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Here, we show that optogenetic control of protein kinase A (PKA) activity via light-regulated modulation of intracellular cyclic AMP (cAMP) levels can enhance heterologous production of \u03b2-carotene and cordycepin in\n                      <jats:italic toggle=\"yes\">Saccharomyces cerevisiae<\/jats:italic>\n                      . To enable exclusive, glucose-independent control of cAMP synthesis, the photoactivatable adenylyl cyclase bPAC from\n                      <jats:italic toggle=\"yes\">Beggiatoa<\/jats:italic>\n                      sp. was introduced into cells lacking the endogenous adenylyl cyclase Cyr1 or with lowered Cyr1 levels using an optogenetically controlled degron. Despite being growth-competent under illumination, the bPAC-containing yeast strain showed alterations in energy metabolism under all conditions. Quantitative proteome analysis using timsTOF mass spectrometry revealed profound changes in central carbon metabolism, sulfur homeostasis, energy charge, and ribosome biogenesis upon uncoupling cAMP from nutrient-dependent regulation, particularly under sustained light activation. These results highlight the critical role of dynamic Cyr1-dependent regulation for central metabolism, and underscore the biotechnological promise of refined PKA-targeted strategies for eukaryotic cell factories.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Carbon-footprint-minimized production of fine chemicals, pharmaceuticals, and biofuels requires optimized microbial cell factories with tailored metabolic performance. We employed optogenetic dynamic metabolic engineering in baker\u2019s yeast by uncoupling nutrient sensing from cAMP signaling using a light-controlled adenylate cyclase. Precise light regulation of intracellular cAMP levels and PKA activity enabled acute control of the metabolism, redirecting resources toward product synthesis, and boosting the production of valuable compounds such as \u03b2-carotene and cordycepin. Quantitative proteomics revealed that uncoupling of the cAMP\u2013PKA axis from glucose sensing profoundly reprograms the central carbon metabolism and other key cellular processes. This approach provides a blueprint for refined, light-tunable strategies targeting the cAMP\u2013PKA axis directly with light, e.g., for enhanced bioethanol production. Moreover, our data provide evidence for the profound influence of the cAMP\u2013PKA axis on metabolism and balanced energy production that are fundamental for efficient production in microbial cell factories.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/aem.02498-25","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T15:35:25Z","timestamp":1779118525000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Global impact on metabolic capacity of yeast cell factories by optogenetic control of the cAMP\u2013PKA axis"],"prefix":"10.1128","volume":"92","author":[{"given":"Mohamed","family":"Watad","sequence":"first","affiliation":[{"name":"Unit for Structural Biochemistry, Department of Chemistry, Philipps-University Marburg","place":["Marburg, 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