Browsing pathways

Rosuvastatin inhibits cholesterol synthesis via the mevalonate pathway by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol synthesis by this pathway. The active form of statins bears a chemical resemblance to the reduced HMG-CoA reaction intermediate that is formed during catalysis. Structure-activity relationship studies have demonstrated that statins bind to HMG-CoA reductase at the same site as the reduced intermediate and are held in place by similar chemical interactions. Unlike Lovastatin and simvastatin, which undergo in vivo hydrolysis to their active form rosuvastatin is synthetically produced in active form. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.

Roxithromycin is a semi-synthetic macrolide antibiotic. It is very similar in composition, chemical structure and mechanism of action to erythromycin, azithromycin, or clarithromycin. Roxithromycin prevents bacteria from growing by interfering with protein synthesis. Roxithromycin binds to the 50S subunit of the bacterial ribosome and inhibits the translocation of peptides. Roxithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Legionella pneumophila. It can be used to treat respiratory tract, urinary and soft tissue infections.

S-Adenosylhomocysteine (SAH) Hydrolase Deficiency (Hypermethioninemia, familial) is caused by a defect in the AHCY gene, which codes for S-adenosylhomocysteine hydrolase (SAH). S-adenosylhomocysteine hydrolase catalyzes the hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine. In eukaryotes, this is the major route for disposal of the S-adenosylhomocysteine formed as a common product of each of many S-adenosylmethionine-dependent methyltransferases. SAH Deficiency causes accumulation of guanidinoacetate, homocysteine, methionine, s-adenosylhomocysteine and s-adenosylmethionine in plasma, and methionine in spinal fluid. Symptoms include cerebral atrophy, dysmorphism, strabismus, jaundice, mental and motor retardation.

Saccharopinuria (an excess of saccharopine in the urine), also called saccharopinemia or saccharopine dehydrogenase deficiency, or alpha-aminoadipic semialdehyde synthase deficiency, is a variant form of hyperlysinemia caused by a partial deficiency of the enzyme aminoadipic semialdehyde synthase (AASS), which has lysine ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH) activity. AASS acts in the first 2 steps in lysine degradation. A defect in this enzyme results in accumulation of citrulline, lysine and saccharopin in the plasma; lysine in the spinal fluid; and citrulline, lysine and saccharopin in the urine. Symptoms include growth and mental retardation.

Both the infantile and Finnish (Salla disease; 604369) forms of sialuria are due to mutation in the SLC17A5 gene, which encodes a vesicular excitatory amino acid transporter (VEAT) with dual physiologic functions. When present in synaptic vesicles in the central nervous system, sialin is responsible for vesicular storage and subsequent exocytosis of aspartate and glutamate. When present in lysosomes, it acts as an H+-coupled sialic acid exporter. Mutations in this transporter cause accumulation of free sialic acid in the urine. Symptoms include seizures, mental, growth, and motor retardation, nystagmus, and speech development.

Sarcosinemia (SAR), also called Hypersarcosinemia and SARDH deficiency, is a rare autosomal recessive metabolic disorder characterized by an accumulation of sarcosine in blood plasma and urine. It can result from an inborn error of sarcosine metabolism, or from severe folate deficiency related to the folate requirement for the conversion of sarcosine to glycine. Sarcosine (N-methylglycine) is enzymatically formed from dimethylglycine by dimethylglycine dehydrogenase and converted to glycine by sarcosine dehydrogenase (SARDH). Symptoms include visual impairment, blindness, cardiomyopathy, cranial synostosis, growth and mental retardation.

Selenoamino acids are defined as those amino acids where selenium has been substituted for sulfur. These include selenocysteine, selenohomocysteine and selenomethionine. Selenium and sulfur are chalcogen elements that share many chemical properties and so the substitution of normal (sulfur-containing) amino acids with selenoamino acids has little effect on protein structure and function. Because higher animals have no efficient mechanism for Met synthesis, they are unable to synthesize selenomethionine de novo. Therefore most selenomethionine comes from the diet. However seleniomethionine can be incorporated into body proteins. This allows Se to be stored in the organism and reversibly released by normal metabolic processes. Ingested selenomethionine is absorbed in the small intestine via the Na+-dependent neutral amino acid transport system. Selenocysteine may also be incorporated directly into proteins (for example glutathione peroxidases, tetraiodothyronine 5' deiodinases, thioredoxin reductases, formate dehydrogenases, glycine reductases and some hydrogenases). However, selenocyteine is not coded for directly in the genetic code. Instead, it is encoded in a special way by a UGA codon, which is normally a stop codon. The UGA codon is made to encode selenocysteine by the presence of a SECIS element (SElenoCysteine Insertion Sequence) in the mRNA. In eukaryotes, the SECIS element is in the 3' untranslated region (3' UTR) of the mRNA, and can direct multiple UGA codons to encode selenocysteine residues. In mammals, selenocysteine can be generated from alanine and hydrogen selenide using the enzyme selenocysteine lyase. It can also be generated from selenocystathionine via the enzyme cystathionase. Selenocystathionine can be generated from selenohomocysteine via the enzyme cystathionine-beta synthase. In mammals selenohomocysteine generated from selenomethionine metabolism can be efficiently recycled to selenomethionine. Additionally, selenomethionine from the diet can be converted to Se-adenosyl-selenomethionine and Se-adenosyl-selenohomocysteine through S-adenosylmethionine synthetase and a methyltrasferase. Se-adenosyl-selenohomocysteine can be converted to selenohomocysteine via adenosylhomocysteinase.

Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD Deficiency) is caused by mutation in the gene encoding short-chain acyl-CoA dehydrogenase, an enzyme which normally breaks down short chain fatty acids. SCADD causes accumulation of ammonia in blood; butyrylcarnitine(C4) in plasma; adipic acid, butyrylglycine, ethylmalonic acid; hexanoylglycine and methylsuccinic acid in urine. Symptoms include hypoglycemia, hypotonia, microcephaly, failure to thrive, lactic acidosis, peripheral neuropathy, and vomiting.

Sialidosis (Mucolipidosis type I; ML I; Neuraminidase deficiency) is an inherited lysosomal storage disease that results from a deficiency of the enzyme sialidase. The lack of this enzyme results in an abnormal accumulation of complex carbohydrates known as mucopolysaccharides, and of fatty substances known as mucolipids. Both of these substances accumulate in bodily tissues. The role of sialidase is to remove a particular form of sialic acid (a sugar-like molecule) from sugar-protein complexes (referred to as glycoproteins), which allows the cell to function properly. Because the enzyme is deficient, small chains containing the sugar-like material accumulate in neurons, bone marrow, and various cells that defend the body against infection. Deficiency in sialidase causes accumulation of sialyloligosccarides in urine. Symptoms include visual impairment, hypotonia mental retardation, myoclonus, siezures and progressive neurologic defect.

Sialuria is caused by mutation in the gene encoding uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase, which causes an excessive synthesis of sialic acid (N-acetylneuraminic acid, NeuAc). This causes accumulation of sialic acid in the urine. Symptoms of sialuria include hepatosplenomegaly, hypotonia, frequent upper respiratory infections, gastroenteritis and seizures.