored aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. "This ALDH model for PD etiology may help explain the selective vulnerability of dopaminergic neurons in PD and provide a potential mechanism through which environmental toxicants contribute to PD pathogenesis." [13]

Knockout mouse models further confirm the involvement of ALDH family in neurodegeneration. Mice null for ALDH1a1 and ALDH2 exhibit Parkinson's disease-like age-dependent deficits in motor performance and significant increase in biogenic aldehydes.[14]

The ALDH2-/- mice display age-related memory deficits in various tasks, as well as endothelial dysfunction, brain atrophy, and other Alzheimer’s disease-associated pathologies, including marked increases in lipid peroxidation products, amyloid-beta, p-tau and activated caspases. These behavioral and biochemical Alzheimer’s disease-like deficits were efficiently ameliorated when the ALDH2-/- mice were treated with isotope-reinforced, deuterated polyunsaturated fatty acids (D-PUFA).[15]

Genes

See also

References

  1. ^ a b c d PDB: 1o02​; Perez-Miller SJ, Hurley TD (June 2003). "Coenzyme isomerization is integral to catalysis in aldehyde dehydrogenase". Biochemistry. 42 (23): 7100–9. doi:10.1021/bi034182w. PMID 12795606. 
  2. ^ Marchitti SA, Brocker C, Stagos D, Vasiliou V (June 2008). "Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily". Expert Opinion on Drug Metabolism & Toxicology. 4 (6): 697–720. doi:10.1517/17425255.4.6.697. PMC 2658643Freely accessible. PMID 18611112. 
  3. ^ The oxygen comes from a water molecule. The enzyme is called a dehydrogenase because two hydrogen atoms are removed from the H2O reactant rather than from the aldehyde. By way of contrast, alcohol dehydrogenases remove hydrogens from the alcohol (R–CH2–OH) in producing an aldehyde (R–C(=O)–H).
  4. ^ a b c d e f g h i Crabb DW, Matsumoto M, Chang D, You M (February 2004). "Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology". The Proceedings of the Nutrition Society. 63 (1): 49–63. doi:10.1079/PNS2003327. PMID 15099407. 
  5. ^ Liu ZJ, Sun YJ, Rose J, Chung YJ, Hsiao CD, Chang WR, Kuo I, Perozich J, Lindahl R, Hempel J, Wang BC (April 1997). "The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold". Nature Structural Biology. 4 (4): 317–26. doi:10.1038/nsb0497-317. PMID 9095201. 
  6. ^ Figure 11-4 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5. 
  7. ^ a b Thomasson HR, Edenberg HJ, Crabb DW, Mai XL, Jerome RE, Li TK, Wang SP, Lin YT, Lu RB, Yin SJ (April 1991). "Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men". American Journal of Human Genetics. 48 (4): 677–81. PMC 1682953Freely accessible. PMID 2014795. 
  8. ^ Steinmetz CG, Xie P, Weiner H, Hurley TD (May 1997). "Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion". Structure. 5 (5): 701–11. doi:10.1016/S0969-2126(97)00224-4. PMID 9195888. 
  9. ^ Yokoyama A, Muramatsu T, Ohmori T, Yokoyama T, Okuyama K, Takahashi H, Hasegawa Y, Higuchi S, Maruyama K, Shirakura K, Ishii H (August 1998). "Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics". Carcinogenesis. 19 (8): 1383–7. doi:10.1093/carcin/19.8.1383. PMID 9744533. 
  10. ^ Kamino K, Nagasaka K, Imagawa M, Yamamoto H, Yoneda H, Ueki A, Kitamura S, Namekata K, Miki T, Ohta S (June 2000). "Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population". Biochemical and Biophysical Research Communications. 273 (1): 192–6. doi:10.1006/bbrc.2000.2923. PMID 10873585. 
  11. ^ Grünblatt E, Riederer P (February 2016). "Aldehyde dehydrogenase (ALDH) in Alzheimer's and Parkinson's disease". Journal of Neural Transmission (Vienna, Austria : 1996). 123 (2): 83–90. doi:10.1007/s00702-014-1320-1. PMID 25298080. 
  12. ^ Wood PL (September 2006). "Neurodegeneration and aldehyde load: from concept to therapeutics". Journal of Psychiatry & Neuroscience. 31 (5): 296–7. PMC 1557683Freely accessible. PMID 16951732. 
  13. ^ Fitzmaurice AG, Rhodes SL, Lulla A, Murphy NP, Lam HA, O'Donnell KC, Barnhill L, Casida JE, Cockburn M, Sagasti A, Stahl MC, Maidment NT, Ritz B, Bronstein JM (January 2013). "Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease". Proceedings of the National Academy of Sciences of the United States of America. 110 (2): 636–41. doi:10.1073/pnas.1220399110. PMC 3545765Freely accessible. PMID 23267077. 
  14. ^ Wey MC, Fernandez E, Martinez PA, Sullivan P, Goldstein DS, Strong R (2012). "Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson's disease". PLOS One. 7 (2): e31522. doi:10.1371/journal.pone.0031522. PMC 3284575Freely accessible. PMID 22384032. 
  15. ^ Elharram A, Czegledy NM, Golod M, Milne GL, Pollock E, Bennett BM, Shchepinov MS (December 2017). "Deuterium-reinforced polyunsaturated fatty acids improve cognition in a mouse model of sporadic Alzheimer's disease". The FEBS Journal. 284 (23): 4083–4095. doi:10.1111/febs.14291. PMID 29024570. 

External links

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Aldehyde dehydrogenase family Provide feedback

This family of dehydrogenases act on aldehyde substrates. Members use NADP as a cofactor. The family includes the following members: The prototypical members are the aldehyde dehydrogenases P00352 EC:1.2.1.3. Succinate-semialdehyde dehydrogenase P25526 EC:1.2.1.16. Lactaldehyde dehydrogenase P25553 EC:1.2.1.22. Benzaldehyde dehydrogenase P43503 EC:1.2.1.28. Methylmalonate-semialdehyde dehydrogenase Q02252 EC:1.2.1.27. Glyceraldehyde-3-phosphate dehydrogenase P81406 EC:1.2.1.9. Delta-1-pyrroline-5-carboxylate dehydrogenase P30038 EC: 1.5.1.12. Acetaldehyde dehydrogenase P17547 EC:1.2.1.10. Glutamate-5-semialdehyde dehydrogenase P07004 EC:1.2.1.41. This family also includes omega crystallin P30842 an eye lens protein from squid and octopus that has little aldehyde dehydrogenase activity.

Literature references

  1. Steinmetz CG, Xie P, Weiner H, Hurley TD; , Structure 1997;5:701-711.: Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion. PUBMED:9195888 EPMC:9195888


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR015590

Aldehyde dehydrogenases (EC and EC) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known [PUBMED:2713359]: class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase. These residues are conserved in all the enzymes of this entry.

Some of the proteins in this entry are allergens. Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature Subcommittee King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E., Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed of the first three letters of the genus; a space; the first letter of the species name; a space and an arabic number. In the event that two species names have identical designations, they are discriminated from one another by adding one or more letters (as necessary) to each species designation.

The allergens in this family include allergens with the following designations: Alt a 10 and Cla h 3.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan ALDH-like (CL0099), which has the following description:

The aldehyde dehydrogenases (ALDHs) are a superfamily of multimeric enzymes which catalyse the oxidation of a broad range of aldehydes into their corresponding carboxylic acids with the reduction of their cofactor, NAD(P) into NAD(P)H. The way that the NAD is bound is distinct from other NAD(P)-dependent oxidoreductases. The domain represented by this clan consists of two similar subdomains.

The clan contains the following 4 members:

Aldedh DUF1487 Histidinol_dh LuxC

Alignments

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(96)
Full
(98431)
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NCBI
(407772)
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(23993)
RP15
(18287)
RP35
(55506)
RP55
(91713)
RP75
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  Seed
(96)
Full
(98431)
Representative proteomes UniProt
(262532)
NCBI
(407772)
Meta
(23993)
RP15
(18287)
RP35
(55506)
RP55
(91713)
RP75
(137767)
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  Seed
(96)
Full
(98431)
Representative proteomes UniProt
(262532)
NCBI
(407772)
Meta
(23993)
RP15
(18287)
RP35
(55506)
RP55
(91713)
RP75
(137767)
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Trees

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: aldedh;
Type: Family
Sequence Ontology: SO:0100021
Author: Bateman A , Sonnhammer ELL
Number in seed: 96
Number in full: 98431
Average length of the domain: 410.70 aa
Average identity of full alignment: 25 %
Average coverage of the sequence by the domain: 83.73 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.0 23.0
Trusted cut-off 23.0 23.0
Noise cut-off 22.9 22.9
Model length: 462
Family (HMM) version: 22
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Species distribution

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Interactions

There are 4 interactions for this family. More...

Pro_dh-DNA_bdg Pro_dh Aldedh Pro_dh

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Aldedh domain has been found. There are 1325 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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