Carnitine cycle

The genetically determined defect of membrane carnitine transport is the only known condition that fulfills the criteria for primary carnitine deficiency [4, 9]. This condition, like the other conditions involving the carnitine cycle, is not associated with dicarboxylic aciduria. It is... 

Defects of mitochondrial transport interfere with the movement of molecules across the inner mitochondrial membrane, which is tightly regulated by specific translocation systems. The carnitine cycle is shown in Figure 42-2 and is responsible for the translocation of acyl-CoA thioesters from the cytosol into the mitochondrial matrix. The carnitine cycle involves four elements the plasma membrane carnitine transporter system, CPT I, the carnitine-acyl carnitine translocase system in the inner mitochondrial membrane and CPT II. Genetic defects have been described for each of these four steps, as discussed previously [4,8,9]. 

Ventura FV, Ijlst L, Ruiter J, Ofman R, Costa CG, Jakobs C, Duran M, Tavares de Almeida I, Bieber LL, Wanders RJ. Carnitine palmitoyltransferase II specificity towards beta-oxidation intermediates-evidence for a reverse carnitine cycle in mitochondria. Eur. J. Biochem. 1998 253 614-618. 

Longo, N., Amat di San FiUppo, C., and PasquaU, M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 142 (2006) 77-85. 

Figure 18.15 The carnitine cycle, for transport of fatty acyl-CoAs into... 

Fatty acids usually contain an even number of atoms and are catabolized in sequential cycles to acetyl-coenzyme A. This process is called P-oxidation and occurs inside the mitochondria. First, fatty acids need to enter the mitochondria, a process which occurs via the carnitine cycle. 

Roschinger W, Muntau AC, Duran M, Dorland L, IJlst L, Wanders RJ et al. Carni-tine-acylcarnitine translocase deficiency metabolic consequences of an impaired mitochondrial carnitine cycle. Clin Chim Acta 2000 298 55-68. 

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 ...

Ketogenesis is regulated at three cmcial steps (1) control of free fatty acid mobihzation from adipose tissue (2) the activity of carnitine palmitoyltransferase-1 in hver, which determines the proportion of the fatty acid flux that is oxidized rather than esteri-fied and (3) partition of acetyl-CoA between the pathway of ketogenesis and the citric acid cycle. 

Children with a primary deficiency of the carnitine transporter present with acute episodes of hypoglycaemia leading to loss of consciousness during even a short fast. (See Chapter 9 for a role of carnitine) in the Krebs cycle. 

The most important process in the degradation of fatty acids is p-oxidation—a metabolic pathway in the mitochondrial matrix (see p. 164). initially, the fatty acids in the cytoplasm are activated by binding to coenzyme A into acyl CoA [3]. Then, with the help of a transport system (the carnitine shuttle [4] see p. 164), the activated fatty acids enter the mitochondrial matrix, where they are broken down into acetyl CoA. The resulting acetyl residues can be oxidized to CO2 in the tricarboxylic acid cycle, producing reduced... 

CARNITINE O-ACETYLTRANSFERASE CARNITINE O-OCTANOYLTRANSFERASE CARNITINE O-PALMITOYLTRANSFERASE CARNOSINASE CARNOSINE SYNTHETASE CARNOT CYCLE... 

Acyl coenzyme As are introduced into mitochondria following coenzyme A esterification in the cytoplasm. Mitochondrial entry depends upon a double membrane transport involving carnitine acyltransferases II and I. Excess acetyl CoA is used for KB synthesis. KBs are transported in the blood and ultimately metabolized via the Krebs cycle. KBs are necessary to provide energy to the brain during fasting, a true alternative substrate to glucose. 

Under physiologic conditions, carnitine is primarily required to shuttle long-chain fatty acids across the inner mitochondrial membrane for FAO and products of peroxisomal /1-oxidation to the mitochondria for further metabolism in the citric acid cycle [40, 43]. Acylcarnitines are formed by conjugating acyl-CoA moieties to carnitine, which in the case of activated long-chain fatty acids is accomplished by CPT type I (CPT-I) [8, 44]. The acyl-group of the activated fatty acid (fatty acyl-CoA) is transferred by CPT-I from the sulfur atom of CoA to the hydroxyl group of carnitine (Fig. 3.2.1). Carnitine acylcarnitine translocase (CACT) then transfers the long-chain acylcarnitines across the inner mitochondrial membrane, where CPT-II reverses the action of CPT-I by the formation of acyl-CoA and release of free un-esterified carnitine. 

If fatty acid synthesis and J8 oxidation were to proceed simultaneously, the two processes would constitute a futile cycle, wasting energy. We noted earlier (see Fig. 17-12) that /3 oxidation is blocked by malonyl-CoA, which inhibits carnitine acyltransferase I. Thus during fatty acid synthesis, the production of the first intermediate, malonyl-CoA, shuts down J8 oxidation at the level of a transport system in the mitochondrial inner membrane. This control mechanism illustrates another advantage of segregating synthetic and degradative pathways in different cellular compartments. 

This elaborate chain of reactions provides a number of possible points for regulation of the supply of acyl-CoAs for oxidation. The major control point is carnitine acyltransfer-ase I, which is strongly inhibited by malonyl-CoA. Recall that malonyl-CoA is a major substrate for fatty acid biosynthesis. Thus, high levels of malonyl-CoA, which indicate fatty acid synthesis is in progress, prevent fatty acid catabolism, thus avoiding a futile cycle. 

Orally administered L-carnitine and propionyl-L-carnitine may have metabolic benefits by providing an additional source of carnitine to buffer the cellular acyl CoA pool. In this way, carnitine may enhance glucose oxidation under ischemic conditions and improve energy metabolism in the ischemic skeletal muscle. Propionyl-CoA generated from propionyl-L-carnitine may also improve oxidative metabolism through its anaphoretic actions in priming the Kreb s cycle, secondary to succinyl-CoA production. 

Induction of peroxisome proliferation following treatment with DEHP is not due to the parent compound, but to DEHP metabolites. Studies with MEHP in vitro have demonstrated that the proximate peroxisome proliferators are mono(2-ethyl-5-oxohexyl) phthalate (metabolite VI) and mono(2-ethyl-5-hydroxyhexyl) phthalate, (metabolite IX) and that for 2-ethylhexanol, the proximate proliferator is 2-ethylhexanoic acid (Elcombe and Mitchell 1986 Mitchell et al. 1985a). Similar findings were observed by Maloney and Waxman (1999), who showed that MEHP (but not DEHP) activated mouse and human PPARa and PPARy, while 2-ethylhexanoic acid activated mouse and human PPARa only, and at much higher concentrations. Based on its potency to induce enzyme activities, such as the peroxisomal fatty acid (3-oxidation cycle and carnitine acetyltransferase, DEHP might be considered a relatively weak proliferator. 

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. 

A specific transport protein, the carnitine-acylcarnitine translocase, moves the fatty acylcarnitine into the mitochondrial matrix while returning carnitine from the matrix to the cytoplasm. Once inside the mitochondria, another enzyme, carnitine palmitoyltransferase II (CPT II), located on the matrix side of the mitochondrial inner membrane, catalyzes the reconversion of fatty acylcarnitine to fatty acyl-CoA. Intramitochondrial fatty acyl-CoA then undergoes (3-oxidation to generate acetyl-CoA.Acetyl-CoA can enter the Kreb s cycle for complete oxidation or, in the liver, be used for the synthesis of acetoacetate and P-hydroxybutyrate (ketone bodies). 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

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