Journal
METABOLIC ENGINEERING
Volume 66, Issue -, Pages 259-267Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymben.2021.05.002
Keywords
Human hemoglobin; Heme; Saccharomyces cerevisiae; Reduced degradation; Bilirubin biosensor
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Funding
- Swedish Foundation for Strategic Research (SSF) [RBP14-0055]
- Novo Nordisk Foundation center for Biosustanability
- Knut och Alice Wallenberg Stiftelse
- Sven och Gurli Hanssons
- Novo Nordisk Foundation [NNF19SA0057794]
- Swedish Foundation for Strategic Research (SSF) [RBP14-0055] Funding Source: Swedish Foundation for Strategic Research (SSF)
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By modifying the genes of Saccharomyces cerevisiae, researchers were able to reduce the degradation of human hemoglobin and increase its production to record levels during glucose fermentation. This increased production was accompanied by higher oxygen consumption rate and glycerol yield, indicating the yeast's response to rebalance its NADH levels under conditions of oxygen limitation and increased protein production.
With the increasing demand for blood transfusions, the production of human hemoglobin (Hb) from sustainable sources is increasingly studied. Microbial production is an attractive option, as it may provide a cheap, safe, and reliable source of this protein. To increase the production of human hemoglobin by the yeast Saccharomyces cerevisiae, the degradation of Hb was reduced through several approaches. The deletion of the genes HMX1 (encoding heme oxygenase), VPS10 (encoding receptor for vacuolar proteases), PEP4 (encoding vacuolar proteinase A), ROX1 (encoding heme-dependent repressor of hypoxic genes) and the overexpression of the HEM3 (encoding porphobilinogen deaminase) and the AHSP (encoding human alpha-hemoglobin-stabilizing protein) genes - these changes reduced heme and Hb degradation and improved heme and Hb production. The reduced hemoglobin degradation was validated by a bilirubin biosensor. During glucose fermentation, the engineered strains produced 18% of intracellular Hb relative to the total yeast protein, which is the highest production of human hemoglobin reported in yeast. This increased hemoglobin production was accompanied with an increased oxygen consumption rate and an increased glycerol yield, which (we speculate) is the yeast's response to rebalance its NADH levels under conditions of oxygen limitation and increased protein-production.
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