ALDH7A1

Last updated
ALDH7A1
PDB 2j6l EBI.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ALDH7A1 , ATQ1, EPD, PDE, aldehyde dehydrogenase 7 family member A1
External IDs OMIM: 107323 MGI: 108186 HomoloGene: 913 GeneCards: ALDH7A1
EC number 1.2.1.3
Orthologs
SpeciesHumanMouse
Entrez

501

110695

Ensembl

ENSG00000164904

ENSMUSG00000053644

UniProt

P49419

Q9DBF1

RefSeq (mRNA)

NM_001182
NM_001201377
NM_001202404

NM_001127338
NM_138600

RefSeq (protein)

NP_001173
NP_001188306
NP_001189333

NP_001120810
NP_613066

Location (UCSC) Chr 5: 126.53 – 126.6 Mb Chr 18: 56.64 – 56.71 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Aldehyde dehydrogenase 7 family, member A1, also known as ALDH7A1 or antiquitin, is an enzyme that in humans is encoded by the ALDH7A1 gene. [5] The protein encoded by this gene is a member of subfamily 7 in the aldehyde dehydrogenase gene family. These enzymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This particular member has homology to a previously described protein from the green garden pea, the 26g pea turgor protein. It is also involved in lysine catabolism that is known to occur in the mitochondrial matrix. Recent reports show that this protein is found both in the cytosol and the mitochondria, and the two forms likely arise from the use of alternative translation initiation sites. An additional variant encoding a different isoform has also been found for this gene. Mutations in this gene are associated with pyridoxine-dependent epilepsy. Several related pseudogenes have also been identified. [6]

Contents

Structure

The protein encoded by this gene can localize to the cytosol, mitochondria, or nucleus depending on the inclusion of certain localization sequences. The N-terminal mitochondrial targeting sequence is responsible for mitochondrial localization, while the nuclear localization signal and nuclear export signal are necessary for nuclear localization. Exclusion of the above in the final protein product leads to cytosolic localization. In the protein, two amino acid residues, Glu121 and Arg301, are attributed for the binding and catalyzing one of its substrates, alpha-aminoadipic semialdehyde (α-AASA). [7]

Antiquitin shares 60% homology with the 26g pea turgor protein, also referred to as ALDH7B1, in the green garden pea. [8]

Function

As a member of subfamily 7 of the aldehyde dehydrogenase gene family, antiquitin performs NAD(P)+-dependent oxidation of aldehydes generated by alcohol metabolism, lipid peroxidation, and other cases of oxidative stress, to their corresponding carboxylic acids . [7] [8] [9] In addition, antiquitin plays a role in protecting cells and tissues from the damaging effects of osmotic stress, presumably through the generation of osmolytes. [8] Antiquitin may also play a protective role for DNA in cell growth, as the protein is found to be up-regulated during the G1–S phase transition, which undergoes the highest degree of oxidative stress in the cell cycle. [7] [8] Furthermore, antiquitin functions as an aldehyde dehydrogenase for α-AASA in the pipecolic acid pathway of lysine catabolism. [7] [10]

Localization

Antiquitin function and subcellular localization are closely linked, as it functions in detoxification in the cytosol, lysine catabolism in the mitochondrion, and cell cycle progression in the nucleus. [7] [8] In particular, antiquitin localizes to the mitochondria in kidney and liver to contribute to the synthesis of betaine, a chaperone protein that protects against osmotic stress. [8]

Clinical significance

Mutations in this gene cause pyridoxine-dependent epilepsy, which involves a combination of various seizure types that do not respond to standard anticonvulsants, but are treatable via administration of pyridoxine hydrochloride. [10] [11] These pyridoxine-dependent seizures have been linked to the failure to oxidize α-AASA in patients due to mutated antiquitin. Additionally, antiquitin is implicated in other diseases, including cancer, diabetes, osteoporosis, premature ovarian failure and Huntington's disease, though the exact mechanisms remain unclear. [7] [12]

Interactions

Antiquitin is known to interact with:

Related Research Articles

Lysine Amino acid

Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain lysyl ((CH2)4NH2), classifying it as a basic, charged (at physiological pH), aliphatic amino acid. It is encoded by the codons AAA and AAG. Like almost all other amino acids, the α-carbon is chiral and lysine may refer to either enantiomer or a racemic mixture of both. For the purpose of this article, lysine will refer to the biologically active enantiomer L-lysine, where the α-carbon is in the S configuration.

Acetaldehyde dehydrogenase Class of enzymes

Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetic acid. The oxidation of acetaldehyde to acetate can be summarized as follows:

2-Hydroxyglutaric aciduria Medical condition

2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. It is either autosomal recessive or autosomal dominant.

Aldehyde dehydrogenase Group of enzymes

Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes to carboxylic acids. 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.

Succinic semialdehyde dehydrogenase deficiency Rare disorder involving deficiency in GABA degradation

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

Long-chain-aldehyde dehydrogenase Protein-coding gene in the species Homo sapiens

Fatty aldehyde dehydrogenase is an aldehyde dehydrogenase enzyme that in human is encoded in the ALDH3A2 gene on chromosome 17. Aldehyde dehydrogenase enzymes function to remove toxic aldehydes that are generated by the metabolism of alcohol and by lipid peroxidation.

ALDH2 Enzyme

Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. This protein belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations.

Aldehyde dehydrogenase 3 family, member A1 Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase, dimeric NADP-preferring is an enzyme that in humans is encoded by the ALDH3A1 gene.

Aldehyde dehydrogenase 5 family, member A1 Protein-coding gene in the species Homo sapiens

Succinate-semialdehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH5A1 gene.

IDH2

Isocitrate dehydrogenase [NADP], mitochondrial is an enzyme that in humans is encoded by the IDH2 gene.

D2HGDH Protein-coding gene in the species Homo sapiens

D-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the D2HGDH gene.

ALDH1B1 Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase X, mitochondrial is an enzyme that in humans is encoded by the ALDH1B1 gene.

L2HGDH

L-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the L2HGDH gene, also known as C14orf160, on chromosome 14.

Alpha-aminoadipic semialdehyde synthase

Alpha-aminoadipic semialdehyde synthase is an enzyme encoded by the AASS gene in humans and is involved in their major lysine degradation pathway. It is similar to the separate enzymes coded for by the LYS1 and LYS9 genes in yeast, and related to, although not similar in structure, the bifunctional enzyme found in plants. In humans, mutations in the AASS gene, and the corresponding alpha-aminoadipic semialdehyde synthase enzyme are associated with familial hyperlysinemia. This condition is inherited in an autosomal recessive pattern and is not considered a particularly negative condition, thus making it a rare disease.

ALDH1L1 Protein-coding gene in the species Homo sapiens

10-formyltetrahydrofolate dehydrogenase is an enzyme that in humans is encoded by the ALDH1L1 gene.

Aldehyde dehydrogenase 6 family, member A1 Protein-coding gene in the species Homo sapiens

Methylmalonate-semialdehyde dehydrogenase [acylating], mitochondrial (MMSDH) is an enzyme that in humans is encoded by the ALDH6A1 gene.

ALDH3B1 Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase 3 family, member B1 also known as ALDH3B1 is an enzyme that in humans is encoded by the ALDH3B1 gene.

ALDH1A3

Aldehyde dehydrogenase 1 family, member A3, also known as ALDH1A3 or retinaldehyde dehydrogenase 3 (RALDH3), is an enzyme that in humans is encoded by the ALDH1A3 gene,

ALDH1A1 Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an enzyme that is encoded by the ALDH1A1 gene.

Pyridoxine-dependent epilepsy Medical condition

Pyridoxine-dependent epilepsy (PDE) is a rare genetic disorder characterized by intractable seizures in the prenatal and neonatal period. The disorder was first recognized in the 1950s, with the first description provided by Hunt et al. in 1954. More recently, pathogenic variants within the ALDH7A1 gene have been identified to cause PDE.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000164904 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000053644 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Skvorak AB, Robertson NG, Yin Y, Weremowicz S, Her H, Bieber FR, Beisel KW, Lynch ED, Beier DR, Morton CC (December 1997). "An ancient conserved gene expressed in the human inner ear: identification, expression analysis, and chromosomal mapping of human and mouse antiquitin (ATQ1)". Genomics. 46 (2): 191–9. doi:10.1006/geno.1997.5026. PMID   9417906.
  6. ↑ "Entrez Gene: ALDH7A1".
  7. 1 2 3 4 5 6 Chan, CL; Wong, JW; Wong, CP; Chan, MK; Fong, WP (30 May 2011). "Human antiquitin: structural and functional studies". Chemico-Biological Interactions. 191 (1–3): 165–70. doi:10.1016/j.cbi.2010.12.019. PMID   21185811.
  8. 1 2 3 4 5 6 Brocker C, Lassen N, Estey T, Pappa A, Cantore M, Orlova VV, Chavakis T, Kavanagh KL, Oppermann U, Vasiliou V (June 2010). "Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress". J. Biol. Chem. 285 (24): 18452–63. doi: 10.1074/jbc.M109.077925 . PMC   2881771 . PMID   20207735.
  9. ↑ Brocker C, Cantore M, Failli P, Vasiliou V (May 2011). "Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity". Chem. Biol. Interact. 191 (1–3): 269–77. doi:10.1016/j.cbi.2011.02.016. hdl:2158/513857. PMC   3387551 . PMID   21338592.
  10. 1 2 Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT (Mar 2006). "Mutations in antiquitin in individuals with pyridoxine-dependent seizures". Nature Medicine. 12 (3): 307–9. doi:10.1038/nm1366. PMID   16491085. S2CID   27940375.
  11. ↑ Scharer G, Brocker C, Vasiliou V, Creadon-Swindell G, Gallagher RC, Spector E, Van Hove JL (Oct 2010). "The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1". Journal of Inherited Metabolic Disease. 33 (5): 571–81. doi:10.1007/s10545-010-9187-2. PMC   3112356 . PMID   20814824.
  12. ↑ Giacalone NJ, Den RB, Eisenberg R, Chen H, Olson SJ, Massion PP, Carbone DP, Lu B (May 2013). "ALDH7A1 expression is associated with recurrence in patients with surgically resected non-small-cell lung carcinoma". Future Oncology. 9 (5): 737–45. doi:10.2217/fon.13.19. PMC   5341386 . PMID   23647301.
  13. ↑ Wang H, Tong L, Wei J, Pan W, Li L, Ge Y, Zhou L, Yuan Q, Zhou C, Yang M (Dec 2014). "The ALDH7A1 genetic polymorphisms contribute to development of esophageal squamous cell carcinoma". Tumour Biology. 35 (12): 12665–70. doi:10.1007/s13277-014-2590-9. PMID   25213698. S2CID   12775026.

Further reading

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