Fatty acid metabolism beta-oxidation

Fatty acids undergo beta oxidation in the liver and form acetyl CoA. If acetyl CoA accumulates instead of traversing the citric-acid cycle, the liver becomes more dependent on beta oxidation than on the citric-acid cycle for its source of high-energy phosphate. To continue beta oxidation, coenzyme A is required. If all the CoA is tied up as fatty-acyl CoA and acetyl CoA, no beta oxidation occurs. However, there is a metabolic pathway, unique to the liver, through which to overcome this apparent dilemmaketone-body formation (Fig. 14.3). It occurs as follows in the mitochondrial matrix. 

A large amount of energy is obtained when fatty acids undergo oxidation in the mitochondria to yield acetyl-CoA. In stage 2 of fat metabolism, fatty acids undergo beta-oxidation (/3-oxidation), which removes two-carbon segments, one at a time, from the carboxyl end. 

To date there are no true inborn errors associated with essential fatty acid metabolism. However, we do know that the final step of DHA formation is the peroxisomal beta-oxidation of a homologous C24 fatty acid [7]. Consequently, patients with a generalised defect of peroxisomal function, such as Zellweger syndrome, are prone to develop deficiencies of essential fatty acids including DHA [9]. 

In order to carry out all of these different functions, peroxisomes are equipped with a unique set of enzyme proteins, catalysing the different reactions involved. In addition, the peroxisomal membrane contains specific transporters in order to take up substrates from the cytosol and release the end products of peroxisomal metabolism. Since peroxisomes lack a citric acid cycle as well as a respiratory chain, the end products of peroxisomal metabolism, such as acetyl-CoA, propionyl-CoA and a range of other acyl-Co A esters predominantly derived from fatty acid beta-oxidation, are exported from the peroxisomal interior and shuttled to mitochondria for full oxidation to C02 and H20. The same applies to the NADH produced during beta-oxidation, which is reoxidised via redox-shuttles so that the NADH generated in peroxisomes is ultimately reoxidised in the mitochondrial respiratory chain at the expense of molecular oxygen. 

Side effects. The common dose-related side effects of valproate include nausea, vomiting and gastrointestinal distress weight gain is frequent (estimated as high as 30%) and may be associated with a drug-induced decrease in the beta oxidation of fatty acids. Sedation is also frequent. Alopecia is an unusual side effect of valproate, possibly caused by an abnormal metabolite. Valproate has a number of metabolically linked side... 

Fatty acids are cleaved from triglycerides and metabolized through beta oxidation. This process is shown in Figure 12.41. This process clips the fatty acids into two-carbon fragments. The two-carbon fragments emerge from beta oxidation as acetyl CoA. Each acetyl CoA molecule is accompanied by the production of an NADH and a QHr Of course, when the chain is finally cut down to just two carbons, they are as an acetyl CoA. Since there are no carbon-carbon bonds to oxidatively cleave, no NADH or QH2 are produced. 

The authors suggested that this patient had a defect in lipid metabolism, based on the muscle biopsy. Muscle mitochondria are a principle site for beta-oxidation of fatty acids. Microvesicular steatosis can progress to liver failure with severe and prolonged impairment of beta-oxidation. This metabolic defect may have exacerbated the direct toxic effects of cocaine. 

Cleavage of the ether linkage of the 2,4-dichlorophenoxyalkanoic acids by a strain of Flavobacterium to yield the intact alkanoic acid and 2,4-dichlorophenol has also been observed (34,35). The intact alkanoic acid is further metabolized by beta oxidation. The bacterium produced the free fatty acid corresponding to the aliphatic moieties of six omega-linked dichlorophenoxyalkanoic acids in the series from 3-(2,4-dichloro-phenoxy) propionic acid to 8-(2,4-dichlorophenoxy)octanoic acid. 

R.J. Wanders, E G van Grunsven, and GA. Jansen. 2000. Lipid metabolism in peroxisomes Enzymology, functions and dysfunctions of the fatty acid alpha- and beta-oxidation systems in humans Biochem. Soc. Trans. 28 141-149. (PubMed)... 

Ketogenesis occurs in the matrix of liver mitochondria. Fatty acids are first broken down to acetyl CoA via beta-oxidation (providing energy for liver metabolism from the reducing equivalents generated). The acetyl CoA is then used in ketogenesis ... 

The year 23004 marked the centenary of two important discoveries in the field of metabolism The discovery of beta-oxidation of fatty acids by Franz Knoop (1904), and the discovery of the oxygen dependence for normal pump function of the heart by Hans Winterstein (1904).2 The year 2004 also marked the 50th anniversary of the discovery, by Richard Bing and his colleagues, that the human heart prefers fatty acids for respiration.3... 

PN solutions therefore may need to be modified by clinicians to provide supplemental amounts of CEAAs. Cysteine is a CEAA in preterm and term infants that may be added to PN solutions at the time of compounding. An additional benefit of including cysteine is that it enhances calcium and phosphate solubility in PN solutions by decreasing the solution s pH. Carnitine is a qnarternary amine required for transport of free fatty acids into the mitochondria for beta-oxidation and energy prodnction. Newborns are at risk for carnitine deficiency becanse of their immature synthetic and conservation mechanisms. Decreased plasma carnitine concentrations are associated with impaired lipid metabolism in patients receiving intravenous lipid emulsion (TVLE). ... 

To some extent this may be subjective, imposing a human interpretation on the observations, but it also reflects an objective reality some reactions carry a greater flux of metabohtes than others, some are active in a wider range of cell types than others, and so on. To understand the entire chart, therefore, it is useful to collect the reactions into groups of transformation sequences known as metabolic pathways. The number of steps considered to be one pathway can be very small if very few steps are needed to convert one important metabolite into another. For example, serine biosynthesis is a three-step pathway, in which the aminoacid serine is synthesized from 3-phosphoglycerate. At the other extreme, beta-oxidation, the process that converts fatty acids from the form in which they are stored in fat cells into the form in which they are metabolically active, involves seven repetitions of the same four types of step, making an unbranched pathway of nearly 30 reactions. 

The liver is the main origin of ketones in laboratory animals, where the long chain fatty acids are released from plasma albumin and bound to fatty acid-binding proteins in the hepatocytes. The long chain fatty acids react with CoA and then can be used to synthesize triacylglycerol or undergo beta-oxidation to acetyl CoA. When the levels of plasma fatty acids are elevated, acetyl CoA can be metabolized to form acetoacetate and 3-hydroxybutyrate or enter the tricarboxylic acid cycle. In ketosis, the levels of acetone, acetoacetate, and 3-hydroxybutyrate (also known as beta-hydroxybutyrate) are increased in both plasma and urine these three compounds historically were collectively called ketone bodies. Urine test strips can be used to test for ketonuria, and there are several enzymatic assays for 3-hydroxybutyrate and acetoacetate. 

Tsemg, K.-Y. Jin, SJ. (1991) J. Biol Chem., 266, 11614-11620, NADPH-dependent reductive metabolism of cis-5 unsaturated fatty acids. A revised pathway for the beta-oxidation of oleic acid. 

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