Biochemical basis for the dominant inheritance of hypermethioninemia associated with the R264H mutation of the MAT1A gene - A monomeric methionine adenosyltransferase with tripolyphosphatase activity

Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylm ethionine (AdoMet), the main alkylating agent in living cells. Additionally , in the liver, MAT is also responsible for up to 50% of methionine catabol ism. Humans with mutations in the gene MAT1A, the gene that encodes the cat alytic subunit of MAT I and III, have decreased MAT activity in liver, whic h results in a persistent hypermethioninemia without homocystinuria. The hy permethioninemic phenotype associated with these mutations is inherited as an autosomal recessive trait. The only exception is the dominant mild hyper methioninemia associated with a G-A transition at nucleotide 791 of exon VI I, This change yields a MAT1A-encoded subunit in which arginine 264 is repl aced by histidine, Our results indicate that in the homologous rat enzyme, replacement of the equivalent arginine 265 by histidine (R265H) results in a monomeric MAT with only 0.37% of the AdoMet synthetic activity. However t he tripolyphosphatase activity is similar to that found in the wild type (W T) MAT and is inhibited by PP,, Our in vivo studies demonstrate that the R2 65H MAT I/III mutant associates with the WT subunit resulting in a dimeric R265H-WT MAT unable to synthesize AdoMet. Tripolyphosphatase activity is ma intained in the hybrid MAT, but is not stimulated by methionine and ATP, in dicating a deficient binding of the substrates. Our data indicate that the active site for tripolyphosphatase activity is functionally active in the m onomeric R265H MAT I/III mutant. Moreover, our results provide a molecular mechanism that might explain the dominant inheritance of the hypermethionin emia associated with the R264H mutation of human MAT I/III.