Towards a more complete view of a cell's functions through genome scale models of metabolism, protein synthesis, post-translational modification, and secretion

In mammalian cells, metabolism is a core process driving homeostasis, but variations in other cell processes largely define cell type identity and cell-type specific functions. The profile of secreted and membrane proteins show substantial cell-type specificity and drive many tissue specific functions. These proteins, encoded by up to 1/3 of mammalian protein-coding genes, include hormones, membrane proteins, and enzymes that modulate the extracellular space, and these are synthesized and trafficked through the secretory pathway. The pathway complexity, however, obfuscates its impact on the secretion of different proteins. Unraveling its impact on diverse proteins is particularly important since the pathway is implicated in many diseases and harnessed for biopharmaceutical production. We have delineated the core secretory pathway functions and integrated them with genome-scale metabolic models of human, mouse, and Chinese hamster ovary cells. Here I will discuss our efforts to use this conceptual expansion of constraint-based metabolic modeling to obtain insights into bioenergetic demands imposed by protein synthesis and secretion, and how these models can be deployed in efforts to engineer mammalian cells for enhanced secretion of high-value biologic drugs. Thus, this work represents a knowledge-base of the mammalian secretory pathway that serves as a novel tool for systems biotechnology.