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= Aldehyde Dehydrogenase = EC #: 1.2.1.3

The aldehyde dehydrogenase (ALDH) family can primarily be found in the human genome. Collectively, they are involved in a number of metabolic processes. This includes lipid peroxidation, or the free radical oxidation of polyunsaturated fatty acids. ALDH3B2 in particular is involved in sphingolipid biosynthesis. Certain ALDHs are involved in retinoic acid (RA) synthesis. They do this in both normal and cancerous stem cells.

RA Synthesis
ALDHs provide a survival advantage to cancer cells leading to cancer progression and therapy resistance. Their functions are as follows:

- Retinol (vitamin A) absorbed by normal and cancer cells is converted to retinal in the cytosol. ALDH enzymes then oxidize retinal to RA

- In ER positive cancer cells, alternative RA signaling induces the expression of genes related to cell proliferation, stemness, tumor growth and anti-apoptosis. RARE (retinoic acid response elements)

- NOTCH signaling drives ALDH proteins deacetylation by SIRT2. In addition, ALDHs promote the oxidation of toxic reactive aldehydes into less toxic carboxylic acids limiting reactive oxygen species (ROS) production and lipid peroxidation.

- Other functions that allow this include absorbing ultraviolet light, scavenging hydroxyl radicals via cysteine and methionine sulfhydryl groups

Pathways such as these may regulate ALDHs in cancer stem cells (CSCs) at both the transcriptional and post-transcriptional level

Expression
ALDHs have the highest expression in the liver, but they can be found in various bodily organs and glands. In the lung, for instance, macrophages expressing ALDH can promote differentiation of CD4+ T cells to Treg by TGF-β and RA. A specific example to examine in terms of expression will be ALDH3B2 (also known as ALDH8). This enzyme is expressed primarily in the esophagus, skin, placenta, urinary bladder, and salivary glands.

According to Zanoni et al, ALDH overexpression is closely related to resistance to therapies, and to CSCs' self-renewal, differentiation, and protection against oxidative stress. Additionally, cancer cells with high ALDH levels release factors including RA that in turn increase ALDH levels in several cells of the tumor microenvironment. This enhances the CD4+ T cell differentiation of Treg cells, ultimately leading to immune tolerance.

Active Site
"The active site for ALDHs binds to either NAD+ or NADP+ (this serves as a cofactor) and an aldehyde. Their substrate interacts with both cysteine and glutamate molecules."

Reaction Mechanism
The catalysis mechanism performed by ALDHs is as follows:

- An aldehyde enters active site through a channel from the surface of enzyme

- A sulfur from a cysteine in the active site makes a nucleophilic attack on the carbonyl carbon of the aldehyde

- Hydrogen is kicked off as a hydride and attacks NAD(P)+ to make NAD(P)H; a water molecule can now interact with the substrate

- Water is primed by glutamate (via substrate-glutamate interaction) in the active site and performs a nucleophilic attack on the carbonyl carbon of the aldehyde

- Sulfur is kicked off as the leaving group