ALDH1A2, or Aldehyde Dehydrogenase 1 Family Member A2, is an enzyme found within the human body. This protein functions as a catalyst, meaning it helps to speed up specific chemical reactions. As a member of the aldehyde dehydrogenase family, ALDH1A2 is involved in various metabolic processes that are fundamental to biological function. Its presence and activity are widespread, contributing to a range of bodily systems and cellular activities.
The Role of ALDH1A2 in the Body
ALDH1A2 plays a specific and important role in the body’s metabolism of vitamin A, also known as retinol. This enzyme is responsible for an irreversible step in converting a form of vitamin A called retinaldehyde into all-trans retinoic acid.
Retinoic acid is not merely a byproduct; it is a powerful signaling molecule. It acts as a ligand for retinoid nuclear receptors, which are proteins that bind to specific DNA sequences and regulate gene expression.
The enzyme’s activity is NAD-dependent, utilizing nicotinamide adenine dinucleotide as a co-factor in the oxidation reaction. While ALDH1A2 primarily focuses on retinaldehyde, it can also metabolize other aldehyde substrates like octanal and decanal, although with less efficiency than its primary substrate. The precise control of retinaldehyde concentration is important because too much or too little retinoic acid can be detrimental to tissues.
ALDH1A2 and Development
ALDH1A2 has a profound impact on embryonic development, with its function being necessary for the proper formation of various bodily structures before birth. The retinoic acid produced by ALDH1A2 guides the development of multiple organ systems, including the heart, limbs, and the central nervous system. For instance, its activity is involved in regulating cardiac progenitor differentiation, the formation of the heart’s outflow tract, and myocardial cell proliferation.
Studies in animal models, such as mice, show that a lack of ALDH1A2 leads to severe developmental delays and widespread morphological abnormalities. These can include issues with the hindbrain, heart, vasculature, and body axis. The enzyme works in conjunction with other enzymes, like CYP26A1, to carefully balance retinoic acid levels in the embryo, which helps in the development of posterior organs and prevents conditions like spina bifida.
The proper function of ALDH1A2 is also connected to the formation of the forebrain, pancreas, foregut, and lungs. Disruptions in its activity during these early stages can lead to congenital anomalies.
ALDH1A2 and Health Conditions
Dysfunction of ALDH1A2, whether through reduced or excessive activity, has implications for human health, particularly in the context of certain diseases. Alterations in ALDH1A2 activity can disrupt the delicate balance of retinoic acid signaling, which can contribute to various health issues.
One notable area of involvement is in cancer, where ALDH1A2 can serve as a marker for cancer stem cells or contribute to drug resistance. For example, high expression of ALDH1A2 has been correlated with poor prognosis in neuroblastoma patients and is linked to the growth and undifferentiation of neuroblastoma xenografts, as well as resistance to certain chemotherapy drugs like 13-cis-retinoic acid. The enzyme’s ability to detoxify aldehydes may allow cancer cells to survive chemotherapy.
Beyond cancer, disruptions in the retinoic acid pathway due to ALDH1A2 alterations can lead to developmental disorders. A newly recognized multiple congenital anomaly syndrome is associated with biallelic sequence variants in the ALDH1A2 gene. Children with this syndrome can present with a range of malformations, including tetralogy of Fallot (a heart defect), an absent thymus, diaphragmatic eventration, and talipes equinovarus (clubfoot).