Abstract

MAT converts ATP and raethionine (met) to S-adenosylmethionine (SAM), a methyl donor and intermediate in transsulfuration to homocysteine (HS). HS is catabolized to inorganic sulfate for excretion, or is remethylated using betaine or N5-methyltetra-hydrofolate (formed by methylenetetrahydrofolate reductase, MTHFR). he studied sulfur and methyl balances in a man with severe but incomplete hepatic MAT def. This clinically normal individual lives with 20-30X normal plasma met (0.72 mM) and excretes 2.7 mmol/ day of met and L-met-d-sulfoxide. His hepatic SAM is low, 18 nmol/gm wet wt. Steady state balances revealed that he converts only 65% of ingested sulfur to inorganic sulfate (nl, 80.1±5.3%). Even with a large met load, he converted only 6-7 mmol/day of met to inorganic sulfate, yet he produced at least 18 mmol/day of SAM and HS. Of the 18 mmol, 9.5 was remethylated, and 6.6 mmol of the methyl groups were contributed by N5-methyltetrahydrofolate. This methylneogenesis appeared very high considering his enormous met load. These findings support the view that SAM regulates the distribution of HS between remethylation and transsulfuration. In the patient, a low steady state SAM may fall to inhibit MTHFR or activate cystathionine synthase; the consequence would be enhanced HS methylation, as observed. Measurement of α-keto-γ-methylthiobutyrate production in this patient also placed an upper limit on the capacity of met transamination to catabolize met in the presence of an elevated body load of met.

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