Cell survival enabled by leakage of a labile metabolic intermediate
Cell survival enabled by leakage of a labile metabolic intermediate
Many metabolic pathways are of ancient origin and have evolved over long periods of time (Noda-Garcia et al., 2018). Yet, new pathways can also emerge in short time scales in response, for instance, to the presence of anthropogenic chemicals in the environment (Copley, 2009). Models of metabolic pathway emergence and evolution often emphasize the acquisition of new reactions through horizontal gene transfer and promiscuous enzyme functionalities (Pál et al., 2005; Schulenburg & Miller, 2014; Copley, 2015; Noda-Garcia et al., 2018; Peracchi, 2018). A fundamentally different mechanism of metabolic innovation is revealed by the evolutionary repair experiments reported here. A block in the proline biosynthetic pathway that compromises cell survival is efficiently rescued by many single mutations (12 at least) in the gene of glutamine synthetase. The mutations cause the leakage to the intracellular milieu of a sequestered phosphorylated intermediate common to the biosynthetic pathways of proline and glutamine, thus generating a new route to proline. Metabolic intermediates may undergo a variety of chemical and enzymatic transformations, but are typically protected as shielded reaction intermediates or through channeling in multi-enzyme complexes and metabolons (Srere, 1987; Huang et al., 2001; Grunwald, 2018; Pareek et al., 2021). Our results show that intermediate leakage can readily occur and contribute to organismal adaptation. Enhanced availability of reactive molecules may enable the generation of new biochemical pathways. We therefore anticipate applications of mutation-induced leakage in metabolic engineering.
Manssour-Triedo Fadia、Gamiz-Arco Gloria、Mota Antonio J.、Rein¨| Pablo、Ortega-Mu?oz Mariano、Sanchez-Ruiz Jose M.、Cuerva Juan Manuel、Andr¨|s-Le¨?n Eduardo、Newton Matilda S.、Medina-Carmona Encarnaci¨?n、Ibarra-Molero Beatriz、Ortega-Roldan Jose Luis、Seelig Burckhard、Gutierrez-Rus Luis I.
Departamento de Quimica Fisica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaDepartamento de Quimica Fisica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaDepartamento de Quimica Inorganica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaDepartamento de Quimica Organica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaDepartamento de Quimica Organica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaDepartamento de Quimica Fisica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaDepartamento de Quimica Organica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaUnidad de Bioinform¨￠tica, Instituto de Parasitolog¨aa y Biomedicina ?°Lopez Neyra?±, CSICDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota BioTechnology Institute, University of Minnesota||Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder Cooperative Institute for Research in Environmental Sciences, University of Colorado BoulderDepartamento de Quimica Fisica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaDepartamento de Quimica Fisica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de GranadaSchool of Biosciences, University of KentDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota BioTechnology Institute, University of MinnesotaDepartamento de Quimica Fisica, Facultad de Ciencias, Unidad de Excelencia de Quimica Aplicada a Biomedicina y Medioambiente (UEQ). Universidad de Granada
生物化学分子生物学细胞生物学
Manssour-Triedo Fadia,Gamiz-Arco Gloria,Mota Antonio J.,Rein¨| Pablo,Ortega-Mu?oz Mariano,Sanchez-Ruiz Jose M.,Cuerva Juan Manuel,Andr¨|s-Le¨?n Eduardo,Newton Matilda S.,Medina-Carmona Encarnaci¨?n,Ibarra-Molero Beatriz,Ortega-Roldan Jose Luis,Seelig Burckhard,Gutierrez-Rus Luis I..Cell survival enabled by leakage of a labile metabolic intermediate[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/2022.05.20.492833.点此复制
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