Ohren Jeffrey, Parungao Gwenn G, Viola Ronald E
Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA.
Acta Crystallogr F Struct Biol Commun. 2019 Apr 1;75(Pt 4):290-298. doi: 10.1107/S2053230X19002772. Epub 2019 Apr 2.
S-Adenosyl-L-methionine (AdoMet), the primary methyl donor in most biological methylation reactions, is produced from ATP and methionine in a multistep reaction catalyzed by AdoMet synthetase. The diversity of group-transfer reactions that involve AdoMet places this compound at a key crossroads in amino-acid, nucleic acid and lipid metabolism, and disruption of its synthesis has adverse consequences for all forms of life. The family of AdoMet synthetases is highly conserved, and structures of this enzyme have been determined from organisms ranging from bacteria to humans. Here, the structure of an AdoMet synthetase from the infectious parasite Cryptosporidium parvum has been determined as part of an effort to identify structural differences in this enzyme family that can guide the development of species-selective inhibitors. This enzyme form has a less extensive subunit interface than some previously determined structures, and contains some key structural differences from the human enzyme in an allosteric site, presenting an opportunity for the design of selective inhibitors against the AdoMet synthetase from this organism.
S-腺苷-L-甲硫氨酸（AdoMet）是大多数生物甲基化反应中的主要甲基供体，它由ATP和甲硫氨酸通过腺苷甲硫氨酸合成酶催化的多步反应生成。涉及AdoMet的基团转移反应的多样性使该化合物处于氨基酸、核酸和脂质代谢的关键交叉点，其合成的中断会对所有生命形式产生不利影响。腺苷甲硫氨酸合成酶家族高度保守，并且已经确定了从细菌到人类等多种生物体中该酶的结构。在这里，作为识别该酶家族中可指导物种选择性抑制剂开发的结构差异的努力的一部分，已确定了来自感染性寄生虫微小隐孢子虫的腺苷甲硫氨酸合成酶的结构。这种酶形式的亚基界面比一些先前确定的结构要小，并且在变构位点与人类酶存在一些关键的结构差异，这为设计针对该生物体的腺苷甲硫氨酸合成酶的选择性抑制剂提供了机会。
