The Relationship between Human MAT1A Mutations and Disease: A Folding and Association Problem? pp. 261-288
Authors: (María A. Pajares, Claudia Pérez, Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain, and others)
Abstract: Methionine adenosyltransferases (MATs) are a family of highly conserved oligomers that catalyze the only known reaction for the synthesis of S-adenosylmethionine (AdoMet), the main cellular methyl donor. Their catalytic subunits exhibit a characteristic structure, organized in three domains formed by nonconsecutive stretches of the sequence. The active sites locate at the interface between subunits in the dimer with amino acids of each monomer contributing to catalysis. Changes in activity, oligomerization level and expression have been detected in several hepatic diseases; the knockout mouse for MAT1A spontaneously developing hepatocellular carcinoma (HCC). However, none of the patients with persistent hypermethioninemia caused by mutations in this gene exhibits hepatic problems, instead a few cases showing demyelination have been described. This chapter discusses aspects related to the structural features of these enzymes and the impact that the mutations found in the human MAT1A gene may have in the final protein structure. The influence of the redox environment in MAT folding and association is also analyzed, in light of the effects that drugs and metals that alter the GSH/GSSG ratio produce in the activity and association level. The recent report of the nuclear localization of the MAT I/III isoenzymes, along with their presence in tissues other than liver opened the option to MAT moonlighting. The possibility exists that disease development is related not only to a decrease in AdoMet production, but also to the role of these particular isoenzymes in different subcellular compartments. Therefore, the influence of MAT1A mutations, especially those leading to protein truncations, on folding and subcellular localization is discussed, paying special attention to the Hazelwood’s hetero-oligomerization hypothesis to explain the demyelination process in patients with persistent hypermethioninemia.
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