Aldehyde dehydrogenase

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Not to be confused with aldehyde oxidase.

Aldehyde dehydrogenase (NAD+)

Monomer of human aldehyde dehydrogenase 2 (ALDH2) with a space-

filling model of NAD+ in the active site.[1]

Identifiers

EC no. 1.2.1.3

CAS no. 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

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Aldehyde dehydrogenases (EC 1.2.1.3) are a group

of enzymes that catalyse the oxidation of aldehydes.[2] They convert aldehydes (R–
C(=O)–H) to carboxylic acids (R–C(=O)–O–H). The oxygen comes from a water
molecule. 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.

Contents

 1Function
 2Active site
 3Mechanism
 4Pathology (aldehyde dehydrogenase deficiency)
 5Genes
 6See also
 7References
 8External links

Function[edit]
Aldehyde dehydrogenase is a polymorphic enzyme[3] responsible for
the oxidation of aldehydes to carboxylic acids, which leave the liver and are metabolized
by the body’s muscle and heart.[3] 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.[3]

Active site[edit]
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 molecule of either NAD+ or NADP+, which functions
as a cofactor. Cysteine and glutamate molecules interact with the aldehyde substrate.
Many other residues will interact with NAD(P)+ to hold it in place. Magnesium may be
used to help the enzyme function, although the degree to which magnesium assists the
enzyme varies 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[edit]
The overall reaction catalysed by the aldehyde dehydrogenases is:

 RCHO + NAD+ + H2O → RCOOH + NADH + H+

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 Rossmann fold, and interactions between the cofactor and the fold allow for the action
of the active site.[4]

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) [edit]

Role of aldehyde dehydrogenase (shown in red box) in norepinephrine degradation, creating vanillylmandelic
acid, the major catecholamine metabolite.[5]

ALDH2 plays a crucial role in maintaining low blood levels of acetaldehyde during
alcohol oxidation.[6] In this pathway (ethanol to acetaldehyde to acetate), the
intermediate structures can be toxic, and health problems arise when those
intermediates cannot be cleared.[3] 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.[3] 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.[3] 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. [3] The deficiency is
manifested by slow acetaldehyde removal, with low alcohol tolerance perhaps leading
to a lower frequency of alcoholism.[3][7]
These symptoms are the same as those observed in people who drink while being
treated by the drug disulfiram, which is why disulfiram 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.[3] 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]

Demir et al. found that ALDH1 is a potentially important, poor prognostic factor in breast
cancer, associated with high histological grade, estrogen/progesteron receptor
negativity and HER2 positivity.[10]
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). [11] Moreover,
ALDH gene, protein expression and activity are substantially decreased in
the substantia nigra of Parkinson's disease patients.[12] These reports are in line with
findings implementing toxic lipid oxidation-derived aldehydes in these diseases and
in neurodegeneration in general.[13]
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." [14]
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.[15]
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).[16]

Genes[edit]
 ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1
L1, ALDH1L2
 ALDH2
 ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2
 ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1, ALDH8
A1, ALDH9A1, ALDH16A1, ALDH18A1

See also[edit]
 Alcohol dehydrogenase

References[edit]
1. ^ Jump up to:        PDB: 1o02; Perez-Miller SJ, Hurley TD (June
a b c d

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  2658643.  PMID  1
8611112.
3. ^ Jump up to: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.
4. ^ 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.  S2CID 21436
007.
5. ^ Figure 11-4 in: Rod Flower; Humphrey P. Rang; Maureen
M. Dale; Ritter, James M. (2007). Rang & Dale's
pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-
443-06911-6.
6. ^ Edenberg, Howard J.; McClintick, Jeanette N.
(2018).  "Alcohol Dehydrogenases, Aldehyde
Dehydrogenases, and Alcohol Use Disorders: A Critical
Review". Alcoholism, Clinical and Experimental
Research.  42  (12): 2281–
2297.  doi:10.1111/acer.13904.  ISSN  1530-0277. PMC  6286
250.  PMID  30320893.
7. ^ Jump up to: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  1682953.  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  919588
8.
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. ^ Demir, Hale; Dulgar, Ozgecan; Gulle, Bugra Taygun; Turna,
Hande; Ilvan, Sennur (2018-11-07).  "Prognostic value of
aldehyde dehydrogenase 1 (ALDH1) in invasive breast
carcinomas".  Bosnian Journal of Basic Medical
Sciences.  18  (4): 313–
 319.  doi:10.17305/bjbms.2018.3094.  ISSN  1840-4812. PMC 
6252102. PMID 29924962.
11. ^ 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.
12. ^ Grünblatt E, Riederer P (February 2016). "Aldehyde
dehydrogenase (ALDH) in Alzheimer's and Parkinson's
disease". Journal of Neural Transmission.  123  (2): 83–
90.  doi:10.1007/s00702-014-1320-1. PMID 25298080.  S2CI
D 24270982.
13. ^ Wood PL (September 2006). "Neurodegeneration and
aldehyde load: from concept to therapeutics". Journal of
Psychiatry & Neuroscience. 31 (5): 296–
7. PMC  1557683.  PMID  16951732.
14. ^ 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.  Bibcode:2013PNAS..110..636F. doi:10.1073/pnas.12203
99110. PMC  3545765.  PMID  23267077.
15. ^ 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. Bibcode:2012PLoSO...731522W.  doi:10.1371/journa
l.pone.0031522. PMC  3284575.  PMID  22384032.
16. ^ 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. PMC  5716852.  PMID  290245
70.

External links[edit]
 Aldehyde+dehydrogenase at the US National Library
of Medicine Medical Subject Headings (MeSH)
show

Aldehyde dehydrogenases (EC 1.2.1)
 show

Aldehyde/oxo oxidoreductases (EC 1.2)

show

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