Betaine-homocysteine

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

BETAINE-ALDEHYDE DEHYDROGENASE BETAINE-HOMOCYSTEINE S-METHYL-TRANSFERASE... 

Metabolism of homocysteine. Abbreviations BHMI betaine homocysteine methyltransferase ... 

An alternative reaction for the remethylation of homocysteine to methionine can be accomplished by betaine homocysteine methyltrans-ferase, which uses betaine instead of 5-MTHF as the methyl donor. Unlike the MS reaction, which is believed to be ubiquitously present in all tissues, the betaine homocysteine methyl-transferase reaction occurs only in the liver and kidney. Betaine is not a required nutrient since the liver can synthesize betaine from choline. Betaine supplements, however, have been shown to lower plasma total homocysteine concentrations successfully in subjects with deficient homocysteine remethylation due to defects in MTHFR or MTRR and in those with deficient CBS activity. 

This functional deficiency of folate is exacerbated by the associated low concentrations of methionine and S-adenosyl methioitine, although most tissues (apart from the central nervous system) also have betaine-homocysteine methyltransferase that may be adequate to maintain tissue pools of methionine. Under normal conditions S-adenosyl methioitine inhibits methylene-tetrahydrofolate reductase and prevents the formation of further methyl-tetrahydrofolate. Relief of this inhibition results in increased reduction of one-carbon substituted tetrahydrofolates to methyl-tetrahydrofolate. 

Although, as shown in Table 10.1, there are plausible mechanisms to suggest that homocysteine is a causative factor in cardiovascular disease, it is possible that hyperhomocysteinemia is a result of the renal damage that is an early event in cardiovascular disease, thus a proxy marker of disease rather than a causative factor (Jacobsen, 1998 hangman and Cole, 1999 Kircher and Sinzinger, 2000). in chronic renal failure, hyperhomocysteinemia is associated with cardiovascular disease, probably because of both impaired excretion of homocysteine and impaired activity of betaine homocysteine methyl-transferase elevated plasma dimethylglycine predicts plasma homocysteine (McGregor et al., 2001). 

Garrow, T. A. (1996). Purification, kinetic properties, and cDNA cloning of mammalian betaine-homocysteine mefhyitransfease. /. Biol. Chm. 271,22531-22838. 

FIGURE 9.13 Complete oxidation of choline to carbon dioxide. The oxidation of choline to CO2 requires the participation of enzymes of the mitochondria and cytoplasm. This means that some of the intermediates are expected to leave and reenter the mitochondria in the course of the pathway. The pathway involves the participation of three folate-requiring enzymes. Betaine-homocysteine methyitransferase is not a folate-requiring enzyme. 

Figure 8 Extended folate metabolism, including compartmentation. MTHFR, methylenetetrahydrofolate reductase SHMT, serine hydroxymethyltransferase BHMT, betaine homocysteine methyltransferase, MAT, methionine adenosyltransferase SAH-hydrolase, S-adenosylhomocysteine hydrolase MT, methyltransferase CBS, cystathionine /i-synthase SAM, S-adenosylmethionine SAH, S-aden-osylhomocysteine THF, tetrahydrofolate and 5-MeTHF, 5-methyltetrahydrofolate. (Reproduced from Van der Put etal. (2001) Folate, homocysteine and neural tube defects An overview. Experimental Biology and Medicine 226 243-270.)...

Homocysteine can be recycled back to methionine either by transfer of a methyl group from betaine catalyzed by betaine-homocysteine methyltransferase, or from N -methyltetrahydrofolate(N -methyl-FH4)catalyzedbyN -methyl-FH4-methyltransferase, which requires methyl cobalamin ... 

Fig. 20.3 Pathway of methionine metabolism. The numbers represent the following enzymes or sequences (1) methionine adenosyltransferase (2) S-adenosylmethionine-dependent transmethylation reactions (3) glycine methyltransferase (4) S-adenosylhomocysteine hydrolase (5) betaine-homocysteine methyltransferase (6) 5-methyltetrahydrofolate homocysteine methyltransferase (7) serine hydroxymethyltransferase (8) 5,10-methylenetetrahydrofolate reductase (9) S-adenosylmethionine decarboxylase (10) spermidine and spermine synthases (11) methylthio-adenosine phosphorylase (12) conversion of methylthioribose to methionine (13) cystathionine P-synthase (14) cystathionine y-lyase (15) cysteine dioxygenase (16) cysteine suplhinate decarboxylase (17) hypotaurine NAD oxidoreductase (18) cysteine sulphintite a-oxoglutarate aminotransferase (19) sulfine oxidase. MeCbl = methylcobalamin PLP = pyridoxal phosphate...

The demonstration by Phillips and Laiigdon (1956) that the level of TPNH-cytochromc c reductase is increased in the livers of hyperthyroid rats and reduced in those of hypothyroid animals is of particular interest. Since the activity of this enzyme results in the production of triphospho-pyridiiie nucleotide (TPN), a cofactor required for many oxidative enzymes, this change is probably a direct reflection of the general over-all acceleration of oxidative processes, and, more specifically, of those which are TPN-linked. Decreased activity of lactic dehydrogenase (Vcstling and Knocpfelmacher, 1950) is compatible with the demonstrated ability of thyroxine to inhibit this enzyme in vitro (Wolff and Wolff, 1957 Radsma et al., 1957). Decreases in the in vivo activity of such enzymes as tyrosine oxidase, DOPA-decarboxylase, betaine-homocysteine transmethylase, and... 

The remethylation cycle allows the conversion of homocysteine back to methionine by two pathways. The first and major pathway is catalyzed by the enzyme, methionine synthase, and links the folate cycle with homocysteine metabolism. Methionine synthase requires the cofactor, meth-ylcobalamin. The second pathway utilizes the enzyme, betaine-homocysteine methyltransfer-ase [8]. This pathway remethylates homocysteine using a methyl group derived from betaine, formed via oxidation of choline, and is presumably responsible for up to 50 % of homocysteine remethylation [10]. Both methionine and homocysteine play important roles in protein synthesis, folding, and function. 

Transmethylation Methionine adenosyl transferase Betaine-homocysteine methyltransferase iV -methyltetrahydrofolate-homocysteine 5-methyltransferase... 

Figure 29.6 Pathways for the metabolism of homocysteine. Normal transsulfuration requires cystathionine P-synthase with vitamin Bg as cofactor. Reme-thylation requires 5,10-methylenetetrahydrofolate reductase and methionine synthase. The latter requires folate as cosubstrate and vitamin Bi2 (cobalamin) as cofactor. An alternative remethylation pathway also exists using the cobalamin independent betaine-homocysteine methyltransferase (Robinson 2000).

Figure 44.1 Folate-mediated one carbon metabolism network. Enzymes and transport proteins are enclosed in rectangular boxes. AHCY S-adenosyDiomocys-teine hydrolase AICART 5-aminoimidazole carboxamide ribonucleotide transferase BHMT betaine homocysteine methyltransferase CBS cystathionine beta-synthase DHFR dihydrofolate reductase FR folate receptor FTCD formimidoyltransferase cyclodeaminase GART glycinamide ribonucleotide transformylase MATs (MATI/MATIII) adenosylmethionine transferase enzyme I/III MS methionine synthase MSR methionine synthase reductase MT methyltransferase MTHFD methylenetetrahydrofolate dehydrogenase MTHFR 5,10-methylenete-trahydrofolate reductase MTHFS 5,10-methylenetetrahydrofolate synthase. RFC reduced folate AdoMet 5-adenosylmethionine AdoHcy S-adenosylhomocysteine Hey homocysteine SHMT serine hydroxymethyltransferase TS thymidylate synthase.

Homocysteine metabolism involves three key enzymes methionine synthase, betaine homocysteine methyl transferase (BHMT) and cystathione p-synthase. Both vitamin B12 and folate are required in the methylation of homocysteine to methionine via metheonine synthase after donation of a methyl group from SAM during the methylation process. Homocysteine is also methylated by betaine in a reaction catalysed by BHMT and does not involve vitamin B12 and folate. The other metabolic fate for homocysteine is the transsulfuration pathway which degrades homocysteine to cysteine and taurine, and is catalysed by cystathione p-synthase with vitamin Bg as coenzyme. 

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