Galactosidase, beta 1, also known as GLB1, is a protein which in humans is encoded by the GLB1 gene. [5] [6]
The GLB1 protein is a beta-galactosidase that cleaves the terminal beta-galactose from ganglioside substrates and other glycoconjugates. [7] The GLB1 gene also encodes an elastin binding protein. [8]
In corn ( Zea mays ), Glb1 is a gene coding for the storage protein globulin.
GM1-gangliosidosis is a lysosomal storage disease that can be caused by a deficiency of β-galactosidase (GLB1). Some cases of Morquio syndrome B have been shown to be due to GLP1 mutations that cause patients to have abnormal elastic fibers. [9]
The RNA transcript of the GLB1 gene is alternatively spliced and produces 2 mRNAs. The 2.5-kilobase transcript encodes the beta-galactosidase enzyme of 677 amino acids. The alternative 2.0-kb mRNA encodes a beta-galactosidase-related protein (S-Gal) that is only 546 amino acids long and that has no enzymatic activity. The S-Gal protein does bind elastin and fragments of elastin that are generated by proteolysis. [10]
The S-Gal protein is a peripheral membrane protein that functions as part of an elastin receptor complex on the surface of cells. [11] The elastin receptor complex includes S-Gal, neuraminidase and Cathepsin A. When elastin-derived peptides bind to the S-Gal protein then the associated neuraminidase enzyme activity is activated and responding cells can have altered signal transduction involving extracellular signal-regulated kinases and regulated matrix metallopeptidase production. Elastin-derived peptides are chemotactic for some cell types [12] and can alter cell cycle progression. [13] The ability of the GLB1-derived elastin binding protein and the elastin receptor complex to influence cell proliferation appears to be indirect and involve removal of sialic acid from extracellular and cell surface proteins such as growth factor receptors.
The S-Gal protein functions during the normal assembly of elastin into extracellular elastic fibers. Elastin is initially present as newly synthesized tropoelastin which can be found in association with S-Gal. The enzymatic activity of neuraminidase in the elastin receptor complex is involved in the release of tropoelastin molecules from the S-Gal chaperone. [14] Cathepsin A is also required for normal elastin biosynthesis. [15]
β-galactosidase, also called lactase, beta-gal or β-gal, is a family of glycoside hydrolase enzymes that catalyzes the hydrolysis of β-galactosides into monosaccharides through the breaking of a glycosidic bond. β-galactosides include carbohydrates containing galactose where the glycosidic bond lies above the galactose molecule. Substrates of different β-galactosidases include ganglioside GM1, lactosylceramides, lactose, and various glycoproteins.
Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.
Elastic fibers are an essential component of the extracellular matrix composed of bundles of proteins (elastin) which are produced by a number of different cell types including fibroblasts, endothelial, smooth muscle, and airway epithelial cells. These fibers are able to stretch many times their length, and snap back to their original length when relaxed without loss of energy. Elastic fibers include elastin, elaunin and oxytalan.
Sandhoff disease is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B. These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides. Accumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death. The rare autosomal recessive neurodegenerative disorder is clinically almost indistinguishable from Tay–Sachs disease, another genetic disorder that disrupts beta-hexosaminidases A and S. There are three subsets of Sandhoff disease based on when first symptoms appear: classic infantile, juvenile and adult late onset.
GM2-gangliosidosis, AB variant is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. It has a similar pathology to Sandhoff disease and Tay–Sachs disease. The three diseases are classified together as the GM2 gangliosidoses, because each disease represents a distinct molecular point of failure in the activation of the same enzyme, beta-hexosaminidase. AB variant is caused by a failure in the gene that makes an enzyme cofactor for beta-hexosaminidase, called the GM2 activator.
Alpha-galactosidase is a glycoside hydrolase enzyme that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. Glycosidase is an important class of enzyme catalyzing many catabolic processes, including cleaving glycoproteins and glycolipids, and polysaccharides. Specifically, α-GAL catalyzes the removal of the terminal α-galactose from oligosaccharides.
The GM2 gangliosidoses are a group of three related genetic disorders that result from a deficiency of the enzyme beta-hexosaminidase. This enzyme catalyzes the biodegradation of fatty acid derivatives known as gangliosides. The diseases are better known by their individual names: Tay–Sachs disease, AB variant, and Sandhoff disease.
Hexosaminidase is an enzyme involved in the hydrolysis of terminal N-acetyl-D-hexosamine residues in N-acetyl-β-D-hexosaminides.
Beta-hexosaminidase subunit beta is an enzyme that in humans is encoded by the HEXB gene.
N-acetylgalactosamine-6-sulfatase is an enzyme that, in humans, is encoded by the GALNS gene.
Cathepsin A is an enzyme that is classified both as a cathepsin and a carboxypeptidase. In humans, it is encoded by the CTSA gene.
GM2 ganglioside activator also known as GM2A is a protein which in humans is encoded by the GM2A gene.
Hexosaminidase A , also known as HEXA, is an enzyme that in humans is encoded by the HEXA gene, located on the 15th chromosome.
Frizzled-4 is a protein that in humans is encoded by the FZD4 gene. FZD4 has also been designated as CD344.
Proto-oncogene tyrosine-protein kinase MER is an enzyme that in humans is encoded by the MERTK gene.
Alpha-N-acetylgalactosaminidase is an enzyme that in humans is encoded by the NAGA gene.
Lysosomal integral membrane protein 2 (LIMP-2) is a protein that in humans is encoded by the SCARB2 gene. LIMP-2 is expressed in brain, heart, liver, lung and kidney, mainly in the membrane of lysosome organelles; however, in cardiac muscle, LIMP-2 is also expressed at intercalated discs. LIMP-2 in a membrane protein in lysosomes that functions to regulate lysosomal/endosomal transport. Mutations in LIMP-2 have been shown to cause Gaucher disease, myoclonic epilepsy, and action myoclonus renal failure syndrome. Abnormal levels of LIMP-2 have also been found in patients with hypertrophic cardiomyopathy.
Receptor-type tyrosine-protein phosphatase kappa is an enzyme that in humans is encoded by the PTPRK gene. PTPRK is also known as PTPkappa and PTPκ.
Sialidase 1 , also known as NEU1 is a mammalian lysosomal neuraminidase enzyme which in humans is encoded by the NEU1 gene.
Galactosialidosis, also known as Neuraminidase deficiency with beta-galactosidase deficiency, is a genetic lysosomal storage disease. It is caused by a mutation in the CTSA gene which leads to a deficiency of enzymes β-galactosidase and neuraminidase. This deficiency inhibits the lysosomes of cells from functioning properly, resulting in the accumulation of toxic matter within the cell. Hallmark symptoms include abnormal spinal structure, vision problems, coarse facial features, hearing impairment, and intellectual disability. Because galactosialidosis involves the lysosomes of all cells, it can affect various areas of the body, including the brain, eyes, bones, and muscles. Depending on the patient's age at the onset of symptoms, the disease consists of three subtypes: early infantile, late infantile, and juvenile/adult. This condition is considered rare, with most cases having been in the juvenile/adult group of patients.
