Carnitine metabolic functions

In addition to the established vitamins, a number of organic compounds have clear metabolic functions they can be synthesized in the body, but it is possible that under some circumstances (as in premature infants and patients maintained on long-term total parenteral nutrition) endogenous synthesis may not be adequate to meet requirements. These compounds include biopterin (Section 10.4), carnitine (Section 14.1), choline (Section 14.2), creatine (Section 14.3), inositol (Section 14.4), molybdopterin (Section 10.5), taurine (Section 14.5), and ubiquinone (Section 14.6). 

Hagen, T. M., Liv, J., Lykkesfeldt, J., Wehr, C. M., ingersoll, R. T., Vinarsky, V., Bartholomew, J. C. and Ames, B. N. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proceedings of the National Academy of Sciences USA 99 1870-1875 2002. 

Carnitine acyltransferases are involved in the transfer of acyl groups from acyl-CoAs to L-camitine i.e. in the reversible conversion of acyl-CoA into acylcamitine. Th enzymes have a wide and overlapping chain-length specificity and a range of cellular loc zations and metabolic functions. The best characterized carnitine acyltransferases are the mitochondrial carnitine palmitoyltransferases (CPT EC 2.3.1.21) flie CPTI and CPTII. The latest progress and current view of the stmctural, functional, regulatory and... 

Carnitine acyltransferases in mitochondria, peroxisomes and the endc lasmic reticulum are different gene products and serve different metabolic functions in the cell. Here we summarize briefly evidence that carnitine octanoyltransferase (COT) from the peroxisomes and carnitine palmitoyltransferase II (CPT-II) from the mitochondria (both matrix facing enzymes) differ kinetically and demonstrate that they differ in their sensitivity to conformationally constrained inhibitors that mimic the reaction intermediate. Medium chain inhibitors are 15 times more effective on COT than on CPT-II and long chain inhibitors, such as hemipalmitoylcamitinium, 80 times more effective on the mitochondrial enzyme. Thus, it may be possible to develop inhibitors to inhibit mitochondrial P-oxidation with minimal effects on peroxisomtd P-oxidation and other acyl-CoA dependent reactions. 

Rebouche CJ, Paulson DJ. Carnitine metabolism and function in humans. Anna Rev... 

With respect to the values obtained from our investigations the plant mitochondrial carnitine acyltransferase should be named a CPT. However, other enzyme properties differ considerably from those of CPTs characterized from mammalian tissues. According to its biochemical properties the enzyme rather appears to be a CAT in spite of its good activity with palmitoyl-CoA. The different metabolic functions of the organells in mammalian and plant cells might be reflected in the properties of the carnitine acyltransferases. 

The physiological functions of carboxylesterases are still partly obscure but these enzymes are probably essential, since their genetic codes have been preserved throughout evolution [84] [96], There is some evidence that microsomal carboxylesterases play an important role in lipid metabolism in the endoplasmic reticulum. Indeed, they are able to hydrolyze acylcamitines, pal-mitoyl-CoA, and mono- and diacylglycerols [74a] [77] [97]. It has been speculated that these hydrolytic activities may facilitate the transfer of fatty acids across the endoplasmic reticulum and/or prevent the accumulation of mem-branolytic natural detergents such as carnitine esters and lysophospholipids. Plasma esterases are possibly also involved in fat absorption. In the rat, an increase in dietary fats was associated with a pronounced increase in the activity of ESI. In the mouse, the infusion of lipids into the duodenum decreased ESI levels in both lymph and serum, whereas an increase in ES2 levels was observed. In the lymph, the levels of ES2 paralleled triglyceride concentrations [92] [98],... 

Pharmacology Vitamin C, a water-soluble vitamin, is an essential vitamin in man however, its exact biological functions are not fully understood. It is essential for the formation and the maintenance of intercellular ground substance and collagen, for catecholamine biosynthesis, for synthesis of carnitine and steroids, for conversion of folic acid to folinic acid and for tyrosine metabolism. 

Carnitine deficiency leads to impaired carnitine shuttle activity the resulting decreased LCFA metabolism and accumulation of LCFAs In tissues and wasting of acyl-carnitine in urine can produce cardiomyopathy, skeletal muscle myopathy, encephalopathy, and impaired liver function. 

As it is similar to a fatty acid, it forms an acyl CoA and a carnitine derivative. This depletes CoA from the intramitochondrial pool and carnitine. Also, valproic acid is metabolized to an unsaturated fatty acid analogue, which is incorporated into p-oxidation in mitochondria. The reactive analogue depletes GSH and damages mitochondria. Function is compromised and ATP depleted. 

Carnitine is present in biological systems as both carnitine and acylcarnitines generated in tissues (see next section). Carnitine deficiency may be a primary defect due to a genetic defect in carnitine transport systems or may be secondary to other metabolic derangements. Normal carnitine homeostasis requires reabsorption of carnitine in the renal tubule via a specific transport protein. This same transport protein is responsible for the accumulation of carnitine in heart and skeletal muscle. If this transport system is not functional, then carnitine cannot reach tissues, and primary carnitine... 

The major functions of pantothenic acid are in CoA (Section 12.2.1) and as the prosthetic group for AGP in fatty acid synthesis (Section 12.2.3). In addition to its role in fatty acid oxidation, CoA is the major carrier of acyl groups for a wide variety of acyl transfer reactions. It is noteworthy that a wide variety of metabolic diseases in which there is defective metabolism of an acyl CoA derivative (e.g., the biotin-dependent carboxylase deficiencies Sections 11.2.2.1 and 11.2.3.1), CoA is spared by formation and excretion of acyl carnitine derivatives, possibly to such an extent that the capacity to synthesize carnitine is exceeded, resulting in functional carnitine deficiency (Section 14.1.2). 

Biochemical Functions. Ascorbic acid has various biochemical fimctions, involving, for example, coUagen synthesis, immune fimction, drug metabohsm, folate metabolism, cholesterol catabolism, iron metabolism, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting directly with nitrites, and consequently may potentially reduce cancer risk. 

Carnitine is required for transport of longoxidative metabolism as well as in the formation of ketone bcidies, The concentration of free carnitine in muscle is about 4,0 mmol/kg. The concentration of carnitine bound to long-chain fatty adds (fatty acyl-camitine) is lower, about 0,2 mmol/kg. Short-chain fatty adds, including acetic, are also esterified to carnitine, but the functions of these complexes are not clear. There is some indication that keto forms of BCAAs (BCKAs) can also be esterified to carnitine. These complexes can then be transported into the mitochondria for complete oxidation of the BCKAs, The importance of this mode of BCKA transport is not dear (Takakura et ai., 1997). 

SNPs were identified in the Japanese population for the organic cation transporter 1 (OCTI), and when functionally characterized in vitro, the uptake of cations was reduced significantly for some of these mutations, indicating that this would likely contribute to interindividual variations in metabolism of drugs that are transported via OCTI [13]. The sodium-dependent carnitine cotransporter OCTN2 can also possess mutations that result in primary carnitine deficiency, thus impacting fatty acid oxidation that is characterized by many clinical manifestations [14]. 

---