Transsulfuration in an adult with hepatic methionine adenosyltransferase deficiency.

Abstract

We investigated sulfur and methyl group metabolism in a 31-yr-old man with partial hepatic methionine adenosyltransferase (MAT) deficiency. The patient's cultured fibroblasts and erythrocytes had normal MAT activity. Hepatic S-adenosylmethionine (SAM) was slightly decreased. This clinically normal individual lives with a 20-30-fold elevation of plasma methionine (0.72 mM). He excretes in his urine methionine and L-methionine-d-sulfoxide (2.7 mmol/d), a mixed disulfide of methanethiol and a thiol bound to an unidentified group X, which we abbreviate CH3S-SX (2.1 mmol/d), and smaller quantities of 4-methylthio-2-oxobutyrate and 3-methylthiopropionate. His breath contains 17-fold normal concentrations of dimethylsulfide. He converts only 6-7 mmol/d of methionine sulfur to inorganic sulfate. This abnormally low rate is due not to a decreased flux through the primarily defective enzyme, MAT, since SAM is produced at an essentially normal rate of 18 mmol/d, but rather to a rate of homocysteine methylation which is abnormally high in the face of the very elevated methionine concentrations demonstrated in this patient. These findings support the view that SAM (which is marginally low in this patient) is an important regulator that helps to determine the partitioning of homocysteine between degradation via cystathionine and conservation by reformation of methionine. In addition, these studies demonstrate that the methionine transamination pathway operates in the presence of an elevated body load of that amino acid in human beings, but is not sufficient to maintain methionine levels in a normal range.

Intravenous Cysteamine Therapy for Nephropathic Cystinosis

“…or oral cysteamine is an offensive breath odor, here attributable to dimethylsulfide. A similar finding has been reported in a 31-y-old man with methionine adenosyltransferase deficiency (38).…”

In Vivo Metabolism of l-Methionine in Mice: Evidence for Stereoselective Formation of Methionine-d-Sulfoxide and Quantitation of Other Major Metabolites

“…MetO was also detected in the blood, plasma, and urine of children with homocysteinuria (Perry et al, 1967), but the stereochemistry of the detected MetO was not investigated. Interestingly, Gahl et al (1988) detected exclusively Met-d-O in the urine of a human with MAT1A deficiency that caused a 20-to 30-fold elevation of plasma Met (0.72 mM). Hernandez et al (2004) recently identified a novel FMO gene cluster in mice and humans.…”

“…3-MTP formation has been detected in rat and monkey tissue homogenates incubated with Met (Steele and Benevenga, 1978;Scislowski and Pickard, 1993). 3-MTP has also been detected in the urine of humans with cystathionine ␤-synthase deficiency or partial hepatic MAT1A deficiency (Gahl et al, 1988;Tangerman et al, 2000). Further metabolism of 3-MTP to yield methanethiol has been demonstrated in rats (Finkelstein and Benevenga, 1986;Scislowski and Pickard, 1993).…”

“…Such a range is significantly higher than normal free Met plasma concentrations in healthy humans (40 -60 M). However, homocystinuric children, patients with alcoholic liver disease, and humans with defects in the Met transmethylation and trans-sulfuration pathway may exhibit plasma Met levels from 0.1 to 1.9 mM (Gahl et al, 1988;Blom et al, 1989;Tangerman et al, 2000;Finkelstein, 2003;Mashima et al, 2003). Liver Met levels were not measured directly in these cases, but such high plasma Met concentrations may indicate high liver Met levels as well.…”

Hypermethioninaemia due to methionine adenosyltransferase I/III (MAT I/III) deficiency: Diagnosis in an expanded neonatal screening programme

“…However, there is concern that such limitation may be counterproductive if it further reduces synthesis of AdoMet in those with some residual MAT I/III activity. At methionine levels above 300 mmol/L, metabolites produced by transamination may give rise to the offensive body odour seen in some patients, although there is no clear evidence that this is otherwise harmful (Andria et al 2005;Gahl et al 1988;Mudd et al 1995). We therefore consider that strict limitation of dietary methionine intake is unnecessary and indeed inadvisable.…”