Biotechnology and Bioprocess Engineering 2021; 26(4): 669-676  
A Novel Two-stage pH Control Strategy for the Production of 5-Aminolevulinic Acid Using Recombinant Streptomyces coelicolor
Diep Ngoc Pham and Chang-Joon Kim
Diep Ngoc Pham, Chang-Joon Kim*
Department of Chemical Engineering and RIGET, Gyeongsang National University, Jinju 52828, Korea
Tel: +82-55-772-1787; Fax: +82-55-772-1789
Chang-Joon Kim
Department of Materials Engineering and Convergence Technology, Gyeongsang National University, Jinju 52828, Korea
Received: November 29, 2020; Revised: January 15, 2021; Accepted: January 16, 2021; Published online: August 30, 2021.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
5-aminolevulinic acid (ALA) has extensive use in photodynamic cancer therapy, tumor diagnosis, and agriculture. In the microbial production of ALA, most efforts have focused on engineering enzymes and the metabolic pathways involved in ALA biosynthesis. The aim of this study was to enhance ALA production using recombinant Streptomyces coelicolor expressing the ALA synthase gene (hem A) of Rhodobacter sphaeroides with a novel two-stage pH control strategy. Batch cultures were performed in production medium at different pH values. Although cells grew well at neutral pH (6.8-7.2), the highest amount of ALA was produced with a long culture time (140 h) at a weakly acidic pH (5.5-6.0). In response, a two-stage pH control strategy was developed in which pH was maintained at 6.8-7.2 for cell growth and then shifted to 5.5-6.0 to promote ALA synthesis, resulting in a significant enhancement in ALA production compared to a one-stage pH control strategy. The titer of ALA was further improved up to 482 mg/L in the two-stage pH culture by supplying more glucose in the medium and shifting the pH during the early phase of cultivation.
Keywords: recombinant Streptomyces coelicolor, 5-aminolevulinic acid, pH-controlled bioreactor culture, pH stress, two-stage pH control strategy

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