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Background   Pichia pastoris  has been recognized as an effective host for recombinant protein production. A number of studies have been reported for improving this expression system. However, its physiology and cellular metabolism still remained largely uncharacterized. Thus, it is highly desirable to establish a systems biotechnological framework, in which a comprehensive  in silico  model of  P. pastoris  can be employed together with high throughput experimental data analysis, for better understanding of the methylotrophic yeast's metabolism.    Results  A fully compartmentalized metabolic model of  P. pastoris  ( iPP 668), composed of 1,361 reactions and 1,177 metabolites, was reconstructed based on its genome annotation and biochemical information. The constraints-based flux analysis was then used to predict achievable growth rate which is consistent with the cellular phenotype of  P. pastoris  observed during chemostat experiments. Subsequent  in silico  analysis further explored the effect of various carbon sources on cell growth, revealing sorbitol as a promising candidate for culturing recombinant  P. pastoris  strains producing heterologous proteins. Interestingly, methanol consumption yields a high regeneration rate of reducing equivalents which is substantial for the synthesis of valuable pharmaceutical precursors. Hence, as a case study, we examined the applicability of  P. pastoris  system to whole-cell biotransformation and also identified relevant metabolic engineering targets that have been experimentally verified.    Conclusion  The genome-scale metabolic model characterizes the cellular physiology of  P. pastoris , thus allowing us to gain valuable insights into the metabolism of methylotrophic yeast and devise possible strategies for strain improvement through  in silico  simulations. This computational approach, combined with synthetic biology techniques, potentially forms a basis for rational analysis and design of  P. pastoris  metabolic network to enhance humanized glycoprotein production.

Genome-scale metabolic reconstruction and in silico analysis of methylotrophic yeast Pichia pastoris for strain improvement