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ATP Regulation in Bioproduction


ATP Regulation in Bioproduction

Kiyotaka Y Hara et al. Microb Cell Fact.


Adenosine-5'-triphosphate (ATP) is consumed as a biological energy source by many intracellular reactions. Thus, the intracellular ATP supply is required to maintain cellular homeostasis. The dependence on the intracellular ATP supply is a critical factor in bioproduction by cell factories. Recent studies have shown that changing the ATP supply is critical for improving product yields. In this review, we summarize the recent challenges faced by researchers engaged in the development of engineered cell factories, including the maintenance of a large ATP supply and the production of cell factories. The strategies used to enhance ATP supply are categorized as follows: addition of energy substrates, controlling pH, metabolic engineering of ATP-generating or ATP-consuming pathways, and controlling reactions of the respiratory chain. An enhanced ATP supply generated using these strategies improves target production through increases in resource uptake, cell growth, biosynthesis, export of products, and tolerance to toxic compounds.


Fig. 1
Fig. 1
ATP generation in heterotrophic cell factories. Fermentative glycolytic and respiratory generation of ATP may be compared to the front and rear axles, respectively, of four-wheel drive vehicles
Fig. 2
Fig. 2
Cell factories utilize carbon source to generate ATP by glycolysis and respiratory chain. Cell factories engineered in the pathways toward target product consume much more ATP for (i) sugar uptake, (ii) cell growth, (iii) biosynthesis and (iv) export of target products, and (v) tolerance to toxic compounds. Cell factories improve intracellular ATP supply to drive various cellular thermodynamically unfavorable reactions with keeping high ATP supply for better bioproductions. ATP supply of the cell factories is enhanced by (1) addition of energy substrates, (2) control of pH condition, (3) metabolic engineering of pathways involved in ATP generation or ATP consumption and (4) enhancement of respiratory chain reaction
Fig. 3
Fig. 3
Pathways involved in ATP generation or ATP consumption. Glk glucokinase, Pfk 6-phosphofructokinase, Pgk phosphoglycerate kinase, Pyk pyruvate kinase, Ldh lactate dehydrogenase, Adh alcohol dehydrogenase, Pdc pyruvate decarboxylase, Aldh aldehyde dehydrogenase, Pta phosphate acetyltransferase, Ack acetate kinase, Pc pyruvate carboxylase, Pck PEP carboxy kinase, Ppc PEP carboxylase, Pfl pyruvate-formate lyase, Cs citrate synthase, Cl citrate lyase, Scs succinyl-CoA synthase, Mdh malate dehydrogenase, ME malic enzyme, PEP phosphoenolpyruvate, OAA oxaloacetate

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