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The impact of addition of methylthioadenosine (MTA), a stimulator of cell‐specific productivity (CSP) in Chinese hamster ovary (CHO) cells, is concentration and time dependent. Moreover, MTA affects cell cycle, cell size, and viability. Transcript analysis of post‐MTA addition revealed interesting targets for cell line and process engineering., A major goal for process and cell engineering in the biopharmaceutical industry is enhancing production through increasing volumetric and cell‐specific productivities (CSP). Here, we present 5′‐deoxy‐5′‐(methylthio)adenosine (MTA), the degradation product of S‐(5′‐adenosyl)‐L‐methionine (SAM), as a highly attractive native additive which can boost CSP by 79% when added to exponentially growing cells at a concentration of 250–300 μm. Notably, cell viability and cell size remain higher than in non‐treated cultures. In addition, cell cycle arrests first in S‐, then in G2‐phase before levelling out compared to non‐treated cultivations. Intensive differential gene analysis reveals that expression of genes for cytoskeleton mediated proteins and vesicle transport is amplified by treatment. Furthermore, the interaction of MTA with cell proliferation additionally stimulated recombinant protein formation. The results may serve as a promising starting point for further developments in process and cell engineering to boost productivity.

Increasing markets for biopharmaceuticals, including monoclonal antibodies, have triggered a permanent need for bioprocess optimization. Biochemical engineering approaches often include the optimization of basal and feed media to improve productivities of Chinese hamster ovary (CHO) cell cultures. Often, l‐tyrosine is added as dipeptide to deal with its poor solubility at neutral pH. Showcasing IgG1 production with CHO cells, we investigated the supplementation of three l‐tyrosine (TYR, Y) containing dipeptides: glycyl‐l‐tyrosine (GY), l‐tyrosyl‐l‐valine (YV), and l‐prolyl‐l‐tyrosine (PY). While GY and YV led to almost no phenotypic and metabolic differences compared to reference samples, PY significantly amplified TYR uptake thus maximizing related catabolic activity. Consequently, ATP formation was roughly four times higher upon PY application than in reference samples.