CryoEM structures reveal allosteric regulation of the catalytic activity of the multi-protein human MAT enzyme complexes

S-Adenosyl me­thio­nine (SAMe), the biological methyl donor essential for sustaining the life of most complex organisms, is the second most widely used cofactor, after ATP, in biochemical reactions and is synthesized by the enzyme me­thio­nine adenosyl transferase (MAT) from ATP and me­thio­nine. MAT, also known as S-adenosylme­thio­nine synthetase, is found in almost every organism. SAMe is employed universally by different methyl­transferases that catalyze the methyl­ation of biomolecules such as nucleic acids, proteins and lipids. In plant cells SAMe produced by MAT enzymes controls the level of critical metabolites such as ethyl­ene, polyamines and biotin, and regulates essential cellular processes such as cell division and synthesis of cell wall, chloro­phyll and membrane. MAT enzyme complex MATα2β, comprising the catalytic unit MATα2 and the regulatory protein MATβ, is found in nearly all human tissues and is essential for providing the necessary SAMe flux for methyl­ation of DNA and various proteins including histones. The enzymatic activity of MATα2 is enhanced by several fold upon complexation with both variants of MATβ (βV1 and βV2). Using cryogenic electron microscopy, we determined the high-resolution resting-state structures of the MATα24βV12 and MATα24βV22 complexes, providing insights into the allosteric regulation of MAT catalytic activity, revealing how MATβV association could facilitate substrate binding, stabilize the transition state and promote product release to drive the catalytic cycle, and opening new possibilities for inhibitor binding.