Browsing Pathways

Rabeprazole is a drug that belongs to the anti secretory drug class. It is used as an anti-ulcer medication, and helps relieve gastric acid reflux, gastric irritation and gastric pain. It inhibits the proton pump action of ATPase, which blocks the final step of gastric acid secretion. The pathway begins in the parietal cell in the stomach, where rabeprazole and a hydrogen ion use the active metabolite in rabeprazole —rabeprazole thioether — to inhibit potassium-transporting ATPase at the secretory surface of the gastric parietal cell. Now in the gastric endothelial cell, these secretory surfaces are inhibited by rabeprazole and by G-Protein signalling cascade through somatostatin receptor type 4, which is activated by somatostatin. At the same time, potassium-transporting ATPase is activated by the G-protein signalling cascade, through histamine H2 receptor, gastrin/cholecystokinin type B receptor, and muscarinic acetylcholine receptor M3 which are activated by histamine, gastrin and acetylcholine, respectively. The potassium transporting ATPase also converts water and ATP to a phosphate molecule and ADP. Alongside the transporters, potassium is brought into the cell. Carbonic anhydrase 1 uses water and carbon dioxide to create hydrogen carbonate and a hydrogen ion, which are both transported out of the endothelial cell, into the gastric lumen. A chloride ion is transported into the gastric endothelial cell through a chloride anion exchanger and is transported out of the cell through a chloride intracellular channel protein 2, back into the gastric lumen.

Betazole, also known as ametazole and Histalog, is a histamine H2 agonist that causes an increase in gastric acid secretion. Betazole is commonly used to evaluate acid production. Betazole binds to the H2 receptor to enhance the G protein signaling cascade to increase gastric secretion into the lumen. Gastric acid digests protein and absorbs calcium, iron and vitamin B12. Gastric acidity may also interfere with medication bioavailability. Measuring gastric acid secretion is useful to manage diseases involving acid production such as gastroesophageal reflux disease.

Hyperprolinemia Type II (HPII), also known as 1-pyrroline-5-carboxylate dehydrogenase deficiency, is an extremely rare inborn error of metabolism (IEM) and autosomal recessive disorder of the arginine and proline metabolism pathway. It is caused by a mutation in the ALDH4A1 gene (also called the P5CDH gene) that encodes the mitochondrial enzyme delta-1-pyrroline-5-carboxylate dehydrogenase. This enzyme is responsible for catalyzing the dehydrogenation of 1-pyrroline-5-carboxylic acid or L-glutamic gamma-semialdehyde into L-glutamic acid. If mutated, allows L-proline, 4-hydroxyproline and D-proline, compounds further upstream from these reactions, to accumulate. HPII is characterized by an accumulation of proline in the blood. Symptoms include hydroxyprolinuria and hyperglycinuria, and can include seizures and some amount of mental retardation. However, the disorder varies in severity and these symptoms may not be present in all individuals. There are no currently known treatments for HPII, and a reduced proline diet has not been shown to reduce symptoms. There are no current estimates for the frequency of this disorder.

Galactosemia III also called GALE deficiency or UDP-Galactose-4-Epimerase deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by either a homozygous or compound heterozygous mutation in the UDP-galactose-4-epimerase (GALE) gene. GALE catalyses the reversible conversion of UDP-galactose to UDP-glucose in galactose metabolism. Symptoms are similar to classic galactosemia, including jaundice, vomiting, hypotonia, failure to thrive, hepatomegaly, moderate generalized amino aciduria and marked galactosuria. Treatment usually includes galactose restricted diets instead of galactose free diets in the management of this disorder because unlike patients with galactokinase deficiency and classic galactosemia, patients with galactose epimerase deficiency cannot utilize the endogenous pathway for synthesis of UDP-galactose. This makes patients dependent on exogenous galactose.

Zoledronate (also named zoledronic acid, Zometa or Reclast) is a type of medication that used to treat numbers of bone diseases because of its affinity for hydroxyapatite. Zoledronate targets farnesyl pyrophosphate (FPP) synthase by inhibiting the function of this enzyme in the mevalonate pathway, which prevent the biosynthesis of Geranyl-PP and farnesyl pyrophosphate. Geranyl-PP and farnesyl pyrophosphate are important for geranylgeranylation and farnesylation of GTPase signalling proteins. Lack of Geranyl-PP and farnesyl pyrophosphate will result in decreased rate of bond resorption and turnover as well as block the osteoclast activity, which lead to an increasing mass gain in bone (i.e. net gain in bone mass).

Lysosomal acid lipase deficiency, also called cholesteryl ester storage disease [CESD], LIPA deficiency or Wolman disease, is a rare autosomal recessive inborn error of metabolism. It's caused by not enough lysosomal acid lipase enzyme is produced at lysosome, which act to break down the fatty material. Lysosomal acid lipase enzyme catalyzes the conversion of cholesterol and fatty acid into cholesterol ester. This disorder is characterized by a large accumulation of cholesterol in the endoplasmic reticulum (ER). Symptoms of the disorder include vomiting, diarrhea, weight loss (i.e. feeding difficulties) and swelling of the abdomen. Lysosomal acid lipase deficiency can be treated with sebelipase alfa.

Desmosterolosis is caused by a mutation in the DHCR24 gene, which codes for the enzyme 24-dehydrocholesterol reductase, which catalyzes the reduction of the delta-24 double bond of sterol intermediates. A defect in 24-dehydrocholesterol reductase causes accumulation of desmosterol in plasma. Symptoms include cleft palate, clubfoot, dysmorphism, mental and motor retardation, and speech development.

Acute intermittent porphyria (AIP), also called Swedish porphyria, is a rare inborn error of metabolism (IEM) and autosomal dominant disorder of heme biosynthesis caused by a defective HMBS gene. The HMBS gene codes for the protein hydroxymethylbilane synthase (porphobilinogen deaminase) which catalyzes the synthesis of porphobilinogen into hydroxymethylbilane. This disorder is characterized by a large accumulation of 5-aminolevulinic acid or porphobilinogen in both urine and serum. Most patients are asymptomatic between attacks. Symptoms of the disorder include abdominal pain, constipation, vomiting, hypertension, muscle weakness, seizures, delirium, coma, and depression. Treatment involves undertaking a high-carbohydrate diet and, during severe attacks, a glucose 10% infusion. It is estimated that AIP affects 5.9 per 1 000 000 people.

2-Methyl-3-hydroxybutyryl CoA dehydrogenase deficiency (Hydroxyl-CoA dehydrogenase deficiency; MHBD) is a rare inborn disease of metabolism caused by a mutation in the HSD17B10 gene which codes for 3-hydroxyacyl-CoA dehydrogenase type-2. A deficiency in this enzyme results in accumulation of L-lactic acid in blood, spinal fluid, and urine; 2-ethylhydracrylic acid, 2-methyl-3-hydroxybutyric acid, and tiglylglycine in urine. Symptoms include cerebal atrophy, motor and mental retardation, overactivity and behavior issues, seizures and progressive neurological defects leading to early death. Treatment includes a high carbohydrate and low protein diet.

3-Methylglutaconic aciduria type 1 (3-Methylglutaconicaciduria; Aciduria, 3-methylglutaconic type I) is an autosomal recessive disease caused by a mutation in the AUH gene which codes for methylglutaconyl-CoA hydratase. A deficiency in this enzyme results in accumulation of 3-hydroxyisovaleric acid, 3-methylglutaconic acid, and methylglutaric acid in urine. Symptoms include hypoglycemia, low birth weight, coma, seizures, and mental retardation. Treatment includes a low protein diet.