Browsing Pathways

Beta-oxidation is the major degradative pathway for fatty acid esters in humans. Fatty acids and their CoA esters are found throughout the body, playing roles such as components of cellular lipids, regulators of enzymes and membrane channels, ligands for nuclear receptors, precursor molecules for hormones, and signalling molecules. Beta-oxidation occurs in the peroxisomes and mitochondria, the latter of which is depicted here. Whether beta-oxidation starts in the mitochondria or the peroxisome depends on the length of the fatty acid. Medium to long chain fatty acids go directly to the mitochondria, whereas very long chain fatty acids (>22 carbons) may be first metabolized down to octanyl-CoA in the peroxisomes and then transported to the mitochondria for the remainder of the oxidation. Beta-oxidation begins with activation of fatty acids by an acyl-coenzyme A synthetase. ATP is used to produce reactive fatty acyl adenylate that can then react with coenzyme A to produce a fatty acyl-CoA. Short and medium chain fatty acids can enter the mitochondria directly via diffusion where they are activated in the mitochondrial matrix by acyl-coenzyme A synthetases. In the first step of the beta-oxidation cycle, a double bond between C-2 and C-3 is formed, producing a trans-Δ2-enoyl-CoA. This is catalyzed by acyl-CoA-dehydrogenases in the mitochondria, which have forms specific to the different lengths of fatty acids. In the second step, enoyl CoA hydratase hydrates the newly formed double bond between C-2 and C-3, producing an L-beta-hydroxyacyl CoA. Next, L-beta-hydroxyacyl CoA dehydrogenase converts the hydroxyl group into a keto group, producing a beta-ketoacyl CoA. In the fourth and final step, the enzyme beta-ketothiolase cleaves the β-ketoacyl CoA and inserts the thiol group of another CoA between C-2 and C-3, reducing the acyl-CoA by 2 carbons and generating acetyl-CoA. The final two steps also have enzymatic forms specific to short chain fatty acids. Additionally, there is a trifunctional protein complex with enzymatic activity capable of performing all of the final 3 steps (hydratase, dehydrogenase, thiolase) in medium to very long chain fatty acids. This four step cycle repeats, removing 2 carbons from the fatty acid each time until it becomes acetyl-CoA. Acetyl-CoA is necessary for the citric acid cycle, among other cellular processes.

Fatty acids and their CoA byproducts can be found in many places in the body, playing major roles in many basic functions of the body. These include signalling roles, energy creation roles and enzyme regulation. Beta-oxidation is a process that occurs in the peroxisomes and in the mitochondria, although this pathway is focused on the mitochondrial piece of that process. Depending on the length of the fatty acid, beta-oxidation will either begin in the peroxisomes or the mitochondria. Very long chain fatty acids, fatty acids that consist of more than 22 carbons, can be reduced in the peroxisome where they become octanyl-CoA before moving to the mitochondria for the rest of the oxidation process. Stearoylcarnitine is transported by a mitochondrial carnitine/acylcarnitine carrier protein into the mitochondrial matrix, where it is converted to stearoyl-CoA through the enzyme carnitine o-palmitoyltransferase 2. Stearoyl-CoA then is catalyzed into (2E)-octadecenoyl-CoA by the enzyme long-chain specific acyl-CoA dehydrogenase. Then, enoyl-CoA hydratase converts (2E)-octadecenoyl-CoA into (s)-hydroxyoctadecanoyl-CoA. The pathway continues as hydroxyacyl-coenzyme A dehydrogenase cleaves (s)-hydroxyoctadecanoyl-CoA into 3-oxooctadecanoyl-CoA. 3-oxooctadecanoyl-CoA then uses 3-ketoacyl-CoA thiolase to create acetyl-CoA (necessary for the citric acid cycle) and uses trifunctional enzyme subunits alpha and beta to create palmityl-CoA. This palmityl-CoA is then converted by long-chain specific acyl-CoA dehydrogenase to (2E)-hexadecenoyl-CoA. Enoyl-CoA then converts (2E)-hexadecenoyl-CoA to 3-hydroxyhexadecanoyl-CoA, which is then turned into 3-oxohexadecanoyl-CoA by the enzyme hydroxyacyl-coenzyme A dehydrogenase. 3-ketoacyl-CoA thiolase then creates acetyl-CoA with the help of trifunctional enzyme subunits alpha and beta, which also produce tetradecanoyl-CoA from 3-oxohexadecanoyl-CoA. Long-chain specific acyl-CoA dehydrogenase then converts tetradecanoyl-CoA to (2E)-tetradecenoyl-CoA. (2E)-tetradecenoyl-CoA is then converted by the enzyme enoyl-CoA hydratase into 3-hydroxytetradecanoyl-CoA, which then creates 3-oxotetradecanoyl-CoA through the enzyme hydroxyacyl-coenzyme A dehydrogenase. Finally, the 3 enzymes 3-ketoacyl-coA thiolase, trifunctional enzyme subunit alpha and trifunctional enzyme subunit beta convert 3-oxotetradecanoyl-CoA into acetyl-CoA and lauroyl-CoA which can then be beta-oxidized as medium chain saturated fatty acids.

Dimethylglycine dehydrogenase deficiency, also called DMGDH deficiency and dimethylglycinuria, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of glycine metabolism caused by a defective DMGDH gene. DMGDH codes for the mitochondrial protein dimethylglycine dehydrogenase which catalyzes the conversion of dimethylglycine into sarcosine. This disorder is characterized by a large accumulation of N,N-dimethylglycine (DMG) and creatinine kinase in serum, and DMG in the urine. Symptoms of the disorder include an unusual fish-like odour and muscle weakness. It is estimated that DMGDH deficiency affects 1 in 1 000 000 individuals.

Nonketotic hyperglycinemia (GCE) is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by a defective GLDC gene. GLDC encodes for the enzymes involved in the conversion of glycine to CO2, NH3 and hydroxymethyltetrahydrofolic acid. Most patients have abnormally low oxalate excretion in the urine. Other symptoms start presenting in the first few days of life and include lethargy, hypotonia, and myoclonic jerks, and progressing to apnea. GCE often leads to death, and those who regain spontaneous respiration develop intractable seizures and profound mental retardation. Currently there is no cure for Nonketotic hyperglycinemia therefore treatment involves managing symptoms. Frequency for Nonketotic hyperglycinemia has not been documented worldwide.

DOPA-Responsive Dystonia is a condition in which the muscles contract, experience tremors and uncontrolled movements (dystonia). Some cases are mild, while others can be severe. The beginning signs of this condition are dystonia in the legs, and clubfeet. The cause of this condition is usually a mutation in the GCH1 gene, but can sometimes be attributed to mutations in the TH or SPR genes. Tetrahydrobiopterin is an important compound in the production of neurotransmitters, specifically dopamine and serotonin, and the processing of quite a few amino acids, The mutation on GCH1 causes GTP cyclohydrase production to be reduced or absent which causes the first three steps of tetrahydrobiopterin biosynthesis to be compromised. The mutation on the SPR gene affects tetrahydrobiopterin biosynthesis by interfering with the production of sepiapterin reductase, which is needed to complete the final step of tetrahydrobiopterin biosynthesis. The TH gene mutation also affects dopamine production through the decreased function of an enzyme called tyrosine hydroxylase, which is responsible for converting tyrosine to dopamine. Dopamine is imperative in maintaining smooth muscle movements, which is why patients with DOPA-responive dystonia experience tremors and movement problems.

Hyperphenylalaninemia is the high presence of phenylalanine in the system/blood caused by a genetic mutation. In this case a missense error in the gene which encodes GTP cyclohydrolase. Consequently, this form of hyperphenylalaninemia is also called GTP cyclohydrolase I deficiency and/or dopa-responsive dystonia. It is an autosomal recessive mutation. The mutation results in a reduction in the production of BH4 which is a necessary component in the reaction which transforms phenylalanine to other products in the body. Common symptoms include: abnormality of eye mpvement, choreoathetosis, dysphagia, dystonia, excessive salivation, hypekinesis, lethargy, limb hyptertonia, seizures, tremor, among others.

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.

Hyperphenylalaninemia due to dihydropteridine reductase deficiency (DHPR) is the high presence of phenylalanine in the system/blood caused by a genetic mutation. More specificially, mutations in the QDPR gene are the root cause of the condition. One observes that such a mutation results in an error encoding a reductase enzyme, and from there a chain reaction of effects lead to the observed effects of the disease. The mutation is autosomal recessive. When tetrahydrobiopterin levels drop, the breakdown of many several amino acids, such as phenylalanine, is reduced and as a result their levels in the blood augment. Symptoms of hyperphenylalaninemia due to dihydropteridine reductase deficiency include: dysphagia, global development delay, microcephaly, and intellectual disability (among others). Treatment consists of BH4 supplements as well as other medical treatments.

Segawa syndrome is a condition in which the affected individual has a clumsy or unusual gait, and experiences involuntary muscle contractions and uncontrolled movements (dystonia). Some cases are mild, while others can be severe. The beginning signs of this condition are dystonia in the legs, and clubfeet. The cause of this condition is a mutation in the GCH1 gene. Tetrahydrobiopterin is an important compound in the production of neurotransmitters, specifically dopamine and serotonin, and the processing of quite a few amino acids, The mutation on GCH1 causes GTP cyclohydrase 1 production to be reduced or absent which causes the first three steps of tetrahydrobiopterin biosynthesis to be compromised. Dopamine is imperative in maintaining smooth muscle movements, which is why patients with Segawa syndrome experience movement problems and an unusual gait.

Sepiapterin reductase deficiency results from a metabolic disorder; namely, the underproduction of Sepiapterin. The cause of this underproduction is an autosomal recessive genetic mutation in the SPR gene. This gene is responsible for Sepiapterin production, and naturally, when the gene malfunctions the production of this metabolite is altered leading to a range of effects on the body. In this case, some symptoms of Sepiapterin Deficiency are: motor and speech delay, axial hypotonia, dystonia, weakenss microcephaly, dysarthria, autonomic dysfunction, oculogyric crises, drowsiness, among others.