Carnitine, fatty acid oxidation

What would be the consequences of a carnitine deficiency for fatty acid oxidation ... 

Figure 3. Mitochondrial fatty acid oxidation. Long-chain fatty acids are converted to their CoA-esters as described in the text, and their fatty-acyl-groups transferred to CoA in the matrix by the concerted action of CPT 1, the acylcarnitine/carnitine exchange carrier and CPT (A) as described in the text. Medium-chain and short-chain fatty acids (Cg or less) diffuse directly into the matrix where they are converted to their acyl-CoA esters by a acyl-CoA synthase. The mechanism of p-oxidation is shown below (B). Each cycle of P-oxidation removes -CH2-CH2- as an acetyl unit until the fatty acids are completely converted to acetyl-CoA. The enzymes catalyzing each stage of P-oxidation have different but overlapping specificities. In muscle mitochondria, most acetyl-CoA is oxidized to CO2 and H2O by the citrate cycle (Figure 4) some is converted to acylcamitine by carnitine acetyltransferase (associated with the inner face of the inner membrane) and exported from the matrix. Some acetyl-CoA (if in excess) is hydrolyzed to acetate and CoASH by acetyl-CoA hydrolase in the matrix. Enzymes ...

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

Camitine deficiency can occur particularly in the newborn—and especially in preterm infants—owing to inadequate biosynthesis or renal leakage. Losses can also occur in hemodialysis. This suggests a vitamin-fike dietary requirement for carnitine in some individuals. Symptoms of deficiency include hypoglycemia, which is a consequence of impaired fatty acid oxidation and hpid accumulation with muscular weakness. Treatment is by oral supplementation with carnitine. 

Carnitine deficiency is a clinically useful term describing a diversity of biochemical disorders affecting fatty acid oxidation. Carnitine deficiency may be tissue-specific or generalized. 

The activity of carnitine palmitoyltransferase-I plays an important role in the regulation of fatty acid oxidation malonyl-CoA is an allosteric exhibitor of the enzyme. Malonyl-CoA is a key intermediate in fatty acid synthesis, which ensures that fatty acid oxidation is decreased when synthesis is taking place. Nonetheless, malonyl-CoA has a major role in the control of fatty acid oxidation in all tissues in which fatty acid oxidation occurs, even if no synthesis takes place. 

Figure 7.15 Inhibition of acetyl-CoA carboxylase by cyclic AMP dependent protein kinase and AMP dependent protein kinase the dual effect of glucagon. Phosphorylation of acetyl-CoA carboxylase by either or both enzymes inactivates the enzyme which leads to a decrease in concentration of malonyl-CoA, and hence an increase in activity of carnitine palmitoyltransferase-I and hence an increase in fatty acid oxidation. Insulin decreases the cyclic AMP concentration maintaining an active carboxylase and a high level of malonyl-CoA to inhibit fatty acid oxidation.

Defects in several proteins involved in fatty acid oxidation are known. These are carnitine palmitoyltransferases, any of the three acyl-CoA dehydrogenases, or the protein that... 

Malonyl-CoA is also involved in the regulation of fatty acid oxidation, via inhibition of carnitine palmitoyltransferase. In non-lipogenic tissues, the only role of the carboxylase is provision of malonyl-CoA for regulation of the rate of fatty acid oxidation. 

In 1955, Fritz determined that carnitine plays an essential role in fatty acid -oxidation (FAO), and in 1973 the first two clinically relevant disorders affecting this pathway were described primary carnitine deficiency by Engel and Angelini, and carnitine palmitoyltransferase (CPT) type II (CPT-II) deficiency by DiMauro and DiMauro [6, 7]. To date, more than 20 different enzyme deficiency states affecting fatty acid transport and mitochondrial / -oxidaLion have been described [8] and additional enzymes involved in this pathway are still being discovered [9, 10]. 

Schmidt-Sommerfeld E, Bobrowski PJ, Penn D, Rhead WJ, Wanders RJA, Bennet MJ (1998) Analysis of carnitine esters by radio-high performance liquid chromatography in cultured skin fibroblasts from patients with mitochondrial fatty acid oxidation disorders. Pediatr Res 44 210-214... 

The enzymes of fatty acid oxidation in animal cells are located in the mitochondrial matrix, as demonstrated in 1948 by Eugene P. Kennedy and Albert Lehninger. The fatty acids with chain lengths of 12 or fewer carbons enter mitochondria without the help of membrane transporters. Those with 14 or more carbons, which constitute the majority of the FFA obtained in the diet or released from adipose tissue, cannot pass directly through the mitochondrial membranes—they must first undergo the three enzymatic reactions of the carnitine shuttle. The first reaction is catalyzed by a family of isozymes (different isozymes specific for fatty acids having short, intermediate, or long carbon chains) present... 

Mitochondrial P oxidation of fatty acids is the principal source of energy for the heart. Consequently, inherited defects of fatty acid oxidation or of carnitine-assisted transport often appear as serious heart disease (inherited cardiomyopathy). These may involve heart failure, pulmonary edema, or sudden infant death. 

One of the most frequent defects of fatty acid oxidation is deficiency of a mitochondrial acyl-CoA dehydrogenase.50 If the long-chain-specific enzyme is lacking, the rate of P oxidation of such substrates as octanoate is much less than normal and afflicted individuals excrete in their urine hexanedioic (adipic), octanedioic, and decanedioic acids, all products of co oxidation.54 Much more common is the lack of the mitochondrial medium-chain acyl-CoA dehydrogenase. Again, dicarboxylic acids, which are presumably generated by 0) oxidation in the peroxisomes, are present in blood and urine. Patients must avoid fasting and may benefit from extra carnitine. 

Explain the role of carnitine acyltransferases in fatty acid oxidation. 

Bilinsky, E. and Jonas, R.E. (1970). Effects of coenzyme A and carnitine on fatty acid oxidation by rainbow trout mitochondria. Journal of the Fisheries Research Board of Canada 27,857-864. 

The reaction is catalyzed by palmitoyl-CoA-carnitine acyltransferase, which is inhibited by malonyl-CoA (see later), and is the limiting reaction of the fatty acid oxidation process. 

Glucagon exerts a ketogenic action on the liver which is more pronounced in insulin-deficient states. This action is thought to be due mainly to the inhibition of acetyl-CoA carboxylase with resulting decrease in malonyl-CoA. Malonyl-CoA is an inhibitor of carnitine acyltransferase I which is the rate-limiting step for mitochondrial fatty acid oxidation. A decrease in malonyl-CoA is thus postulated to lead to overproduction of acetyl-CoA which is then condensed to form ketone bodies. 

Supplementing the diet with carnitine may stimulate the uptake of long-chain fatty acids into affected cells. Fatty acid oxidation within the mitochondrion will generate acetyl-CoA, which when oxidized in the TCA cycle will produce NADH and FADH2 to feed into the ETC. Carnitine also shuttles potentially toxic fatty acid catabolic by-products out of the mitochondrial matrix to the kidney for excretion in the urine. 

Figure 9-1- Role of carnitine in fatty acid oxidation. Long-chain fatty acids are activated as the thioester of CoA on the cytoplasmic side of the mitochondrial membrane. The fatty acyl group is then transferred to form the corresponding carnitine ester in a reaction catalyzed by carnitine palmitoyltransferase I (CPT ]) The acylcarnitine then enters the mitochondrial matrix in exchange for carnitine via the carnitine-acylcarnitine translocase. The acyl group is transferred back to CoA in the matrix by carnitine palmitoyltransferase II (CPT II). The intramitochondrial acyl-CoA can then undergo P-oxidation.

Figure 9-2. Carnitine palmitoyltransferase reaction. Palmitoyl-CoA is shown as a proto-typic substrate. Carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) are shown illustrating the direction of the reaction catalyzed by each enzyme during physiological fatty acid oxidation.

Biochemical stress can be minimized by using frequent feedings to minimize dependence on fatty acid oxidation, particularly for the liver. Meals should have a high-carbohydrate, low-fat content. Medium-chain triglycerides (synthetic or derived from coconut or palm kernel oils) can be used as these lipids can be oxidized independent of carnitine. These steps are particularly important when any external metabolic stress, such as a viral illness, is present. 

Figure 32-5. P-oxidation and ketogenesis in the liver. The rate-limiting step in fatty acid oxidation and subsequent ketone body production is the activity of carnitine acyltrans-ferase I (CAT I).The activity of CAT I is inhibited by malonyl-CoA. Insulin deficiency results in inhibition of acetyl-CoA carboxylase, decreased levels of maloyl-CoA, and thus increased activity of CAT-I.Adapted from Foster and McGarry (1983).

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