Browsing Pathways

Joubert syndrome is a condition in which brain development is not completed as it should be, including the lack or underdevelopment of the part of the brain that regulates balance and coordination and an abnormal brain stem. The symptoms affect a variety of body parts in the patient, including apnea, ataxia brought on by hypotonia, abnormal eye movements and intellectual disability. Many different gene mutations are responsible for Joubert syndrome, all of the proteins created from these genes affecting the cilia that are found on the cell surface. It can be confirmed through its hallmark molar tooth imprint that shows up on brain scans of the patient, a visualization of the malformed brain stem and cerebellar vermis.

Cyclooxygenase is the major producer of prostacyclin. Prostacyclin binding to its receptor increases vasodilation and decreases platelet aggregation. The receptor is a G-protein coupled receptor, upon its binding it activates G proteins causing the activation of adenylyl cyclase and production of cAMP messenger molecules. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.In vasodilation, the PKA activity causes phosphorylation of MLCK, decreasing its activity, resulting in dephosphorylation of MLC of myosin. This leads to smooth muscle relaxation resulting in vasodilation.

Alkaptonuria (Homogentisic acid oxidase deficiency) is an autosomal recessive disease caused by a mutation in the HGD gene which codes for homogentisate 1,2-dioxygenase. A mutation in this enzyme results in accumulation of homogentisic acid in urine. Symptoms, which present in adulthood, include arthritis, black or brown urine, and urolithiasis. Treatment includes a low-protein diet with vitamin C.

BH4-deficient hyperphenylalaninemia has several causes. One such cause is a PTS deficiency resultant from a genetic mutation. (In particular, a mutation in the gene encoding 6-pyruvoyl-tetrahydropterin synthase.) The mutation is autosomal recessive. Common symptoms include: muscular hypotonia, ataxia, bradykinesia, choreoathetosis, depressivity, dysphagia, hyperkinesis, hypsarrhythmia, myoclonus, and others. BH4 is a cofactor involved in many things and associated with neurotransmitter synthesis. In short, the reduction of levels of BH4 creates issues in the metabolism of phenylalanine. This cascade of reactions produces the aforementioned symptoms.

Galactokinase deficiency also called Galactosemia type II, is a rare inborn error of metabolism (IEM) and an autosomal recessive disorder of galactokinase caused by a mutation in the GALK1 gene on chromosome 17q24. Galactokinase uses 1 ATP to catalyse the phosphorylation of α-D-galactose to galactose 1-phosphate and catalyses β-D-galactose to glucose 1-phosphate. Symptoms include cataract formation in children who are exposed to lactose in their diets. Cataract formation is the result of osmotic phenomena caused by the accumulation of galactitol in the lens. Treatment includes immediately removing lactose from patient’s diet, however symptoms such as delayed speech, cognitive learning and motor skills can still be present.

Fenoprofen (also named Nalfon) is a nonsteroidal anti-inflammatory drug. Fenoprofen can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis in many animal model's cell is caused by presence of Fenoprofen.

Salicylate-sodium (also named salsonin or clin) is a nonsteroidal anti-inflammatory drug (NSAID). It can be used for relieving pain and reducing fever. Salicylate-sodium can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis in many animal model's cell is caused by presence of salicylate-sodium.

Hypoxia-inducible factor In many tumours, oxygen availability becomes limited (hypoxia) very quickly during cancer development. The major regulator of the response to hypoxia is the HIF transcription factor. Under normal oxygen levels, the protein levels of HIF alpa is very low due to constant degradation, mediated by a sequence of post-translational modification events catalyzed by the enzymes PHD1,2 and 3, (also known as EglN2,1 and 3). Under hypoxic conditions, HIF alpha escapes hydroxylation and degration. Succinate dehydrogenase (SDH) is a collection of housekeeping genes (SDHA,B,C,D), but mutations in those genes allows for succinate to accumulate and cross the mitochondrial barrier through a dicarboxylate carrier. Once in the cytosol, it inhibits the activity of the PHD1,2 and 3 since succinate is a product of the enzyme, it acts as feedback inhibition.

Sarcosine is a compound derived from the amino acid glycine and is involved in both its synthesis and degradation, and is an intermediate in the metabolism of choline to glycine. In cases of prostate cancer, the cancer cells seem to produce higher levels of sarcosine. Elevated levels of sarcosine found in the urine of patients with prostate cancer, and it has been suggested that these elevated levels are responsible for the development of the cancer. This pathway begins with choline’s transport into the mitochondrial matrix via xolute carrier family protein 44 A1 and the choline transporter-like protein 2. Once in the matrix, choline is oxidized to betaine aldehyde by choline dehydrogenase, and in the process reduces an acceptor. Betaine aldehyde is then converted to betaine by the addition of a water molecule by alpha-aminoadipic semialdehyde dehydrogenase. Following this, betaine is transported out of the mitochondria by an unknown transporter, where it then reacts with homocysteine to form dimethylglycine and L-methionine in a reaction catalyzed by betaine-homocysteine S-methyltransferase 1. The dimethylglycine is then transported back into the mitochondrial matrix by another unknown transporter, where it can react with tetrahydrofolate to form sarcosine and 5-methyltetrahydrofolic acid in a reaction catalyzed by dimethylglycine dehydrogenase. In at least some cases of prostate cancer cells, the SARDH gene is mutated, which encodes the sarcosine dehydrogenase protein. This can lead to an increase of sarcosine in the cells, as sarcosine dehydrogenase typically converts sarcosine to glycine, which is then converted to and from L-serine by serine hydroxymethyltransferase. With a non-functional or less functional enzyme, sarcosine levels will be increased, and serine and glycine levels will be reduced. A separate set of reactions outside of the mitochondria begins with the L-methionine produced by betaine—homocysteine S-methyltransferase 1, which is then converted to S-adenosylmethionine by a complex consisting of S-adenosylmethionine synthase and methionine adenosyltransferase. S-adenosylmethionine then reacts with glycine reversibly to form S-adenosylhomocysteine, as well as sarcosine. The expression of the gene encoding glycine N-methyltransferase, GNMT, can also be elevated in cancer tissues, leading to an increased concentration of sarcosine outside of the mitochondria as well.

Hyperlysinemia type I is a rare inherited inborn error of metabolism (IEM) of lysine metabolism. It is an autosomal recessive disorder that is caused by a defect in the alpha-aminoadipic semialdehyde synthase gene (AASS). The AASS gene encodes a bifunctional enzyme that contains lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type I, both enzymatic functions of AASS are defective. AASS is involved in the first two steps of the lysine degradation pathway. Lysine-alpha-ketoglutarate reductase catalyzes the metabolism of lysine to saccharopine, which is then cleaved to alpha-aminoadipic semialdehyde and glutamic acid by saccharopine dehydrogenase. Hyperlysinemia type I is characterized by elevated blood levels of the amino acid lysine, a building block of most proteins. Pipecolic acid can also be increased in serum and urine, while ornithine is typically decreased. Clinical symptoms of hyperlysinemia are highly variable. The descriptions range from symptom-free to severe developmental delay, spastic diplegia, seizures, rigidity, coma, episodic vomiting, and diarrhea. For the vast majority of people, hyperlysinemia typically causes no health problems, and most people with elevated lysine levels are unaware that they have this condition.