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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
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MetaCyc Enzyme: mitochondrial aldehyde dehydrogenase

Gene: ALDH2 Accession Number: G-38 (MetaCyc)

Synonyms: ALDM, aldehyde dehydrogenase, mitochondrial, ALDH class 2, ALDHI, ALDH-E2, aldehyde dehydrogenase class 2, ALDH-2

Species: Homo sapiens

Subunit composition of mitochondrial aldehyde dehydrogenase = [ALDH2]4
         mitochondrial aldehyde dehydrogenase subunit = ALDH2

Summary:
Aldehyde dehydrogenases catalyze the pyridine nucleotide-dependent oxidation of aldehydes to acids [Sladek03]. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme [Braun87] that has relatively high affinity for acetaldehyde such that under physiological conditions it mediates essentially all hepatic acetaldehyde oxidation.

The active enzyme is a homotetramer [RodriguezZavala02] and exhibits a relatively low Km for acetaldehyde (0.2 +/- 0.02 uM) [Rashkovetsky94]. By comparison, the liver cytosolic aldehyde dehydrogenase isoenzyme (ALDH-1) has a Km for acetaldehyde that is approximately three orders of magnitude greater [Rashkovetsky94].

ALDH2 is one of three distinct aldehyde dehydrogenase isolated from the human liver [Agarwal87, Hempel85]. Isoenzymes are differentiated based on electrophoretic mobility, kinetic properties, and subcellular localizations. The broader superfamily of human aldehyde dehydrogenases consists of at least 17 distinct enzymes differentiated on the basis of physical properties, tissue distribution, subcellular location, substrate specificity, and cofactor preference. The chromosomal locations and organization of all genes encoding members of this superfamily have been defined [Sladek03, Yoshida92a].

A variant of the enzyme that results from a single nucleotide polymorphism (SNP) of the ALDH2 gene is found in approximately 50% of the Asian population [Yoshida]. The SNP is associated with phenotypic reduction of catalytic activity in both heterozygotes and homozygotes. This reduced activity is caused by a structural point mutation at amino acid position 487 resulting in substitution of Lys for Glu (E487K) [Harada01a]. Reduced ALDH2 activity results in higher acetaldehyde levels after alcohol intake and this is thought to contribute to the flushing and other vasomotor symptoms observed in some Asians after alcohol consumption [Xiao96]. The reduced catalytic activity of the variant enzyme results from an increased Km for NAD(+) and a decreased specific activity.

Heterotetramers of human liver mitochondrial (class 2) aldehyde dehydrogenase have been expressed in Escherichia coli. Km for NAD of recombinant human enzyme increased more than 150-fold. Furthermore, heterotetrameric enzymes exhibited 16-18% of the activity of "wild type" enzyme whilst E487K homotetramers exhibited 8% of native enzyme activtiy, i.e., in heterotetramers composed of both subunit types, the variant subunit was dominant over the wild type [Zhou00b, Wang96c].

The structure of bovine mitochondrial aldehyde dehydrogenase 2 has been solved at 2.65A in its free form. The form complexed with NAD+ has also been solved (to 2.75A). The structure consists of three domains; a small three-stranded beta-sheet domain and two dinucleotide-binding domains. The beta sheet plays a role in subunit interactions [Steinmetz97, RodriguezZavala02, Ni99a]

Locations: mitochondrion

Molecular Weight of Polypeptide: 56.381 kD (from nucleotide sequence)

Molecular Weight of Multimer: 220.0 kD (experimental) [RodriguezZavala02]

Unification Links: ArrayExpress:P05091 , DIP:DIP-40262N , DisProt:DP00383 , Mint:MINT-1368102 , ModBase:P05091 , PhosphoSite:P05091 , PhylomeDB:P05091 , Pride:P05091 , Protein Model Portal:P05091 , SMR:P05091 , String:9606.ENSP00000261733 , Swiss-Model:P05091 , UniProt:P05091

Relationship Links: Entrez-Nucleotide:PART-OF:X05409 , InterPro:IN-FAMILY:IPR015590 , InterPro:IN-FAMILY:IPR016160 , InterPro:IN-FAMILY:IPR016161 , InterPro:IN-FAMILY:IPR016162 , InterPro:IN-FAMILY:IPR016163 , PDB:Structure:1CW3 , PDB:Structure:1NZW , PDB:Structure:1NZX , PDB:Structure:1NZZ , PDB:Structure:1O00 , PDB:Structure:1O01 , PDB:Structure:1O02 , PDB:Structure:1O04 , PDB:Structure:1O05 , PDB:Structure:1ZUM , PDB:Structure:2ONM , PDB:Structure:2ONN , PDB:Structure:2ONO , PDB:Structure:2ONP , PDB:Structure:2VLE , PDB:Structure:3INJ , PDB:Structure:3INL , PDB:Structure:3N80 , PDB:Structure:3N81 , PDB:Structure:3N82 , PDB:Structure:3N83 , PDB:Structure:3SZ9 , PDB:Structure:4FQF , PDB:Structure:4FR8 , Pfam:IN-FAMILY:PF00171 , Prosite:IN-FAMILY:PS00070 , Prosite:IN-FAMILY:PS00687

Gene-Reaction Schematic: ?

Instance reactions of [an aldehyde + NAD+ + H2O → a carboxylate + NADH + 2 H+] (1.2.1.3):
i1: fluoroacetaldehyde + NAD+ + H2O → fluoroacetate + NADH + 2 H+ (1.2.1.69)

i2: benzaldehyde + NAD+ + H2O ↔ benzoate + NADH + 2 H+ (1.2.1.28)

i3: 4-methylbenzaldehyde + NAD+ + H2O → 4-toluenecarboxylate + NADH + 2 H+ (no EC#)

i4: all-trans-retinal + NAD+ + H2O = all-trans-retinoate + NADH + 2 H+ (1.2.1.36)

i5: acetaldehyde + NAD+ + H2O → acetate + NADH + 2 H+ (1.2.1.3)

i6: octanal + NAD+ + H2O → octanoate + NADH + 2 H+ (1.2.1.3)

i7: phytenal + NAD+ + H2O → phytenate + NADH + 2 H+ (1.2.1.3)

i8: (2E,6E)-farnesal + NAD+ + H2O → (2-trans-6-trans)-farnesoate + NADH + 2 H+ (1.2.1.3)

i9: salicylaldehyde + NAD+ + H2O → salicylate + NADH + 2 H+ (1.2.1.65)

i10: (R)-lactaldehyde + NAD+ + H2O → (R)-lactate + NADH + 2 H+ (no EC#)

i11: (S)-lactaldehyde + NAD+ + H2O → (S)-lactate + NADH + 2 H+ (1.2.1.22)

i12: methylglyoxal + NAD+ + H2O → pyruvate + NADH + 2 H+ (1.2.1.23)

GO Terms:

Cellular Component: GO:0005739 - mitochondrion [Rooke00]


Enzymatic reaction of: 3,4-dihydroxyphenylglycolaldehyde dehydrogenase (mitochondrial aldehyde dehydrogenase)

EC Number: 1.2.1.3

3,4-dihydroxyphenylglycolaldehyde + NAD+ + H2O <=> 3,4-dihydroxymandelate + NADH + 2 H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: noradrenaline and adrenaline degradation

Summary:
Both the mitochondrial and cytoplasmic isozymes of human liver aldehyde dehydrogenase were shown to be similarly effective in oxidizing 3,4-dihydroxyphenylglycolaldehyde to its corresponding acid [MacKerell86]. However, other aldehyde dehydrogenase isozymes may also participate in 3,4-dihydroxyphenylglycolaldehyde metabolism (reviewed in [Marchitti07]).

Kinetic Parameters:

Substrate
Km (μM)
Citations
3,4-dihydroxyphenylglycolaldehyde
18.0
[MacKerell86]


Enzymatic reaction of: phenylacetaldehyde dehydrogenase (mitochondrial aldehyde dehydrogenase)

EC Number: 1.2.1.39

phenylacetaldehyde + NAD+ + H2O <=> phenylacetate + NADH + 2 H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

This reaction is reversible.

In Pathways: phenylalanine degradation IV (mammalian, via side chain)

Summary:
Purified human mitochondrial aldehyde dehydrogenase (ALDH2) was shown to use phenylacetaldehyde as a substrate, with a low Km value (see below). A variety of other substrates were also tested [Klyosov96].

The oxidation of phenylacetaldehyde to phenylacetate has been shown to be due primarily to aldehyde dehydrogenase in guinea pig liver mitochondria, with some contribution from aldehyde oxidase [Panoutsopoulos04, Panoutsopoulos04a].

Kinetic Parameters:

Substrate
Km (μM)
Citations
phenylacetaldehyde
0.029
[Klyosov96]


Enzymatic reaction of: 5-hydroxyindole acetaldehyde dehydrogenase (mitochondrial aldehyde dehydrogenase)

EC Number: 1.2.1.3

5-hydroxyindole acetaldehyde + NAD+ + H2O <=> 5-hydroxyindole acetate + NADH + 2 H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: serotonin degradation

Kinetic Parameters:

Substrate
Km (μM)
Citations
5-hydroxyindole acetaldehyde
0.8
[MacKerell86]


Enzymatic reaction of: 4-acetamidobutanal dehydrogenase (mitochondrial aldehyde dehydrogenase)

Synonyms: aldehyde dehydrogenase

EC Number: 1.2.1.3

4-acetamidobutanal + NAD+ + H2O <=> 4-acetamidobutanoate + NADH + 2 H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: putrescine degradation III


Enzymatic reaction of: aldehyde dehydrogenase

EC Number: 1.2.1.3

an aldehyde + NAD+ + H2O <=> a carboxylate + NADH + 2 H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: methylglyoxal degradation VI , ethanol degradation II , oxidative ethanol degradation III , ethanol degradation IV


Enzymatic reaction of: acetaldehyde dehydrogenase (mitochondrial aldehyde dehydrogenase)

Synonyms: aldehyde dehydrogenase

EC Number: 1.2.1.3

acetaldehyde + NAD+ + H2O <=> acetate + NADH + 2 H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: ethanol degradation II , oxidative ethanol degradation III , ethanol degradation IV


References

Agarwal87: Agarwal DP, Goedde HW (1987). "Human aldehyde dehydrogenase isozymes and alcohol sensitivity." Isozymes Curr Top Biol Med Res 16;21-48. PMID: 3610592

Braun87: Braun T, Bober E, Singh S, Agarwal DP, Goedde HW (1987). "Evidence for a signal peptide at the amino-terminal end of human mitochondrial aldehyde dehydrogenase." FEBS Lett 215(2);233-6. PMID: 3582651

Harada01a: Harada S (2001). "[Classification of alcohol metabolizing enzymes and polymorphisms--specificity in Japanese]." Nihon Arukoru Yakubutsu Igakkai Zasshi 36(2);85-106. PMID: 11398342

Hempel85: Hempel J, Kaiser R, Jornvall H (1985). "Mitochondrial aldehyde dehydrogenase from human liver. Primary structure, differences in relation to the cytosolic enzyme, and functional correlations." Eur J Biochem 153(1);13-28. PMID: 4065146

Klyosov96: Klyosov AA (1996). "Kinetics and specificity of human liver aldehyde dehydrogenases toward aliphatic, aromatic, and fused polycyclic aldehydes." Biochemistry 35(14);4457-67. PMID: 8605195

MacKerell86: MacKerell AD, Blatter EE, Pietruszko R (1986). "Human aldehyde dehydrogenase: kinetic identification of the isozyme for which biogenic aldehydes and acetaldehyde compete." Alcohol Clin Exp Res 10(3);266-70. PMID: 3526948

Marchitti07: Marchitti SA, Deitrich RA, Vasiliou V (2007). "Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase." Pharmacol Rev 59(2);125-50. PMID: 17379813

Ni99a: Ni L, Zhou J, Hurley TD, Weiner H (1999). "Human liver mitochondrial aldehyde dehydrogenase: three-dimensional structure and the restoration of solubility and activity of chimeric forms." Protein Sci 8(12);2784-90. PMID: 10631996

Panoutsopoulos04: Panoutsopoulos GI, Kouretas D, Gounaris EG, Beedham C (2004). "Metabolism of 2-phenylethylamine and phenylacetaldehyde by precision-cut guinea pig fresh liver slices." Eur J Drug Metab Pharmacokinet 29(2);111-8. PMID: 15230339

Panoutsopoulos04a: Panoutsopoulos GI, Kouretas D, Gounaris EG, Beedham C (2004). "Enzymatic oxidation of 2-phenylethylamine to phenylacetic acid and 2-phenylethanol with special reference to the metabolism of its intermediate phenylacetaldehyde." Basic Clin Pharmacol Toxicol 95(6);273-9. PMID: 15569272

Rashkovetsky94: Rashkovetsky LG, Maret W, Klyosov AA (1994). "Human liver aldehyde dehydrogenases: new method of purification of the major mitochondrial and cytosolic enzymes and re-evaluation of their kinetic properties." Biochim Biophys Acta 1205(2);301-7. PMID: 8155713

RodriguezZavala02: Rodriguez-Zavala JS, Weiner H (2002). "Structural aspects of aldehyde dehydrogenase that influence dimer-tetramer formation." Biochemistry 41(26);8229-37. PMID: 12081471

Rooke00: Rooke N, Li DJ, Li J, Keung WM (2000). "The mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway: a potential site of action of daidzin." J Med Chem 43(22);4169-79. PMID: 11063613

Sladek03: Sladek NE (2003). "Human aldehyde dehydrogenases: potential pathological, pharmacological, and toxicological impact." J Biochem Mol Toxicol 17(1);7-23. PMID: 12616643

Steinmetz97: Steinmetz CG, Xie P, Weiner H, Hurley TD (1997). "Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion." Structure 5(5);701-11. PMID: 9195888

Wang96c: Wang X, Sheikh S, Saigal D, Robinson L, Weiner H (1996). "Heterotetramers of human liver mitochondrial (class 2) aldehyde dehydrogenase expressed in Escherichia coli. A model to study the heterotetramers expected to be found in Oriental people." J Biol Chem 271(49);31172-8. PMID: 8940116

Xiao96: Xiao Q, Weiner H, Crabb DW (1996). "The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced flushing increases turnover of the enzyme tetramers in a dominant fashion." J Clin Invest 98(9);2027-32. PMID: 8903321

Yoshida: Yoshida A, Ikawa M, Hsu LC, Tani K "Molecular abnormality and cDNA cloning of human aldehyde dehydrogenases." Alcohol 2(1);103-6. PMID: 4015823

Yoshida92a: Yoshida A (1992). "Molecular genetics of human aldehyde dehydrogenase." Pharmacogenetics 2(4);139-47. PMID: 1306115

Zhou00b: Zhou J, Weiner H (2000). "Basis for half-of-the-site reactivity and the dominance of the K487 oriental subunit over the E487 subunit in heterotetrameric human liver mitochondrial aldehyde dehydrogenase." Biochemistry 39(39);12019-24. PMID: 11009616


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sun Nov 23, 2014, BIOCYC13B.