Cryo-elec­tron micro­scopy – Reac­tion cycle of an enzyme for CO2 fix­a­tion decoded

Before the start of pho­to­syn­thes­is in Earth’s his­tory and accu­mu­la­tion of oxy­gen in the atmo­sphere, anaer­obic microor­gan­isms lived here, which do not need oxy­gen for their meta­bol­ism. Anaer­obic car­bon fix­a­tion is con­sidered one of the old­est and most effi­cient pro­cesses of its spe­cies and also plays a cent­ral role in mod­ern eco­sys­tems — for example in vol­can­ic swamps or in the anim­al digest­ive tract. The enzyme com­plex CO-dehyd­ro­genase-acet­yl-CoA-syn­thase (CODH/ACS) essen­tial for this has been pre­served in microor­gan­isms for over 3.5 bil­lion years.
Cata­lys­is, i.e. the accel­er­a­tion of chem­ic­al pro­cesses in CODH/ACS, is based on vari­ous nick­el-iron met­al clusters that con­vert car­bon diox­ide into the import­ant bio­molecule acet­yl-CoA in sev­er­al reac­tion steps. The effi­ciency of this reac­tion makes CODH/ACS a prom­ising enzyme can­did­ate for bio­fuel pro­duc­tion from car­bon diox­ide. Research­ers from the Uni­ver­sity of Pots­dam and Hum­boldt-Uni­versität Ber­lin have now used high-res­ol­u­tion cryo-elec­tron micro­scopy (cryo-EM) for the first time to elu­cid­ate the cata­lyt­ic cycle of CODH/ACS. Cryo-EM has a wide range of applic­a­tions and can be used for the struc­tur­al ana­lys­is of vari­ous enzymes and biopoly­mers.
​“Our cryo-EM maps of six inter­me­di­ate states of the CODH/ACS are so highly resolved that the molecules bound to the met­al cen­ter can be clearly cor­rel­ated with the move­ments of the pro­tein,” says Jakob Ruick­oldt, first author of the study. ​„The dif­fer­ent bind­ing states of CODH/ACS have not yet been invest­ig­ated using cryo-EM,” says Petra Wend­ler. ​“By using this meth­od, we have dis­covered how the bind­ing of the dif­fer­ent molecules pre­pares the act­ive cen­ter for the next reac­tion step and thus pre­vents side reac­tions and the loss of valu­able reac­tion inter­me­di­ates. This know­ledge will help to util­ize the cata­lys­is of the ancient enzyme com­plex for bio­tech­no­lo­gic­al car­bon fixation.”

Link to Pub­lic­a­tion: Ruick­oldt et al., 2025, Lig­and bind­ing to a Ni-Fe cluster orches­trates con­form­a­tion­al changes of the CO-methyl­at­ing acet­yl-CoA syn­thase, Nature Cata­lys­is, https://​www​.nature​.com/​a​r​t​i​c​l​e​s​/​s​4​1​9​2​9-025 – 01365‑y