Methylgenesis from betaine in cystathionine -beta-synthase deficiency

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homocysteine, producing dimethylglycine. (DMG) and methionine. Homocysteine may also condense with serine to form cystathionine, a reaction catalysed by ...
Biochemical SocietyTransactions ( 1 993) 21

Methylgenesis from betaine in cystathionine -R-synthase deficiency. ?URNS S . P . , ILES R.A., LEONARD J.V.

'RYALLS

M.,

and

Medical Unit, Cellular Mechanisms Research Group, The London HospiFal Medical College, London, El lBB, and Institute of Child Health, London, WClN 1EH.

In man homocysteine may be converted to methionine by two enzymes, 5-methyltetrahydrofolate homocysteine methyl transferase (FHMT) and betaine homocysteine methyl transferase (Fig.1). In the latter reaction betaine donates a methyl group to homocysteine, producing dimethylglycine (DMG) and methionine. Homocysteine may also condense with serine to form cystathionine, a reaction catalysed by cystathionine-Rsynthase (CbS). Inborn errors of both FHMT and CbS are characterised by accumulation of homocysteine and homocystinuria. Betaine therapy has been used to treat both types of homocystinuria to provide additional methyl groups and reduce homocysteine accumulation [l]. However, little is known of the fate of betaine. We have analyzed plasma and urine from patients with CbS deficiency receiving long term betaine therapy, using 'H NMR spectroscopy to estimate the contribution of betaine to methylgenesis. Six patients aged 5.5 to 20 years were studied. All had the characteristic clinical phenotype and were on a low protein diet. Urine samples (24h) were collected, volumes recorded and stored at -20°C until NMR analysis. Plasma samples were collected on the same day as the urine, and stored similarly. Quantitative 'H NMR spectra of 0.5ml samples of urine and plasma were recorded at 400 or 500 MHz. All of the spectra of the urine and plasma samples from the patients whilst on betaine therapy showed signals from betaine and DMG (absent from age matched controls). About 15% of the betaine dose was recovered as betaine t DMG in the urine, the majority of which was DMG. Prominent signals from methionine were detected in the plasma, but not in the urine, of some patients during betaine therapy, presumably reflecting remethylation of homocysteine to methionine, The degree to which the exogenous betaine is contributing to methylgenesis can be estimated from the rate of DMG excretion and we have calculated this rate to be 2.5-7 mmol/day. This is a minimum estimate, as the amount of betaine undergoing further metabolism via glycine (Fig. 1) is not included, although our previous work suggests that this may be significant [21. Abbreviations FHMT: 5 methyl-tetrahydrofolate homocysteine methyltransferase. DMG: N,N-dimethylglycine. CbS: Cystathionine-R-synthase.

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The daily net methyl group requirement is accounted for primarily by creatine synthesis [3], reflected in body creatine incorporation and the sum of. creatine t creatinine excretion [4]. We have estimated this rate in these subjects to be of a similar magnitude to the rates of methylgenesis from betaine recorded above. Thus exogenous betaine could apparently provide most if not all of the daily methyl group requirement in these patients.

Fig.1. Cystathionine Methyl THF

THF

t

Homocysteine

Methionine

4

Sarcosine

c

Glycine

We would like to thank Action Research for financial support at LHMC. References 1.

2. 3. 4.

Smolin, L . A . , Benevenga, N.J., Berlow, S. (1981) J. Pediatr. 99, 467-472. Burns, S.P., Johnson, A. and Iles, RA. (1991). Biochem. SOC. Trans., 19, 402s. Krebs, H.A., Hems, R. and Tyler, B. (1976) Biochem. J. 158, 341-353. Davies, S.E.C. et al. (1992). J. Nutr. Biochemistry 3, 523-530.