L-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). 

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. 

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 b Unpublished data from our laboratory. 

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... 

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... 

Calabrese Y, Calvani M, Butterfield DA. 2006d. Acetyl-L-camitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity Implications for Alzheimer s disease. 

Two EPMEs based on macrocyclic glycopeptide antibiotics—vancomycin and teicoplanin—were designed for the assay of acetyl-L-carnitine [44]. The linear concentration ranges for the proposed electrodes were 10 5-10-2 mol/L for the vancomycin-based electrode and 10 4-10-2 mol/L for the teicoplanin-based electrode, with slopes of 58.1 and 55.0mV/p(acetyl-L-camitine), respectively. The enantioselectivity was determined over D-carnitine. 

H. P. Meyer, Continuous cell-recyde process for L-camitine production performance, engineering and downstream processing aspects compared with discontinuous processes, J. Biotechnol. 

L. Boehlen, and I. Psenicka, Process integration aspeds for the production of fine chemicals illustrated with the biotransformation of y-butyrobetaine into L-camitine, Chem. Eng.J. 1996, 63, 53-61. 

Gross, C.J., L.M. Henderson, and D.A. Savaiano. 1986. Uptake of L-camitine, D-carnitine and acetyl-L-carnitine by isolated guinea-pig enterocytes. Biochim Biophys Acta 886 425. 

After 180 days of treatment there was a significant improvement of 73 9% (mean SE) in maximal walking distance in PAD patients treated with propionyl-L-carnitine compared to placebo (80). Propionyl-L-camitine has been shown to improve treadmill performance and quality of life in patients with claudication. After six months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 222 seconds (a 54% increase) as compared with an improvement of 75 191 seconds (a 25% increase) for those on placebo (p < 0.001) (81). 

Brevetti G, Pema S, Sabba C, et al. Propionyl-L-camitine in intermittent claudication double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995 26(6) 141 I 1416. 

Ethyl 4-chloro-3-hydroxybutyrate (EHCB) is an important intermediate in the production of l-camitine and the cholesterol-lowering Pfizer drug Lipitor (see Chapter 31). The ruthenium catalyst, [Ru(p-cymene)I((S)-TMBTP)]+E, has been reported to reduce ethyl 3-chlorobutyrate in 97% ee with S/C ratios of 20,000 (Scheme 12.48).87,157 This chemistry has been reported at scales >100 kg.87... 

Carnitine deficiency complicates HMG-CoA lyase deficiency and other inborn errors of metabolism, which results in organic acidemia. L-Camitine or P-hydroxy-y-trimethylammonium butyrate is a carrier molecule that transports long-chain fatty acids across the inner mitochondrial membrane for subsequent P-oxi-dation. L-Carnitine also facilitates removal of toxic metabolic intermediates or xenobiotics via urinary excretion of their acyl carnitine derivatives. Indeed, individuals with HMG-CoA lyase deficiency have been shown to excrete 3-methylgluatarylcamitine (Roe et al., 1986). In the absence of ketogenesis, the formation of the acyl carnitine derivative of 3-hydroxy-3-methylglutarate from HMG-CoA also serves to regenerate free CoA in the mitochondria and permits continued P-oxidation of fatty acids. 

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