Pathways

Krabbe disease, also called globoid cell leukodystrophy, is an extremely rare inherited inborn error of metabolism (IEM). It is a degenerative disorder that affects the nervous system. It has an estimated prevalence of 1/100,000 in the Northern European population and a worldwide incidence of 1/100,000-1/250,000 live births. Krabbe disease is an autosomal recessive disorder that is caused by a deficiency of an enzyme called galactosylceramidase. Galactosylceramidase is a lysosomal protein that hydrolyzes the galactose ester bonds of ceramides and ceramide derivatives including galactocerebroside, galactosylsphingosine (psychosine), lactosylceramide, and monogalactosyldiglyceride. More specifically, galactosylceramidase is an enzyme that is involved in the catabolism (via the removal of galactose) of galactosylceramide, a major lipid in myelin, kidney, and epithelial cells of the small intestine and colon. Defects in galactosylceramidase lead to the accumulation of cytotoxic psychosine, which ultimately leads to apoptosis of oligodendrocytes and demyelination. As a result, this enzyme deficiency impairs the growth and maintenance of myelin, the protective sheath around nerve cell axons that ensures that electrical impulses are rapidly transmitted. Krabbe disease is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). Krabbe disease is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that often have multiple nuclei. There are three different phenotypes for Krabbe disease: infantile, juvenile, and late-onset. Neurodegeneration and early death (at age 2-3) occur in most infantile cases. In juvenile patients, the disease is often fatal 2-7 years after the symptoms begin. Adult-onset patients can survive many years after symptoms first manifest. The symptoms of infantile Krabbe disease usually begin during the first year of life. Typically, the initial signs and symptoms include feeding difficulties, episodes of fever without any sign of infection, irritability, stiff posture, muscle weakness, and slowed mental and physical development. Muscles continue to weaken as the disease progresses which decreases the infant's ability to move, chew, swallow, and breathe. It is also common for affected infants to experience vision loss and seizures. Treatment is limited to hematopoietic stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients. Stem cell transplants have been shown to slow the progression of the disease.

Krabbe disease, also called globoid cell leukodystrophy, is an extremely rare inherited inborn error of metabolism (IEM). It is a degenerative disorder that affects the nervous system. It has an estimated prevalence of 1/100,000 in the Northern European population and a worldwide incidence of 1/100,000-1/250,000 live births. Krabbe disease is an autosomal recessive disorder that is caused by a deficiency of an enzyme called galactosylceramidase. Galactosylceramidase is a lysosomal protein that hydrolyzes the galactose ester bonds of ceramides and ceramide derivatives including galactocerebroside, galactosylsphingosine (psychosine), lactosylceramide, and monogalactosyldiglyceride. More specifically, galactosylceramidase is an enzyme that is involved in the catabolism (via the removal of galactose) of galactosylceramide, a major lipid in myelin, kidney, and epithelial cells of the small intestine and colon. Defects in galactosylceramidase lead to the accumulation of cytotoxic psychosine, which ultimately leads to apoptosis of oligodendrocytes and demyelination. As a result, this enzyme deficiency impairs the growth and maintenance of myelin, the protective sheath around nerve cell axons that ensures that electrical impulses are rapidly transmitted. Krabbe disease is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). Krabbe disease is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that often have multiple nuclei. There are three different phenotypes for Krabbe disease: infantile, juvenile, and late-onset. Neurodegeneration and early death (at age 2-3) occur in most infantile cases. In juvenile patients, the disease is often fatal 2-7 years after the symptoms begin. Adult-onset patients can survive many years after symptoms first manifest. The symptoms of infantile Krabbe disease usually begin during the first year of life. Typically, the initial signs and symptoms include feeding difficulties, episodes of fever without any sign of infection, irritability, stiff posture, muscle weakness, and slowed mental and physical development. Muscles continue to weaken as the disease progresses which decreases the infant's ability to move, chew, swallow, and breathe. It is also common for affected infants to experience vision loss and seizures. Treatment is limited to hematopoietic stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients. Stem cell transplants have been shown to slow the progression of the disease.

Kynurenine is an indole uremic toxin compound that is formed through metabolism from dietary tryptophan in liver hepatic cells. After being transported into a hepatocyte from portal circulation the amino acid tryptophan undergoes a reaction with the enzyme tryptophan-2,3-dioxygenase to form kynurenine. When this compound enters into systemic circulation it is shown to be a major uremic toxin when high levels of it are retained in the blood and not excreted in urine. Kynurenine is shown to activate aryl hydrocarbon receptors that can lead to renal impairment, and it also disrupts the electron transport chain and oxidative phosphorylation causing muscle atrophy.

L-alanine is an essential component of proteins and peptidoglycan. The latter also contains about three molecules of D-alanine for every L-alanine. Only about 10 percent of the total alanine synthesized flows into peptidoglycan.There are at least 3 ways to begin the biosynthesis of alanine. The first method for alanine biosynthesis begins with L-cysteine produced from L-cysteine biosynthesis pathway. L-cysteine reacts with an [L-cysteine desulfurase] L-cysteine persulfide through a cysteine desulfurase resulting in a release of [L-cysteine desulfurase] l-cysteine persulfide and L-alanine. The second method starts with pyruvic acid reacting with L-glutamic acid through a glutamate-pyruvate aminotransferase resulting in a oxoglutaric acid and L-alanine. The third method starts with L-glutamic acid interacting with Alpha-ketoisovaleric acid through a valine transaminase resulting in an oxoglutaric acid and L-valine. L-valine reacts with pyruvic acid through a valine-pyruvate aminotransferase resulting Alpha-ketoisovaleric acid and L-alanine. This first step of the pathway, which can be catalyzed by either of two racemases (biosynthetic or catabolic), also serves an essential role in biosynthesis because its product, D-alanine, is an essential component of cell wall peptidoglycan (murein). D-alanine is metabolized by an ATP driven D-alanine ligase A and B resulting in D-alanyl-D-alanine. This product is incorporated into the peptidoglycan biosynthesis. L-alanine is metabolized with alanine racemase, either catabolic or metabolic resulting in a D-alanine. This compound reacts with water and a quinone through a D-amino acid dehydrogenase resulting in Pyruvic acid, hydroquinone and ammonium, thus entering the central metabolism and thereby can serve as a total source of carbon and energy. The role of the dadX racemase is degradative and dadX racemase can be induced by alanine and is subject to catabolite repression.