Aldehyde dehydrogenase 3 family, member A1

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

is_associated_with::Aldehyde dehydrogenases oxidize various is_associated_with::aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-derived acetaldehyde and in the metabolism of is_associated_with::corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. The enzyme encoded by this gene forms a cytoplasmic homodimer that preferentially oxidizes aromatic aldehyde substrates. The gene is located within the is_associated_with::Smith-Magenis syndrome region on chromosome 17.

ALDH3A1 expression is notably high in the is_associated_with::cornea of mammalian species, comprising from 5 to 50% of soluble protein content, but is almost absent from the cornea of other vertebrates.

Structure and mechanism
ALDH3A1 is a homodimer consisting of alpha helices (43.8%), beta sheets (4.2%), p-loop turns (28.2%) and random coils (23.8%). The catalytic residue–Cys244—is located on an active site that contains a is_associated_with::Rossman fold that binds the enzyme's cofactor, NAD(P)+.

ALDH3A1’s catalytic mechanism mirrors that of other enzymes of the aldehyde dehydrogenase family. The sulfur atom of Cys244 attacks the carbonyl of the aldehyde substrate in a nucleophilic attack that releases a hydride ion. The hydride ion is accepted by the NAD(P)+ bound to the is_associated_with::Rossman fold. Unique interactions between the cofactor and the is_associated_with::Rossman fold facilitate an isomerization of the enzyme that releases the cofactor while maintaining the integrity of the active site. A water molecule enters the active site and is subsequently activated by a glutamate residue. The activated water then attacks the thioester enzyme-substrate complex in nucleophilic reaction that regenerates the free enzyme, and releases the corresponding carboxylic acid.

Involvement in Lipid Peroxidation
Electronic excitations of alkene and aromatic functional groups allow certain is_associated_with::nucleic acids, is_associated_with::proteins, is_associated_with::fatty acids and organic molecules to absorb is_associated_with::ultraviolet radiation (UVR). Moderate UVR exposure oxidizes specific proteins that eventually serve as signaling agents for an array of is_associated_with::metabolic and inflammatory pathways. Overexposure to UVR, on the other hand, can be detrimental to the tissue. In the presence of molecular oxygen, UVR leads to the formation of is_associated_with::reactive oxygen species (ROS) that are implicated in many degradation pathways. In the case of is_associated_with::lipid peroxidation, ROS react with is_associated_with::polyunsaturated fatty acids situated in the lipid bilayer of the cell membrane to produce lipid radicals. These lipid radicals propagate, further damaging the lipid bilayer and producing lipid hydroperoxides. The eventual degradation of lipid hydroperoxides releases a wide variety of is_associated_with::aldehydes, which, owing to their stability and ability to react cellular nucleophiles, are both is_associated_with::cytotoxic and is_associated_with::genotoxic in nature. ALDH3A1 plays a critical role in the metabolism of these aldehydes to their corresponding is_associated_with::carboxylic acids in mammalian cornea and saliva. is_associated_with::4-Hydroxynonenal (4HNE)—which ALDH3A1 metabolizes with Vmax of 27,754 moles NADPH/min•mg and an apparent Km of 362 micromolar —is the most abundant aldehyde produced in the LPO of is_associated_with::arachidonic acid and is_associated_with::linoleic acid. Its stability and multiple sites of reactivity (carbon-carbon double bond, hydroxyl group, and carbonyl) make 4HNE a potent inhibitor of is_associated_with::cellular growth, enzyme activities, calcium sequestration, and is_associated_with::protein synthesis. It is also involved in the consumption of is_associated_with::glutathione and the alteration of is_associated_with::signal transduction and is_associated_with::gene expression.

Role in the cornea
ALDH3A1 comprises approximately 10-40% of the water-soluble protein in the mammalian is_associated_with::cornea. Direct exposure to UVR and is_associated_with::molecular oxygen, make the cornea susceptible to ROS and 4HNE. Studies in which rabbits were transfected with genes that allow them to overexpress human ALDH3A1 in their corneal stromal fibroblasts document ALDH3A1's most critical function is to protect the cornea from is_associated_with::oxidative stresses. In the cornea ALDH3A1: (1) prevents the formation of 4-HNE protein adducts that would impeded proteins’ function; (2) is more effective at metabolizing 4-HNE than other comparable agents such as is_associated_with::glutathione (GSH); (3) protects the corneal cells from 4-HNE induced is_associated_with::apoptosis; (4) reduces consumption of GSH by relieving 4HNE GSH adducts; (5) and relieves 4-HNE’s inhibition of the 20S is_associated_with::protease activity.

Suicide response to UVR
However, only a fraction of the total concentration of ALDH3A1 in the cornea is used for metabolizing is_associated_with::aldehydes. This observation has sparked multiple investigations of ALDH3A1’s role beyond aldehyde metabolism. Although the full scope of ALDH3A1’s function is yet to be firmly established, there is strong evidence suggesting that ALDH3A1 serves to maintain the cellular redox balance as well as the structural integrity and transparency of the cornea. One study elucidates that ALDH3A1 not only indirectly protects the cornea from UVR induced oxidative stress by metabolizing aldehydes, but also protects the tissue directly, by competitively absorbing UVR in a “suicide response” that reduces damage to other proteins of the cornea In fact, 50% percent of the UVR that the cornea is exposed to is absorbed by ADLH3A1. ALDH3A1’s absorption of UVR oxidizes several key is_associated_with::amino acid residues, leading to conformational changes that convert the alpha and beta sheets into random coils. These conformational changes ultimately relieve the dimer structure. This loss of secondary and tertiary structure leads to protein aggregation and complete loss of is_associated_with::enzymatic activity. is_associated_with::Peptide mapping and spectroscopic experiments reveal that the loss of activity is not a result of Cys244 oxidation (which, together with the active site, remains intact during is_associated_with::photo-excitation), but instead, due to the degradation of other key amino residues (most notably is_associated_with::methionine and is_associated_with::tryptophan). These amino acid residues degrade under oxidative stress, leading to the formation of non-reducible cross-links that stabilize the soluble aggregates. Tryptophan for instance is doubly oxidized to generate ROSs such as H2O2, which elicit further oxidation and adduction. Nevertheless, the abundance of ALDH3A1 in the cornea ensures that this suicide response neither impedes with aldehyde metabolism nor leads to the formation of insoluble aggregates that would affect the transparency of the cornea.



Consequences of ALDH3A1 Deficiency
Further clarification of ALDH3A1’s role in the cornea has been provided by gene-knockout studies in which genes encoding ALDH3A1 were removed from the mice genome. It was found that ALDH3A1-null mice exhibited lower proteasome activity, higher rates of protein degradation/oxidation, and higher GSH, 4HNE and is_associated_with::malondialdehyde protein adduct levels—all of which contributed to the development of is_associated_with::cataracts and opacities in the subcapular regions of the cornea within one month of age. These observations on ALDH3A1-null mice reaffirm that ALDH3A1’s role extends beyond enzymatic metabolism; encompassing functions in maintenance of the structural integrity and transparency of the cornea.