Galactocerebrosidase Enzyme

Krabbe disease affects this production of myelin due to a missing enzyme. People with Krabbe disease do not have the enzyme, galactosylceramidase, or GALC (Stanley 2005). GALC is located in chromosome fourteen (Stanley 2005).

Since children lack the HEXA-A gene it causes progressive damage and eventually the nervous system will shut down because it can no longer produce vital neurons needed to function the nervous system and life. Beta-hexosamindinidase is located in the lysosomes, which are structures in cells that act as recycling centers and breaking down the toxic substance. Beta-hexosamidnidase role is toxic and fatty substances called GM2 ganglioside. If the gangliosides become overpowering or too much, can cause destruction of the neurons. The excessive storage of the gangliosides in lysosomes is another factor that causes Tay-Sachs. Tay-Sachs occurs usually when the individual lacks the protein hexosamindinidase A and defected and alterations on chromosome 15 (specifically 15q23-q24). More than 50 mutations having been discovered on chromosome 15 and HEXA-A enzyme. The mutation can vary as in deletion, insertion, and splitting in which each mutation alters the protein. The mutation and disorder cause a decrease in enzymes activity. The severity of the disorder depends on the degree of the enzyme activity and deficiency. For example, one mutation includes, the mutation includes a G-to-T substitution at the 3-inch end of intron 5, which makes a short mRNA. Then skipping exon 6 and the polypeptide lacking 34 amino acids. (Tanaka

Gaucher disease (GD) is an inherited gene that stops glucocerebroside (type of lipid) to be broken down correctly. When this lipid cannot be broken down, buildups appear in the liver, spleen, and bone marrow which affects normal functioning. These organs begin to grow to an irregular size, amenia becomes present within the patient, and easy bruising appears due to the decrease in blood platelets. Gaucher disease is created during an autosomal recessive pattern, which means that two genes have a mutation, which causes the disorder. Normally, if a child is born with this disease, both parents carry one copy of the mutated gene. The gene that the mutation appears in is the GBA gene. GBA is located in chromosome one. The GBA gene is in charge of creating the instructions for producing an enzyme called beta-glucocerebrosidase. This enzyme breaks down the glucocerebroside into glucose and ceramide (a simpler fat molecule). When mutations appear in the GBA gene, the activity of the beta-glucocerebrosidase is reduced abundantly. Without this important breaking down of the

Fabry Disease occurs due to a disorder in the lysosomes. Lysosomes typically serve as recycling centers within cells; they contain enzymes to digest several different molecules. In Fabry Disease, the affected individual has a mutation in the GLA gene. The GLA gene provides code to produce alpha-galactosidase A. Alpha-galactosidase A is an active enzyme in lysosomes to break down globotriaosylceramide, a fat consisting three sugars attached to a fatty substance. The mutation in the GLA gene can cause an absence or decrease in the amount of alpha-galactosidase A produced. This change in the amount of enzyme produced prevents breakdown of the fat effectively and the fat begins to build up in excess inside the cells. The accumulation of globotriaosylceramide then damages cells and leads to the symptoms seen in Fabry Disease.

mutation is phenylalanine 508 known as delta F508. Delta F508 is a deletion of 3 nucleotides

Tay-Sachs disease is an autosomal recessive disease. Tay Sachs disease can be attributed to the inhibited activity of the hydrolase enzyme b-Hexosaminidase-A (HEX A). The Hex A gene is on the q arm of chromosome 15. When mutated the breakdown of ganglioside from disialotetrahexosylganglioside (GM2) to monosialodihexosylganglioside (GM3) is defective. This results in a buildup of GM2 in the lysosomes in nerve cell. These lysosomes swell in size and can rupture resulting in many neurological defects and hepatosplenomegaly. The accumulation and burst of the lysosome manifest itself in three different, but categorically similar ways depending on the type of mutation in Hex A. While many therapies are in clinical trials most of the treatment options are done just to treat the symptoms of Tay Sachs because no cure exists.

In this experiment, we studied the enzyme activity (Michaelis-Menten kinetics) of beta- galactosidase. We isolated a pure form of beta- galactosidase from a crude extract (Escherichia coli). Beta- galactosidase will catalyze the hydrolysis of beta-D-galactosides (figure 1). It does this by hydrolyzing the terminal non-reducing residues. An example of this is seen in the conversion of ortho-nitrophenol-beta-D-galactoside (ONPG) to othro-nitrophenol (ONP) and galactose. This reaction results in a color change (clear to yellow) of ONP, with a wavelength absorbance of 420 nm which can be measured on a spectrophotometer. The rate of the reaction was determined by varying the concentrations of ONPG (substrate, [S]) and measuring the ONP absorbance (initial velocity, Vo). We also measured the effect of isopropyl beta-D-1-thiogalactopyranoside (IPTG) to inhibit the reaction.

Each of the three types of Gaucher Disease affect many systems of the body. Type I of the disease, which is the most mild form and is most frequently seen, is the only form of Gaucher which does not affect the nervous system. Typically, the average age of onset for Type I Gaucher is 21 years (6) . Approximately 1 in 10 Ashkenazi Jews is heterozygous for type I. Although the condition is non-neuronopathic, patients can exhibit a wide array of symptoms ranging from increased spleen and liver volume, lung compression, a variety of bone problems including lesions, bone tissue death and pain, and anemia and easy bruising. Individuals with Type I Gaucher Disease typically have a life span of 6 to 80 years (5) . Within families, the severity of Type I of the condition varies immensely, thereby making it impossible to determine which family members will suffer from the most severe symptoms. Gaucher Disease is different from most other autosomal recessive conditions in that one of the nonfunctional glucocerebrosidase genes (which are characteristic of Gaucher Disease) is passed o1n to each of the patient's offspring, causing them all to be carriers. Among Ashkenazi Jews, it has been presumed that around 1 in 450 Ashkenazi Jews has two mutated copies of the glucocerebrosidase gene (4) .

Gaucher’s disease is a lipid storage disease similar to Tay Sach’s because its deficiency of a lytic lysosomal enzyme. Gaucher’s disease is in regards to which parts of the body it affects. Tay Sach’s affects the CNS while Gaucher’s affects the spleen and liver. The main treatment option of Gaucher’s is enzyme replacement therapy (ERT). The deficient lytic enzyme (glucoserebrosidase) is injected intravenously and directed toward the lysosomes in

Because of the lack of β-hexosaminidase A, the body cannot break down excess GM2 ganglioside and the fatty substance is able to build up profusely in the nerves and tissues of the brain.

The defects seen in Glanzmann disease are split equally between glycoprotein IIb and glycoprotein IIIa.

As was previously outlined, the cause of Liddle’s syndrome is from ENaC over presenting in the ASDN due to a mutation to the channel is the cause of Liddle’s syndrome. It has been shown that mutations on the gamma and beta subunits are responsible for the gain of function in the ENaC. No mutation has been observed yet for the alpha subunit. Mutations occur at the level of the gene for the beta and gamma subunit and cause either missense, nonsense or frameshift mutations in the mRNA of the PY motif for ENaC(ref). This results in either a truncated protein or elimination of some amino acids from the PY motif, which interfere with the binding ability of Nedd4 ligase and inhibit Nedd4 ligase binding, respectively. Overall, this either decreases or eliminates the possibility of Nedd4-2 ligases’ ability to tag and degrade the ENaC. With the inability to control ENaC surface expression at the kidney, its reabsorption of sodium will be markedly increased due to

Metachromatic Leukodystrophy (MLD) is a disorder which results in the inability to break down sulfatides in the lysosome of oligodendrocytes. The name is of greek origin, Leuko meaning white, dys meaning lack, and troph meaning growth. As a Leukodystrophy, the name implies that the disease is lacking growth in the white matter of the brain. The inability to break down sulfatides in the lysosomal complexes of the cell lead to the degeneration of the myelin sheath which are produced by oligodendrocytes. This disease is most commonly associated with the inability to produce Arylsulfatase-A (ASA), a protein that works to catalyze the breakdown of sulfatides by hydrolyzing the 3-O ester bond [1].

Errors involving ganglioside metabolism heavily impact the central nervous system due to the presence of a higher concentration of gangliosides. TSD is specifically caused by a mutation in the HEXA gene encoding the α-subunit of β-hexosaminidase A. An individual with TSD is able to transport the GM2 ganglioside from the cellular membrane to the lysosome for degradation, but is unable to process it further since the α-subunit of β-hexosaminidase A cannot cleave the terminal N-acetylgalactosamine group. Without this cleavage, the lysosome is unable to digest the GM2

The X-ray structure as well as the amino acid sequence of the kidney-form glutaminase has been determined. The enzyme glutminase is primarily made up of alpha helixes and contains one region of beta sheet structures. The catalytic side is located inside a pocket where the substrate glutamine binds. It interacts with the catalytic site via the formation of several hydrogen bonds, as illustrated in figure 1.