Reduction and conversion of CO2 to chemicals by autotrophic organisms is an attractive approach to reducing the atmospheric level of CO2. The goal of our work is to create artificial photoautotrophic cells with high performance. Based on understanding of metabolic regulatory mechanisms in natural photoautotrophs, we reprogram the energy and material flow of biological systems for improving photosynthetic efficiency.
(1) Regulation of metabolic fluxes in natural photoautotrophs
Understanding of how photosynthetic organisms regulate their metabolism under various environmental conditions may aid in the design of synthetic autotrophs. We are combining dynamic 15N, 13C, and 2H tracer experiments, metabolic flux analysis, and metabolomic analysis to determine the mechanisms used by cyanobacteria to cope with sudden availability and removal of light or essential nutrients. The specific aim is to quantitatively and mechanistically understand the regulatory mechanisms of energy and carbon flow in photoautotrophic cells.
(2) Design and construction of semiconductor biohybrids for efficient light-driven carbon fixation
We are designing and building the biohybrid systems that couple semiconductor materials with heterotrophic or autotrophic bacteria. The key scientific and technological problems that are addressed include the electron transfer at the material-cell interface, intracellular energy transduction, synthetic autotrophic functionality, and optimization of the biohybrids. This study is expected to achieve breakthroughs in the design, construction, and optimization of artificial photoautotrophic cells and improve the techniques for manipulation of abiotic-biotic hybrid systems.
The human gut microbiota constitutes a highly complex and interactive microbial ecosystem, which is integral to the maintenance of health and the regulation of the host immune system. We construct microbial consortia or engineer bacteria to improve therapeutic efficacy or develop novel therapies for cancer and other diseases. Meanwhile, we try to improve our understanding of the host-microbiota metabolic interactions, which is key to the future rational design of microbial biotherapeutics.
(1) Synthetic microbial community for improving efficacy of cancer immunotherapy
Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has become highly successful against an array of distinct malignancies including advanced melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma. Despite the remarkable success of the ICIs targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, the majority of patients have yet to receive durable benefits. Growing evidence suggests that the gut microbiota modulates the efficacy of cancer therapy. By using a bottom-up synthetic ecological approach, we design and assemble a microbial consortium, which is comprised of gut bacterial species derived from patients with NSCLC responsive to PD-1 blockade therapy. The synthetic bacterial community is targeted to enhance anti-tumor immunity and circumvent resistance to ICIs. In addition, we also engineer bacteria to develop novel therapies for cancer and other diseases.
(2) Host-microbiota interactions mediated by gut microbial metabolites
The gut microbiota contributes to host physiology through the production of a myriad of metabolites. Many of human-microbial cometabolites have been implicated in diseases. We investigate the biosynthetic and biotransformation pathways of these metabolites in various gut bacterial species. Moreover, we develop techniques for quantifying metabolic fluxes in microbial communities. Our goal is to identify actionable microbial targets that are relevant for host health.
Zhou, J., Xu, S., Li, H., Xi, H., Cheng, W., Yang, C.*. A ribulose-5-phosphate shunt from the Calvin-Benson cycle to methylerythritol phosphate pathway for enhancing photosynthetic terpenoid production. ACS Synth. Biol., 13: 876-887 (2024).
Xi, H., Nie, X.*, Gao, F., Liang, X., Li, H., Zhou, H., Cai, Y., Yang, C*. A bacterial spermidine biosynthetic pathway via carboxyaminopropylagmatine. Sci. Adv., 9: eadj9075 (2023).
Yao, C., Sun, R., Yang, Y., Zhou, H., Meng, Z., Chi, R., Xia, L., Li, P., Chen, Y., Zhang, G., Sun, H., Lu, S.*, Yang, C*, Wang, Y.*. Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor response. Cell Rep., 42: 112186 (2023).
Dong, W., Nie, X., Zhu, H., Liu, Q., Shi, K., You, L., Zhang, Y., Fan, H., Yan, B., Niu, C.*, Lyu, L.D.*, Zhao, G.P., Yang, C.*. Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence. PNAS, 118: e2019305118 (2021).
Yang, B., Nie, X., Xiao, Y., Gu, Y., Jiang, W., Yang, C.*. Ferrous iron-activated transcriptional factor AdhR regulates redox homeostasis in Clostridium beijerinckii. Appl. Environ. Microbiol., 86: e02782-19 (2020).
Yang, B., Nie, X., Xiao, Y., Gu, Y., Jiang, W., Yang, C.*. Control of solvent production by sigma-54 factor and the transcriptional activator AdhR in Clostridium beijerinckii. Microb. Biotechnol., 13: 328-338 (2020).
Nie, X., Dong, W., Yang, C.*. Genomic reconstruction of σ54 regulons in Clostridiales. BMC Genomics, 20: 565 (2019).
Zhang, H., Liu, Y., Nie, X., Liu, L., Hua, Q., Zhao, G.P., Yang, C.*. The cyanobacterial ornithine-ammonia cycle involves an arginine dihydrolase. Nat. Chem. Biol., 14: 575-581 (2018).
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