ORIGINAL RESEARCH article
Front. Bioeng. Biotechnol.
Sec. Bioprocess Engineering
Volume 13 - 2025 | doi: 10.3389/fbioe.2025.1625009
Hyaluronidases improve the hyaluronic acid yield during the fermentation of Streptococcus zooepidemicus
Provisionally accepted
Chuan-Li Kang1,2,3De-Qiang Zheng1,2,3Zhi-Yuan Yao1
Kang Yang3Yuxue Zhao3Zihan Mao3Yang Liu3Haijun Li3
Jin-Song Gong1Lei Liu2Qingwen Jia2,3Zheng- Hong Xu1,4
Jin-Song Shi1*
Le Xue3- 1Jiangnan University, Wuxi, China
- 2Shandong Focusfreda Biotech Co., Ltd, Qufu, China
- 3Shandong Freda Pharmaceutical Co.,Ltd, Jinan, China
- 4Sichuan University, Chengdu, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Hyaluronic acid (HA), a linear acidic mucopolysaccharide with exceptional biocompatibility, is extensively utilized in pharmaceuticals and cosmetics. Industrial HA production predominantly relies on Streptococcus zooepidemicus fermentation.However, the accumulation of high-molecular-weight (HMW) HA increases broth viscosity, impeding nutrient diffusion and limiting yield. To address this, we evaluated the strategic addition of hyaluronidases (HAases) to degrade HMW HA during fermentation, thereby reducing viscosity and enhancing productivity.Four HAases, HHya1, LHya2, SHya3, and EHya4, were expressed and screened for enzymatic activity. HHya1 and EHya4 exhibited superior expression levels and catalytic efficiency. Purification and functional characterization revealed distinct degradation profiles, HHya1 hydrolyzed HMW HA into saturated tetrasaccharides, while EHya4 generated unsaturated disaccharides.In shake-flask fermentations, supplementation with 1500 U/L EHya4 increased HA titer by 12%, outperforming HHya1. Scaling to bioreactor cultivation with viscosity-controlled HAase dosing further optimized productivity. By administering HAase at intervals corresponding to viscosity thresholds, HA titers reached 10.3 g/L, representing a 14.4% increase over baseline.These findings demonstrate that HAase application alleviates viscosity-associated bottlenecks in S. zooepidemicus fermentations, establishing an optimized process for scalable HA production. This approach balances enzymatic degradation with microbial growth kinetics, offering a practical strategy for industrial HA biosynthesis.
Keywords: Hyaluronidases, Hyaluronic Acid, Enzymatic fermentation, protein expression, Fermentation process optimization
Received: 08 May 2025; Accepted: 23 Jun 2025.
Copyright: © 2025 Kang, Zheng, Yao, Yang, Zhao, Mao, Liu, Li, Gong, Liu, Jia, Xu, Shi and Xue. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jin-Song Shi, Jiangnan University, Wuxi, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.