Camitine

A number of different low molecular weight compounds are known to stablize proteins in their native conformation and, therefore, may be effective in correcting of protein folding abnormalities in vivo. Relevant compounds are iV-acetyl-L-lysine, L-camitine, taurine, betaine, ectoine, and hydroxy-ectoine [4]. Some of these chemical chaperones and pharmacological chaperones are already used in clinical trials to combat protein folding diseases, such as cystic fibrosis. 

Long-chain acyl-CoA esters are then converted to acylcamitine esters by readily reversible reactions with L-camitine catalyzed by carnitine palmitoyltransferase I (CPT I). 

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. 

The transport is accomplished with the participation of carnitine, which takes up the acyl from acyl-CoA on the outer membrane side. Acylcamitine assisted by carnitine translocase diffuses to the inner side of the membrane to give its acyl to the CoA located in the matrix. The process of reversible acyl transfer between CoA and carnitine on the outer and inner sides of the membrane is effected by the enzyme acyl-CoA-camitine transferase. 

Production of Malonyl-CoA for the Fatty Acid Biosynthesis. Acetyl-CoA serves as a substrate in the production of malonyl-CoA. There are several routes by which acetyl-CoA is supplied to die cytoplasm. One route is the transfer of acetyl residues from the mitochondrial matrix across the mitochondrial membrane into the cyto-plasm. This process resembles a fatty acid transport and is likewise effected with the participation of carnitine and the enzyme acetyl-CoA-camitine transferase. Another route is the production of acetyl-CoA from citrate. Citrate is delivered from the mitochondria and undergoes cleavage in the cytoplasm by the action of the enzyme ATP-citrate lyase ... 

D-Camitine 14 L-Carnitine Thyroid inhibitor Multi-enzymatic pathway Agrobacterium sp. Single-stage fermentation of four processes [7]... 

Tolu P, Masi F, Leggio B, Scheggi S, Tagliamonte A, De Montis MG and Gambarana C (2002). Effects of long-term acetyl-L-camitine administration in rats (I) Increased dopamine output in mesocorticolimbic areas and protection toward acute stress exposure. Neuropsychopharmacology, 27, 410 420. 

Organic cation/camitine OCTN1 TEA, pyrilamine, quinidine and verapamil... 

Tamai, I., et al. Molecular and functional characterization of organic cation/camitine transporter family in mice. J. Biol. Chem. 2000, 275, 40064-40072. 

Wang Y, Ye J, Ganapathy V, Longo N. Mutations in the organic cation/camitine transporter OCTN2 in primary carnitine deficiency. Proc Natl Acad Sci USA 1999 96(5) 2356-2360. 

Note Data represent the mean S.E. (n = 3). CLapp, apparent membrane permeability clearance. Absorption was evaluated in our laboratory using the closed loop of die rat colon in situ (urethane anesthesia, 1.125 g/4.5 ml/kg, i.p.) in 60 min for L-camitine and 30 min for die others. 

Note Data represent the mean S.E. (n = 3). MW, molecular weight P0/w, octanol-to-water partition coefficient CLapp, apparent membrane permeability clearance SI, midgut area of the small intestine NA, not available or applicable. Absorption was evaluated in our laboratory using the closed loop of the rat intestine in situ (urethane anesthesia, 1.125 g/4.5 ml/kg, i.p.) in 60 min for riboflavin and L-camitine and 30 min for the others. For those that are transported by carriers in part (riboflavin and glycerol in both colon and SI, and L-carnitine, 5-fluorouracil, and cephradine in SI), absorption was evaluated at higher concentrations where the contribution of carrier-mediated transport is negligible. Values of P0/w were obtained from a report by Leo et al. [30] except for that of D-xylose, which was determined in our laboratory. a Data by single-pass perfusion experiments. b Unpublished data from our laboratory. 

Y. Kato, M. Sugiura, T. Sugiura, T. Wakayama, Y. Kubo, D. Kobayashi, Y. Sai, I. Tamai, S. Iseki, and A. Tsuji. Organic cation/camitine transporter octn2 (slc22a5) is responsible for carnitine transport across apical membranes of small intestinal epithelial cells in mouse. Mol Pharmacol 70 829-837 (2006). 

R.COOH -b CoASH -e ATP R.CO.SCoA -b AMP-b PPj fatty acyl-CoA -b carnitine —> fatty acyl-camitine-b CoASH... 

It is the fatty acyl-camitine that is transported across the inner mitochondrial membrane from the cytosol to the matrix so that two different enzymes are reqnired for the transport. The first enzyme, carnitine palmitoyltransferase-1, is located on the outer surface of this membrane and the second enzyme, carnitine pahnitoyltransferase-II, is located on the inner side of this membrane (Figure 7.11). Carnitine may have this role since it is smaller than CoASH and has no net charge. 

The three major fnels for oxidation within the mitochondria are pymvate, fatty acids in the form of fatty acyl-camitine, and glntamine - all of which require specific transport processes (Fignre 9.14). The hydrogen atoms in the NADH in the cytosol comprise a fonrth fnel that mnst also be transported into the mitochondria for oxidation. 

Tonazzi, A., Giangregorio, N., Indiveri, C. and Palmieri, F. 2005. Identification by site-directed mutagenesis and chemical modification of three vicinal cysteine residues in rat mitochondrial camitine/acylcarnitine transporter. Journal of Biological Chemistry, 280 19607-19612. 

Effect of treatment with glycine and L-camitine in medium-chain acyl-coenzyme A dehydrogenase deficiency. 

Prolonged moderate-intensity exercise without and with L-camitine supplementation in patients with MCAD deficiency. 

Vitamins made by biocatalysis include cyanocobalamin (Rh6ne-Poulenc and Merck Co), vitamin A (Hoffinann-La Roche Orsat 1999), ascorbic acid firom sorbitol via, directly, ketogulonic acid (BASF), riboflavin (Hoffinann-La-Roche, BASF, and Rhone-Poulenc/Archer-Daniels), and niacinamide fi om synthetic materials (Lonza). The list includes a vitamin-like nutrient, L-camitine... 

In the third and final step of the carnitine shuttle, the fatty acyl group is enzymatically transferred from carnitine to intramitochondrial coenzyme A by carnitine acyltransferase II. This isozyme, located on the inner face of the inner mitochondrial membrane, regenerates fatty acyl-CoA and releases it, along with free carnitine, into the matrix (Fig. 17-6). Carnitine reenters the intermembrane space via the acyl-camitine/car-nitine transporter. 

A major factor controlling the oxidation of fatty acids is the rate of entry into the mitochondria. While some long-chain fatty acids (perhaps 30% of the total) enter mitochondria as such and are converted to CoA derivatives in the matrix, the majority are "activated" to acyl-CoA derivatives on the inner surface of the outer membranes of the mitochondria. Penetration of these acyl-CoA derivatives through the mitochondrial inner membrane is facilitated by L-camitine 41 44... 

As many as 1 in 10,000 persons may inherit such prob-lems.48 50a Tire proteins that may be defective include a plasma membrane carnitine transporter carnitine palmitoyltransferases camitine/acylcamitine trans-locase long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases 2,4-dienoyl-CoA reductase (Eq. 17-1) and long-chain 3-hydroxyacyl-CoA dehydrogenase. Some of these are indicated in Fig. 17-2. 

---