Methyl carnitine

Detoxifica.tlon. Detoxification systems in the human body often involve reactions that utilize sulfur-containing compounds. For example, reactions in which sulfate esters of potentially toxic compounds are formed, rendering these less toxic or nontoxic, are common as are acetylation reactions involving acetyl—SCoA (45). Another important compound is. Vadenosylmethionine [29908-03-0] (SAM), the active form of methionine. SAM acts as a methylating agent, eg, in detoxification reactions such as the methylation of pyridine derivatives, and in the formation of choline (qv), creatine [60-27-5] carnitine [461-06-3] and epinephrine [329-65-7] (50). 

A relatively large number of agents have been utilized to treat this intractable disorder folinic acid (5-formyl-tetrahydrofolic acid), folic acid, methyltetrahydrofolic acid, betaine, methionine, pyridoxine, cobalamin and carnitine. Betaine, which provides methyl groups to the beta i ne ho mocystei ne methyltransferase reaction, is a safe treatment that lowers blood homocysteine and increases methionine. 

In water-suppressed muscle spectra, contributions of lipids, methyl and methylene groups of creatine (Crs, Cr2), trimethylammonium-containing compounds (TMA), including signals from carnitine (Ct), choline (Cho), and taurine (Tau) are well observable as demonstrated in Fig. 15. Furthermore, small signals of histidine protons of carnosine (Cs) can be sometimes identified... 

Fig. 15. Comparison of a water suppressed muscle spectrum and a spectrum from yellow bone marrow containing almost pure fat (triglycerides). Measurement parameters STEAM sequence, TE=10 ms, TM=15 ms, TR = 2 s, 40 acq., VOI (11 X 11 X 20) mm. (a) Spectrum from TA muscle recorded after careful positioning of the VOI, avoiding inclusion of macroscopic fatty septa allows separation of extramyocellular (EMCL, broken lines) and intramyocellular lipid signals (IMCL, dotted lines) based on susceptibility differences. For this reason characteristic signals from fatty acids occur double. Signals of creatine (methyl, Crs, and methylene, Cr2) show triplet and doublet structure, respectively, due to dipolar coupling effects. Further signals of TMA (including carnitine and choline compartments), Taurine (Tau), esters, unsaturated fatty acids (-HC=CH-), and residual water are indicated, (b) Spectrum from yellow fatty bone marrow of the tibia with identical measuring parameters, but different amplitude scale.

Fig. 3.2.8a-c Profiles of acylcarnitines as their methyl esters in cell culture medium (precursor of m/z 99 scan) following the in vitro probe assay in fibroblast cultures of a normal control (a) and a patient with the milder (b) and the more severe variant (c) of VLCAD deficiency. Note the more prominent elevation of dodecanoyl- (Ci2 m/z 358 peak 1) and myristoylcarnitine (Ci4 m/z 386 peak 2) compared to a relatively normal accumulation of palmitoylcarnitine ( , m/z 416 peak 3) in the milder VLCAD variant compared to the severe variant, where palmitoylcarnitine is markedly elevated. The asterisks represent the internal standards (from left to right) d3-acetyl-carnitine (C2 m/z 221), d9-isovalerylcarnitine (C5 m/z 269), d3-octanoylcarnitine (C8 m/z 305), d3-dodecanoylcarnitine (Ci2 m/z 361), and d3-palmitoylcarnitine ( m/z 419)... 

The catabolism of lysine merges with that of tryptophan at the level of (3-ketoadipic acid. Both metabolic pathways are identical from this point on and lead to the formation of acetoacetyl-CoA (Figure 20.21). Lysine is thus ketogenic. It does not transaminate in the classic way. Lysine is a precursor of carnitine the initial reaction involves the methylation of e-amino groups of protein-bound lysine with SAM. The N-methylated lysine is then released proteolytically and the reaction sequence to carnitine completed. See Equation (19.6) for the structure of carnitine. 

Carnitine biosynthesis utilizes the essential amino acid lysine, with terminal methyl groups donated by S-adenosylmethionine. Only lysine incorporated into proteins is a substrate for the methylation reaction. In humans, the final reaction in the biosynthetic pathway, catalyzed by a cytosolic hydroxylase, occurs in liver and kidney but not in cardiac or skeletal muscle. The carnitine requirement of these tissues is met by carnitine transported to them via the plasma... 

Individuals with HMG-CoA lyase deficiency are particularly susceptible to carnitine deficiency. With restriction of red meats and dairy products, dietary carnitine intake is quite low. Carnitine is also synthesized endogenously from the modified, methylated lysine resides of various proteins free trimethyllysine is released when the protein is degraded. Since the therapy for patients with HMG-CoA lyase deficiency must minimize their endogenous protein catabolism, they also have limited availability of trimethyllysine for carnitine synthesis. 

As a result of the reduced activity of the mutase in vitamin B12 deficiency, there is an accumulation of methyhnalonyl CoA, some of which is hydrolyzed to yield methylmalonic acid, which is excreted in the urine. As discussed in Section 10.10.3, this can be exploited as a means of assessing vitamin B12 nutritional status. There may also be some general metabolic acidosis, which has been attributed to depletion of CoA because of the accumulation of methyl-malonyl CoA. However, vitamin B12 deficiency seems to result in increased synthesis of CoA to maintain normal pools of metabolically useable coenzyme. Unlike coenzyme A and acetyl CoA, neither methylmalonyl CoA nor propionyl CoA (which also accumulates in vitamin B12 deficiency) inhibits pantothenate kinase (Section 12.2.1). Thus, as CoA is sequestered in these metabolic intermediates, there is relief of feedback inhibition of its de novo synthesis. At the same time, CoA may be spared by the formation of short-chain fatty acyl carnitine derivatives (Section 14.1.1), which are excreted in increased amounts in vitamin B12 deficiency. In vitamin Bi2-deficient rats, the urinary excretion of acyl carnitine increases from 10 to 11 nmol per day to 120nmolper day (Brass etal., 1990). 

Carnitine is synthesized from lysine and methionine by the pathway shown in Figure 14.2 (Vaz and Wanders, 2002). The synthesis of carnitine involves the stepwise methylation of a protein-incorporated lysine residue at the expense of methionine to yield a trimethyllysine residue. Free trimethyllysine is then released by proteolysis. It is not clear whether there is a specific precursor protein for carnitine synthesis, because trimethyllysine occurs in a number of proteins, including actin, calmodulin, cytochrome c, histones, and myosin. 

The V-methyl resonances of carnitine (3) were monitored in the presence of Eu(dcm)3 (dcm = (f,(f-dicamphoyhnethanate) and the Eu(Itl), Pr(lll) and Yb(lll) chelates of tfc and hfc in methanol-(f4 at 500 MHz. Eu(dcm)3 was not soluble enough in methanol, but the tfc and hfc chelates achieved enantiomeric discrimination, enabling detection of 0.5% of the minor enantiomer. Signals were sharp even at high lanthanide-substrate ratios because of the fast substrate exchange in methanol . 

The methylation cycle proceeds as follows. Methionine can be converted to S-adenosylmethionine (SAM). SAM is a universal methyl donor and is required in most or alJ methylation events occurring in the body. For example, SAM is used in the synthesis of creatine and carnitine and in the methylation of nucleic acids and proteins. With the donation of the methyl group, SAM is converted to S-ade-nosylhomocystcine (SAH), as shown in Figure 9-4. SAH is finally broken down to homocysteine, completing the methylation cycle. The point of departure of the 1-carbon unit, derived from serine, from the methylation cycle is indicated by the section symbol (g). 

Carnitine acts catalytically and might be considered to be a cofactor of carnitine fatty acyltransferase. Unlike most cofactors, however, carnitine is not a vitamin and is not derived from a vitamin. Generally, all of the carnitine needed by the body can be S5mthesized by the body. The biosynthesis of carnitine begins in an unusual manner. The starting material, the lysine residues of a variety of proteins, undergo post-translational methylations, as shown in Figure 4.55. The methyl donor is S-adenosylmethionine. Trimethyllysine, liberated from the protein by intracellular hydrolysis, is hydroxylated and then converted to carnitine in three... 

CDs Chiral recognition is based on inclusion of the bulky hydrophobic group of the analyte into the hydrophobic cavity of the CD and on lateral interactions of the hydroxyl groups, such as hydrogen bonds and dipole-dipole interactions, with the analyte. Carboxymethylated P-CD, heptakis- 0-methyl- P-CD, hy dr oxy ethyl- P- CD, mono(6-P-aminoethylamino-6-deoxy)-P-CD, and mono(6-amino-6-deoxy)-P-CD. Acebutolol, acenocoumarol, carnitine, cathinone, ephedrine, epinephrine, glutethimide, ketotifen, thioridazine, etc. 

Carnitine is synthesized from two essential amino acids, lysine and methionine. S-Adenosylmethionine donates three methyl groups to a lysyl residue of a protein with the formation of a protein-bound trimethyllysyl. Proteolysis yields trimethyllysine, which is converted to carnitine (Figure 18-2). In humans, liver and kidney are major sites of carnitine production from there it is transported to skeletal and cardiac muscle, where it cannot be synthesized. 

The two most prominent one-carbon carriers are THF (the biologically active derivative of folic acid) and S-adenosymethionine (SAM). THF plays important roles in the synthesis of several amino acids and the nucleotides. SAM is a methyl donor in the synthesis of numerous biomolecules, for example, phosphatidylcholine, epinephrine, and carnitine. 

Other examples of (Sj-selective amidases are described for the production of (Sj-2-(4 -chlorophenyl)-3-methyl butyric acid[9 , (SJ-ibuprofen1101, (Sj-naproxen1111 and L-carnitine[12, 13]. 

The reducing property of ascorbic acid also assists another vitamin, folic acid (Figure 5.18). This is an essential co-factor in various one-carbon transfers for example the methyl group originating from the essential amino acid methionine is required in the formation of a wide variety of compounds including purines, the pyrimidine thymine, the amino acid serine, choline, carnitine, creatine, adrenalin, and many others. In its functional state, folic acid must be in its most reduced tetrahydrofolate form and this is brought about and/or maintained by ascorbic acid. 

See also Fatty Acids, Carnitine Acyltransferase I, Carnitine Acyltransferase II, Acyl-CoAs, Acyl-Carnitine, CoASH, S-Adenosylmethionine and Biological Methylation... 

In proteins, targets for methylation include lysine, arginine, and residues containing free carboxyl groups. Histones (chromatin proteins), for example, become methylated at specific arginine and lysine residues at particular times in the cell cycle (see here). s-N-Trimethyllysine, which is derived specifically from the hydrolysis of methylated proteins, is a precursor of carnitine, which transports fatty acyl moieties across membranes (see here). 

Carnitine is obtained from the diet or synthesized from the side chain of lysine by a pathway that begins in skeletal muscle, and is completed in the liver. The reactions use S-adenosylmethionine to donate methyl groups, and vitamin C (ascorbic acid) is also required for these reactions. Skeletal muscles have a... 

Because malonyl CoA is a substrate for fatty acid synthase, competition from methyl-malonyl CoA could cause a decrease in the rate of palmitoyl CoA synthesis in the cytosol, which could in turn lead to an increase in the concentration of acetyl CoA because palmitoyl CoA inhibits acetyl CoA carboxylase. In addition, high levels of methylmalonyl CoA could interfere with transport of long-chain fatty acyl chains into mitochondria by inhibiting carnitine acyltransferase, as does malonyl CoA. Thus, both the synthesis and the oxidation of fatty acids could be inhibited by methylmalonyl CoA. 

In capillary electrophoresis (CE), CDs and their ionic and neutral derivatives have been successfully used as additives in the carrier system for the separation of structural isomers and structurally related compounds [53]. The commonly used neutral CDs are the native a-, /3- and y-CDs and the dimethyl, trimethyl, hydroxyethyl and hydroxypropyl forms [54]. The charged CDs are carboxymethyl, sulfobutyl ether, sulfated and amino CDs. The methyl derivatives of the CD are effective in separating chiral compounds, enantiomers of terbutaline, ephedrine and carnitine. The neutral derivatives of hydroxyalkylated /3-CD and the mixture... 

Kiorpes, T.G., Hoerr, D., Ho, W. Weaner, L.F., Inman, M.G. Tutwiler, G.F. (1984) Identification of 2-tetradeoylglycidyl coenzyme A as the active form of methyl 2-tetradecyglycidate (methyl paloxirate) and its characterization as an irreversible, active site-directed inhibitor of carnitine palmitoyltransferase... 

Tutwiler, G.F., Brentzel, H.J. Kiorpes, T.C. (1985) Proc. Soc. Exp. Biol. Med. 178, 288-296. Inhibition of mitochondrial carnitine palmitoyltransferase A in vivo with methyl 2-tetradecylglycidate (methyl palmoxirate) and its relationship to ketonemia and glycemia. 

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