---
title: "Biocatalytic production of Danshensu from L‑Tyrosine using engineered Escherichia coli"
id: "plos-one-1-multienzyme-cascade-biotransformation-of-l-tyrosine-to-danshensu-by-engineered"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-1-multienzyme-cascade-biotransformation-of-l-tyrosine-to-danshensu-by-engineered"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484"
published_at: "2026-10-23T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Biocatalytic production of Danshensu from L‑Tyrosine using engineered Escherichia coli
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-1-multienzyme-cascade-biotransformation-of-l-tyrosine-to-danshensu-by-engineered
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484)
- **Published At:** 2026-10-23T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study engineered Escherichia coli to convert **L‑Tyrosine** into **Danshensu** (DSS) via a four‑enzyme cascade expressed heterologously. - Heterologous genes used: **HpaBC** (mutant 23F9‑M4 variant), **aadL** (L‑amino acid deaminase), **ldhD** (D‑lactate dehydrogenase) and **gdh** (glucose dehydrogenase) for cofactor regeneration. - Initial coexpression in strain 1 produced 5.1 mM DSS in 6 hours under whole‑cell biotransformation conditions (50 mM glucose, 25 mM L‑Tyrosine, 50 g/L wet cells). - Altering plasmid copy number and gene arrangement across seven engineered strains changed transcript levels (RT‑qPCR) and product titres; strain 6 achieved 6.53 mM DSS. - Optimization of induction conditions (OD600, IPTG concentration, induction temperature and time) and reaction parameters (pH, temperature, wet cell loading) further increased yields; final optimized small‑scale yield reached 8.66 mM for strain 6. - Scale‑up in a 5 L bioreactor using whole‑cell biotransformation with strain 6 yielded 19.47 mM DSS within 32 hours; samples were monitored hourly by HPLC. - Analytical confirmation used HPLC and LC–MS; product spectra matched DSS standard. - All experiments were performed in biological triplicate; plasmids and strain constructs were sequence‑verified. - The source did not report downstream purification procedures, product stereochemistry beyond spectral matching, or any in vivo/clinical testing of DSS produced here.
## Clinical Analysis & Structured Key Points
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Multienzyme cascade biotransformation of L-Tyrosine to Danshensu by engineered _Escherichia coli_ * Tianzhen Xiong , Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Writing – review & editing * E-mail: tzxiong@xynu.edu.cn Affiliations Henan Key Laboratory of Tea Plant Biology, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China, Dabie Mountain Laboratory, Xinyang, Henan, China, Henan International Joint Laboratory of Tea-oil tree Biology and High-Value Utilization, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-6868-1269 ](https://orcid.org/0000-0001-6868-1269 "ORCID Registry") ⨯ * Shuqing Li, Roles Data curation, Formal analysis, Writing – original draft Affiliations Henan Key Laboratory of Tea Plant Biology, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China, Henan International Joint Laboratory of Tea-oil tree Biology and High-Value Utilization, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China ⨯ * Xiaoya Li, Roles Data curation, Formal analysis Affiliations Henan Key Laboratory of Tea Plant Biology, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China, Henan International Joint Laboratory of Tea-oil tree Biology and High-Value Utilization, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China ⨯ * Xinmeng Li, Roles Data curation, Investigation Affiliations Henan Key Laboratory of Tea Plant Biology, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China, Henan International Joint Laboratory of Tea-oil tree Biology and High-Value Utilization, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China ⨯ * Mengdan Wu, Roles Data curation Affiliations Henan Key Laboratory of Tea Plant Biology, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China, Henan International Joint Laboratory of Tea-oil tree Biology and High-Value Utilization, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China ⨯ * Jinru Liu, Roles Data curation Affiliations Henan Key Laboratory of Tea Plant Biology, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China, Henan International Joint Laboratory of Tea-oil tree Biology and High-Value Utilization, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China ⨯ * Jinxiu Guo, Roles Data curation Affiliations Henan Key Laboratory of Tea Plant Biology, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China, Henan International Joint Laboratory of Tea-oil tree Biology and High-Value Utilization, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China ⨯ * Xinrui Li Roles Data curation Affiliations Henan Key Laboratory of Tea Plant Biology, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China, Henan International Joint Laboratory of Tea-oil tree Biology and High-Value Utilization, College of Tea and Food Science, Xinyang Normal University, Xinyang, Henan, China ⨯ # Multienzyme cascade biotransformation of L-Tyrosine to Danshensu by engineered _Escherichia coli_ * Tianzhen Xiong, * Shuqing Li, * Xiaoya Li, * Xinmeng Li, * Mengdan Wu, * Jinru Liu, * Jinxiu Guo, * Xinrui Li ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: October 23, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0361484) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0361484) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0361484) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0361484) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#abstract0) * [1 Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#sec001) * [2 Materials and methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#sec002) * [3 Results and discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#sec011) * [4 Conclusions](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#sec016) * [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#sec017) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0361484) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484) ## Abstract Danshensu (DSS), a water-soluble bioactive compound with significant antioxidant, anti-inflammatory, cardioprotective and neuroprotective properties, is widely utilized in cardiovascular and cerebrovascular disease. In this study, we established a multi-enzyme cascade system in engineered _Escherichia coli_ to synthesize DSS from L-Tyrosine. The initial co-expression of 4-hydroxyphenylacetate 3-monooxygenase (HpaBC), L-amino acid deaminase (aadL), glucose dehydrogenase (gdh) and D-lactate dehydrogenase (ldhD) yielded 5.1 mM DSS. The production of DSS increased to 6.53 mM through optimizing plasmid copy number. After optimizing the conditions, the yield of DSS reached 8.66 mM from strain 6. Finally, whole cell biotransformation using strain 6 in bioreactor yielded 19.47 mM DSS within 32h. These findings provide valuable insights for the scalable biosynthesis of pharmaceutically important compound of DSS from naturally available substrates of L-Tyrosine. ## Figures ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.t001) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g003) ![Fig 4](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g004) ![Fig 5](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g005) ![Fig 6](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g006) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.t001) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g003) **Citation:** Xiong T, Li S, Li X, Li X, Wu M, Liu J, et al. (2026) Multienzyme cascade biotransformation of L-Tyrosine to Danshensu by engineered _Escherichia coli_. PLoS One 21(10): e0361484. https://doi.org/10.1371/journal.pone.0361484 **Editor:** Chun-Hua Wang, Foshan University, CHINA **Received:** July 18, 2026; **Accepted:** October 12, 2026; **Published:** October 23, 2026 **Copyright:** © 2026 Xiong et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** All relevant data are within the manuscript and its [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#sec017) files. **Funding:** Scientific and Technological Frontiers in Project of Henan Province (252102310350), Key scientific research project of higher education institutions in Henan Province (24B180017) and Nanhu Scholars Program for Young Scholars of XYNU. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. **Competing interests:** The authors have declared that no competing interests exist. ## 1 Introduction Danshensu (DSS) has emerged as promising therapeutic agent owing to multifaceted pharmacological effects including antioxidant capacities [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref001)], anti-inflammatory [[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref002)], cardioprotective [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref003)] and enhancing cardiac performance [[4](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref004)]. In addition to being directly used as medicine, DSS can also serve as key precursor for synthesis of valuable derivatives. Danshensu Bingpian Zhi (DBZ) was synthesized using DSS and borneol as substrates and can enhance the therapeutic effect of cardiovascular and cerebrovascular diseases compared to DSS [[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref005)]. Isopropyl dihydroxyl hydroxy propionate (IDHP) was synthesized using DSS and isopropyl alcohol as substrates and can enhance the protective effect on the heart muscle compared to DSS [[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref006)]. Many methods have been used for production of DSS. Current industrial production of DSS primarily relies on extraction from _Salvia miltiorrhiza_ roots [[7](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref007)]. However, the extraction of DSS from _Salvia miltiorrhiza_ faces significant limitations. The resources of _Salvia miltiorrhiza_ are limited, a large amount of organic solvents are used, many by-products are produced and the purification of DSS is difficult [[8](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref008)]. Meanwhile, conventional chemical synthesis routes starting from benzaldehyde is facing complex multi-step processes and inadequate stereochemical control [[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref009)]. In recent decades, synthetic biology technology has rapidly developed and has been used to produce large number of high-value natural products [[10](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref010),[11](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref011)]. Biotechnological methods for the sustainable production of DSS conform to modern green chemistry principles. Previous studies have explored the catalytic production of DSS by combining biological and chemical methods. Rao et al. developed a chemo-enzymatic route where L-DOPA was first chemically converted to 3,4-dihydroxyphenylpyruvic acid (DOPP), followed by enzymatic reduction to DSS using dual dehydrogenase system [[12](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref012)]. Metabolic engineering can produce DSS by specifically modifying the metabolic networks of microorganisms or plants. The hydroxylase complexes and D-lactate dehydrogenase were introduced into _Escherichia coli_ to reconstruct DSS synthesis pathway; By knocking out the competitive pathway, enhancing the supply of precursor tyrosine, and combining with the regulation of the fermentation process, the yield of DSS was significantly increased. Finally, the yield of DSS reached 7.1g/L [[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref013)]. The engineered strain constructed by multi-enzyme cascade using cheap substrates as raw materials can also be used to produce DSS. Xiong et al. constructed engineered strain by heterologous expression of L-amino acid deaminase (aadL), D-lactate dehydrogenase (ldhD), glucose dehydrogenase (gdh) or tyrosine aminotransferase (tyrB), glutamate dehydrogenase (cdgdh), aromatic lactate dehydrogenase to produce DSS using L-DOPA as the substrate [[14](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref014),[15](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref015)]. Subsequently, Xiong et al. heterologous expressed Tyrosin-phenol lyase (TPL), aadL, ldhD and gdh to construct engineered strain for production of DSS using catechol and pyruvic acid as substrates [[16](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref016)]. Zhang constructed a cascade reaction system by co-expressing 4-hydroxyphenylacetate 3-hydroxylase (HpaBC), aadL, D-lactate dehydrogenase and formate dehydrogenase using L-Tyrosine as the substrate to produce DSS [[17](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref017)]. In this study, we utilized the readily available natural compound L-Tyrosine as the substrate and constructed engineered strain that incorporates HpaBC, aadL, ldhD and gdh to product DSS ([Fig 1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone-0361484-g001)). The production of DSS was boosted by optimizing culture conditions and fine-tuning pathway genes expression. In comparison with conventional chemical processes, whole-cell biotransformation offers several distinct advantages. These include the capacity to occur under mild conditions (low temperatures and pressures), the absence of utilisation of hazardous chemicals and the elimination of requirement for costly, noxious heavy metal catalysts. In contrast to fermentation-based methods, whole-cell biotransformation has been shown to yield greater yields and to facilitate downstream processing. [![thumbnail](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0361484.g001)](https://journals.plos.org/plosone/article/figure/image?size=medium&id=10.1371/journal.pone.0361484.g001 "Click for larger image") Download: * [PNG larger image](https://journals.plos.org/plosone/article/figure/image?download&size=large&id=10.1371/journal.pone.0361484.g001) * [TIFF original image](https://journals.plos.org/plosone/article/figure/image?download&size=original&id=10.1371/journal.pone.0361484.g001) Fig 1. The proposed pathway for biosynthesis of DSS. aadL: L-amino acid deaminase, gdh: glucose dehydrogenase, ldhD: D-lactate dehydrogenase, HpaBC: 4-hydroxyphenylacetate 3-monooxygenase. [ https://doi.org/10.1371/journal.pone.0361484.g001](https://doi.org/10.1371/journal.pone.0361484.g001) ## 2 Materials and methods ### 2.1 Construction of plasmids and strains The genes of _HpaBC_ (_HpaB_ GenBank ID: ARI00017, _HpaC_ GenBank ID: ARI00016) were amplified from _Escherichia coli_ BL21(DE3). The mutant (23F9-M4) was derivatives from _HpaB_ with mutations at T15P, S210F, A211K, Q212F and D284E [[18](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref018),[19](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref019)] and was used in the construction of engineered strains. _aadL_ (GenBank ID: MH192985) [[20](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref020)], _ldhD_ (GenBank ID: MG653257) [[21](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref021)] and _gdh_ (GenBank ID: MH192986) [[22](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref022)] were obtained from previous studies. All successfully constructed plasmids were verified by sequencing from Tongyong (Anhui, China). [Table S1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.s001) in [S1 File](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.s001) lists primers, Table S2 in [S1 File](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.s001) lists plasmids and strains. ### 2.2 RT-qPCR analysis The relative abundance of messenger RNAs was determined using real-time quantitative PCR (RT-qPCR). Total RNA was extracted using RNA extraction kit (TaKaRa, Dalian, China) from the log-phase culture cells. Complementary DNA and qPCR were performed in one step on a CFX Opus 96 Detection System (bio-rad, America) using the One Step TB Green PrimeScript RT-PCR kit from TaKaRa (Dalian, China). The primers used for the _HpaBC_ , _aadL_ , _ldhD_ and _gdh_ genes in the RT-PCR experiments listed in [Table S1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.s001) in [S1 File](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.s001). The 16S ribosomal RNA is accepted as a stably expressed house-keeping gene and was used as the internal reference gene for relative expression analysis [[23](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref023),[24](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0361484#pone.0361484.ref024)]. Each amplification was performed three
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