ORMDL3
Description
The ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) is a protein-coding gene located on chromosome 17.
ORMDL3 is a protein involved in the regulation of sphingolipid biosynthesis. Variations in its expression are linked to childhood asthma. Mice with an excess of human ORMDL3 show increased levels of IgE, which is associated with an increase in macrophages, neutrophils, eosinophils, CD4+ cells, and Th2 cytokine levels in the lung. The ORMDL family, which includes ORMDL1, ORMDL2, and ORMDL3, is found in the membrane of the endoplasmic reticulum (ER). Each member of this family produces a protein containing 153 amino acids. ORMDL1, ORMDL2, and ORMDL3 are located on chromosomes 2q32, 12q13.2, and 17q21, respectively. ORMDL3 negatively regulates de novo sphingolipid synthesis by interacting with serine palmitoyltransferase (SPT). However, even when overexpressed, ORMDL3 doesn't significantly reduce sphingolipid biosynthesis. ORMDL3 also plays a role in controlling calcium levels in the ER. The ER is vital for the generation, signaling, and storage of intracellular calcium. Channels control the release of calcium from the ER into the cytoplasm, while pumps (SERCA) return calcium back to the ER. Disruptions in calcium levels are linked to various conditions, including SERCA dysfunction, asthma, and Alzheimer's disease.
ORMDL3 plays a crucial role in maintaining the balance of sphingolipid production by regulating the activity of serine palmitoyltransferase (SPT), which is the first enzyme in sphingolipid synthesis. ORMDL3 responds to changes in ceramide levels, acting as a feedback mechanism. When bound to SPT, ORMDL3 binds ceramides at its N-terminal region, leading to a conformational change that blocks substrate access to SPT, thus inhibiting its activity. This mechanism ensures sufficient ceramide levels for the production of complex sphingolipids, but prevents excessive accumulation that could trigger cell death (apoptosis).
ORMDL3 is also known as -.
