Protein-protein interactions involving enzymes of the mammalian methionine and homocysteine metabolism

Enzymes of the methionine and homocysteine metabolism catalyze reactions belonging to the methionine and folate cycles and the transsulfuration pathway. The importance of the metabolites produced through these routes (e.g. S-adenosylmethionine, homocysteine) and their role in e.g. epigenetics or redox mechanisms makes their tight regulation essential for a correct cellular function. Pharmacological or pathophysiological insults induce, among others, changes in activity, oligomerization, protein levels, subcellular localization and expression of these enzymes. The abundance of these proteins in liver has made this organ the preferred system to study their regulation. Nevertheless, knowledge about their putative protein-protein interactions is limited in this and other tissues and cell types. High-throughput methods, including immunoprecipitation, affinity purification coupled to mass spectrometry and yeast two-hybrid have rendered the identification of a number of protein-protein interactions involving these enzymes in several systems. Validation by coimmunoprecipitation and/or pull-down has been made, mainly, after coexpression of bait and prey, but few of the interactions have been confirmed. Additionally, information concerning the role of these interactions in the regulation of this pathway and other cellular processes is scarce. Here, we review the current knowledge on mammalian protein-protein interactions involving methionine adenosyltransferases, S-adenosylhomocysteine hydrolase, betaine homocysteine S-methyltransferases, methionine synthase and cystathionine β-synthase, although references to data obtained in other organisms are also made. Moreover, the verified or putative implication of these interactions in the regulation of methionine and homocysteine metabolism, its interplay with other metabolic pathways and its putative link to pathophysiological processes, such as oncogenesis, is discussed.
This work was supported by grants of the Ministerio de Ciencia,Innovación y Universidades (BFU2005-00050, BFU2008-00666,BFU2009-08977 to MAP; BFU2008-04285 to FP; BIO2015-67580-Pand PGC2018-097019-B-I00 to JV), the Instituto de Salud Carlos III-Fondo de Investigación Sanitaria PRB3 (IPT17/0019-ISCIII-SGEFI/ERDF, ProteoRed to JV), Fundació Marató TV3 (122/C/2015 to JV)and La Caixa Banking Foundation (HR17-00247 to JV). The CNIC issupported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).