*3.1.2. ALDH1A2*

10 Dehydrogenases

*3.1.1. ALDH1A1* 

has been related to the "stemness" characteristics of CSCs. Consequently, its supported by widening evidence that ALDH may be more than just a CSC marker and have an

ALDH proteins can be found in every subcellular region such as cytosol, endoplasmic reticulum, mitochondria, and the nucleus, with some even found in more than one location. ALDH isozymes found in organelles besides cytosol carry signal or leader sequences that make their translocation to specific subcellular regions possible. After translocation or import, while nuclear and microsomal signals remain intact, mitochondrial sequences might be removed (causing mature proteins to be shorter). Most of the ALDHs have a large tissue

*ALDH1A1* encodes a homotetramer that is ubiquitously distributed in the adult epithelia of several organs such as brain, testis, kidney, eye lens, retina, liver and lungs. ALDH1A1 takes its position among the three highly-conserved cytosolic isozymes (see ALDH1A2 and ALDH1A3), which catalyze the oxidation of the retinol metabolite, retinal (retinaldehyde), to RA. ALDH1A1 has great affinity for the oxidation of both all-*trans*-(*K*m < 0.1 μM) and 9 *cis*-retinal. By serving as a ligand for nuclear RA receptors (RAR) and retinoid X receptors (RXR), RA regulates gene expression; therefore its synthesis is crucial for normal growth, differentiation, development and the maintenance of adult epithelia in vertebrate animals. In retinoid-dependent tissues (including the retina), retinal-oxidizing ALDHs have been shown to display differential expression patterns during organogenesis in rodents, reflecting that RA signaling is indeed important for embryogenesis. The *in vivo* function of ALDH1A1 in RA synthesis is proven by the fact that after retinol treatment, while *Aldh1a1*−/−mice are viable and possess normal morphology of the retina, the livers of *Aldh1a1*−/<sup>−</sup> mice have reduced RA synthesis and increased serum retinal levels. Surprisingly, it appeared that *Aldh1a1*−/<sup>−</sup> mice are protected against both diet-induced obesity and insulin resistance and this demonstrates that retinal might regulate the metabolic response to highfat diets transcriptionally, and that the *ALDH1A1* could be a candidate gene for therapeutic targeting. Supression of *ALDH1A1* in cultured hepatocytes reduces both the omegaoxidation of free fatty acids and the production of reactive oxygen species (ROS). Liver ALDH1A1 levels were shown to be decreased in *RXR*α−/<sup>−</sup> mice, which suggests that RA binding is an activating factor in *ALDH1A1* gene expression. The androgen receptor might also be included in modulation of ALDH1A1, which is recognized to be an androgen binding protein. RA is required for testicular development and *ALDH1A1* is absent in genital tissues of humans with androgen receptor-negative testicular feminization. ALDH1A1 is significantly expressed in dopaminergic neurons that are known to require RA for their differentiation and development in the human brain. In these neurons, *ALDH1A1* is under the control of Pitx3, a homeodomain transcription factor that, possibly through *ALDH1A1* upregulation, regulates the particularization and maintenance of

distribution and show distinct substrate specificity (Marchitti*, et al.*, 2008).

accomplishable role in CSC biology (Marcato*, et al.*, 2011).

**3.1. ALDH family members as stem cell markers** 

ALDH1A2 is a cytosolic homotetramer expressed in several embryonic and adult tissues such as brain, kidney, intestine, testis, liver, retina, lung. As ALDH1A1, ALDH1A2 also catalyzes the reaction in which both all-*trans*-retinal and 9-*cis*-retinal oxidize to RA. However, when compared with other ALDH isozymes, ALDH1A2 appears to acquire the highest specificity (*V*max/*K*m = 49 nmol·min−1·mg−1·μM−1) for all-*trans*-retinal. This characteristic may be because of an uncommon discreate loop in its active site that binds all*trans*-retinal in a unique manner.

Taking action in several developmental processes, ALDH1A2 might be a key regulator of RA synthesis in developing tissues. Due to defects in early heart morphogenesis, *Aldh1*α*2*−/<sup>−</sup> mice die in early embryonic stages in which they seem to lack axial rotation, incomplete neural tube closure, reduction of the trunk region and many of the properties of human DiGeorge/velocardiofacial syndrome, a disorder characterized by cleft palate, heart abnormalities and learning disabilities. During early vascular development, aberrations in endothelial cell cycle progression have also been determined in *Aldh1*α*2*−/<sup>−</sup> embryos. *Aldh1a2* has been determined as a key regulator in the development of many tissues including kidney, retina, lung, forebrain, pancreas, and spinal cord by miscellanous animal models (Marchitti*, et al.*, 2008, El Kares*, et al.*, 2010).
