Pathways

Phenylbutazone is a synthetic nonsteroidal anti-inflammatory drug (NSAID) derived from pyrazolone. It is used to treat pain and inflammation, mostly backache, rheumatoid arthritis, and ankylosing spondylitis. This drug has anti-inflammatory, antipyretic, and analgesic activities. Its analgesic effect comes from its ability to reduce the production of prostaglandin H and prostacyclin. Prostaglandin is a molecule that is acting on a wide variety of cells such as vascular smooth muscle cells causing constriction or dilatation, on platelets causing aggregation or disaggregation, and on spinal neurons causing pain. Phenylbutazone binds and inactivates prostaglandin H synthase and prostacyclin synthase through peroxide-mediated deactivation. Due to these two inactivations, the level of prostaglandins decreases and the inflammation is reduced in the surrounding tissues. Phenylbutazone is administered as an oral tablet.

Phenylbutazone is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Phenylbutazone passes through the liver and is then excreted from the body mainly through the kidney.

The process of phenylethylamine metabolism starts with 2-phenylethylamine interacting with an oxygen molecule and a water molecule in the periplasmic space through a phenylethylamine oxidase. This reaction results in the release of a hydrogen peroxide, ammonium and phenylacetaldehyde. Phenylacetaldehyde is introduced into the cytosol and degraded into phenylacetate by reaction with a phenylacetaldehyde dehydrogenase. This reaction involves phenylacetaldehyde interacting with NAD, and a water molecule and then resulting in the release of NADH, and 2 hydrogen ion. Phenylacetate is then degraded. The first step involves phenylacetate interacting with an coenzyme A and an ATP driven phenylacetate-CoA ligase resulting in the release of a AMP, a diphosphate and a phenylacetyl-CoA. This resulting compound the interacts with a hydrogen ion, NADPH, and oxygen molecule through a ring 1,2-phenylacetyl-CoA epoxidase protein complex resulting in the release of a water molecule, an NADP and a 2-(1,2-epoxy-1,2-dihydrophenyl)acetyl-CoA. This compound is then metabolized by a ring 1,2 epoxyphenylacetyl-CoA isomerase resulting in a 2-oxepin-2(3H)-ylideneacetyl-CoA. This compound is then hydrolated through a oxepin-CoA hydrolase resulting in a 3-oxo-5,6-didehydrosuberyl-CoA semialdehyde. This commpound then interacts with a water molecule and NADP driven 3-oxo-5,6-dehydrosuberyl-CoA semialadehyde dehydrogenase resulting in 2 hydrogen ions, a NADPH and a 3-oxo-5,6-didehydrosuberyl-CoA. The resulting compound interacts with a coenzyme A and a 3-oxo-5,6 dehydrosuberyl-CoA thiolase resulting in an acetyl-CoA and a 2,3-didehydroadipyl-CoA. This resulting compound is the hydrated by a 2,3-dehydroadipyl-CoA hydratas resulting in a 3-hydroxyadipyl-CoA whuch is dehydrogenated through an NAD driven 3-hydroxyadipyl-CoA dehydrogenase resulting in a NADH, a hydrogen ion and a 3-oxoadipyl-CoA. The latter compound then interacts with conezyme A through a beta-ketoadipyl-CoA thiolase resulting in an acetyl-CoA and a succinyl-CoA. The succinyl-CoA is then integrated into the TCA cycle.

Phenylketonuria, also called Folling disease, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder that affects the proper processing of phenylalanine caused by a defective phenylalanine hydroxylase. Phenylalanine hydroxylase breaks down phenylalanine from the diet. This disorder is characterized by a large accumulation of phenylalanine in the blood and other tissues. It is also characterized by an accumulation of Phenylpyruvic acid, Mandelic acid, Phenylacetic acid, Phenylacetylglutamine, and Glycine in the blood and urine. Symptoms of the disorder include behavioural problems, psychiatric disorders and seizures. Treatment eating a diet limiting the intake of phenylalanine is very effective. It is estimated that phenylketonuria affects 1 in 15,000 individuals in the United States.