Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, 8560 Progress Drive, Frederick, MD, 21701, USA.
Nutrition Research Institute, University of North Carolina at Chapel Hill, 500 Laureate Way, Kannapolis, NC, 28081, USA.
Commun Biol. 2022 Jan 10;5(1):3. doi: 10.1038/s42003-021-02963-9.
Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO. Cryo-EM structures of tetrameric rat ALDH1L1 revealed the architecture and functional domain interactions of this complex enzyme. Highly mobile N-terminal domains, which remove formyl from 10-formyltetrahydrofolate, undergo multiple transient inter-domain interactions. The C-terminal aldehyde dehydrogenase domains, which convert formyl to CO, form unusually large interfaces with the intermediate domains, homologs of acyl/peptidyl carrier proteins (A/PCPs), which transfer the formyl group between the catalytic domains. The 4'-phosphopantetheine arm of the intermediate domain is fully extended and reaches deep into the catalytic pocket of the C-terminal domain. Remarkably, the tetrameric state of ALDH1L1 is indispensable for catalysis because the intermediate domain transfers formyl between the catalytic domains of different protomers. These findings emphasize the versatility of A/PCPs in complex, highly dynamic enzymatic systems.
假定的肿瘤抑制因子 ALDH1L1 是三个不相关基因自然融合的产物，通过催化烟酰胺腺嘌呤二核苷酸（NAD(P)H）依赖的 10-甲酰四氢叶酸向四氢叶酸和 CO 的转化来调节叶酸代谢。四聚体大鼠 ALDH1L1 的冷冻电镜结构揭示了这种复杂酶的结构和功能域相互作用。高度移动的 N 端结构域从 10-甲酰四氢叶酸中去除甲酰基，经历多次瞬时的结构域间相互作用。C 端醛脱氢酶结构域将甲酰基转化为 CO，与中间结构域形成异常大的界面，该中间结构域与酰基/肽基载体蛋白（A/PCP）的同源物，将甲酰基在催化结构域之间转移。中间结构域的 4'-磷酸泛酰巯基乙胺臂完全伸展并深入 C 端结构域的催化口袋。值得注意的是，ALDH1L1 的四聚体状态对于催化是必不可少的，因为中间结构域在不同的单体的催化结构域之间转移甲酰基。这些发现强调了 A/PCP 在复杂、高度动态的酶系统中的多功能性。
