Enhancing production of 9α-hydroxy-androst-4-ene-3,17-dione (9-OHAD) from phytosterols by metabolic pathway engineering of mycobacteria

Sun, Hong; Yang, Jingli; He, Kun; Wang, Yongping; Song, Hao

doi:10.1016/j.ces.2020.116195

Cited by 15 publications

(10 citation statements)

References 45 publications

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“…ADD and 9-OH-AD are also important intermediates for the synthesis of hormone pharmaceuticals [ 15 , 20 ]. Therefore, most studies focus on those products, and the same strategies used to increase AD production are also evaluated in those studies [ 15 , 20 , 21 , 32 , 33 , 37 , 39 , 40 , 51 ].…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, a new search strategy was carried out, restricting the search to the period from January 2000 to December 2021, since many relevant documents fell within that period. As a result, 108 articles were obtained [ 4 , 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , …”

Section: Methodsmentioning

confidence: 99%

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Biotransformation of Phytosterols into Androstenedione—A Technological Prospecting Study

et al. 2022

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Androstenedione (AD) is a key intermediate in the body’s steroid metabolism, used as a precursor for several steroid substances, such as testosterone, estradiol, ethinyl estradiol, testolactone, progesterone, cortisone, cortisol, prednisone, and prednisolone. The world market for AD and ADD (androstadienedione) exceeds 1000 tons per year, which stimulates the pharmaceutical industry’s search for newer and cheaper raw materials to produce steroidal compounds. In light of this interest, we aimed to investigate the progress of AD biosynthesis from phytosterols by prospecting scientific articles (Scopus, Web of Science, and Google Scholar databases) and patents (USPTO database). A wide variety of articles and patents involving AD and phytosterol were found in the last few decades, resulting in 108 relevant articles (from January 2000 to December 2021) and 23 patents of interest (from January 1976 to December 2021). The separation of these documents into macro, meso, and micro categories revealed that most studies (articles) are performed in China (54.8%) and in universities (76%), while patents are mostly granted to United States companies. It also highlights the fact that AD production studies are focused on “process improvement” techniques and on possible modifications of the “microorganism” involved in biosynthesis (64 and 62 documents, respectively). The most-reported “process improvement” technique is “chemical addition” (40%), which means that the addition of solvents, surfactants, cofactors, inducers, ionic liquids, etc., can significantly increase AD production. Microbial genetic modifications stand out in the “microorganism” category because this strategy improves AD yield considerably. These documents also revealed the main aspects of AD and ADD biosynthesis: Mycolicibacterium sp. (basonym: Mycobacterium sp.) (40%) and Mycolicibacterium neoaurum (known previously as Mycobacterium neoaurum) (32%) are the most recurrent species studied. Microbial incubation temperatures can vary from 29 °C to 37 °C; incubation can last from 72 h to 14 days; the mixture is agitated at 140 to 220 rpm; vegetable oils, mainly soybean, can be used as the source of a mixture of phytosterols. In general, the results obtained in the present technological prospecting study are fundamental to mapping the possibilities of AD biosynthesis process optimization, as well as to identifying emerging technologies and methodologies in this scenario.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Biotransformation of Phytosterols into Androstenedione—A Technological Prospecting Study

et al. 2022

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“…It should be pointed out that engineering of Mycobacterium sp. for enhancing transport of phytosterol across the cell membrane as well as the enzymatic degradation of phytosterols is only efficient [42,43] when phytosterol transport in the extracellular medium is not a rate-limited step.…”

Section: Discussionmentioning

confidence: 99%

Correlation Relationship between Phase Inversion of Pickering Emulsions and Biocatalytic Activity of Microbial Transformation of Phytosterols

et al. 2022

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Microbial transformation of hydrophobic phytosterols into the pharmaceutical steroid precursors AD (androst-4-ene-3, 17-dione) and ADD (androst-4-diene-3, 17-dione) in a water–plant oil two-phase system by Mycolicibacterium neoaurum is a paradigm of interfacial biocatalysis in Pickering emulsions stabilized by bacterial cells. In the present work, phase inversion of Pickering emulsions—i.e., Pickering emulsions turning from water-in-oil (W/O) emulsions into oil-in-water (O/W) ones—was observed during microbial transformation in the presence of high concentrations of crystal phytosterols. It was found that there is a correlation relationship between the phase behaviors of Pickering emulsions and the biocatalytic activity of utilizing M. neoaurum as a whole-cell catalyst. Efficient microbial transformation under the high crystal phytosterol loadings was achieved due to the formation of O/W emulsions where interfacial biocatalysis took place. Under the optimal conditions (volume ratio of soybean oil to water: 15:35 mL, phytosterols concentration in the soybean oil: 80 g/L, glucose as co-substrate in the aqueous culture medium: 10 g/L), the concentrations of AD and ADD reached 4.8 g/L based on the whole broth (16 g/L based on the oil phase) after microbial transformation for 9 days.

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“…This was a 1.45-fold enhancement compared to the parental M. neoaurum MS136 (4.7 g L À 1 ). [46] The previous whole-genomic and enzymatic analyses revealed that the AD-producing strain Mycobacterium neoaurum HGMS2 possessed one kstd gene (kstd211), two kshA genes (kshA226 and kshA395) and one kshB gene (kshB122). [40b] In order to construct an effective AD-producing strain, the kstd and ksh genes were knocked out from the M. neoaurum HGMS2, creating three recombinant strains: HGMS2 Δkstd211 + ΔkshA226 , HGMS2 Δkstd211 + ΔkshA395 and HGMS2 Δkstd211 + ΔkshB122 .…”

Section: Strain Improvement By Metabolic Engineeringmentioning

confidence: 99%

Biotransformation Enables Innovations Toward Green Synthesis of Steroidal Pharmaceuticals

Feng

Zhu

et al. 2022

ChemSusChem

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Steroids have been widely used in birth‐control, prevention, and treatment of various diseases, representing the largest sector after antibiotics in the global pharmaceutical market. The steroidal active pharmaceutical ingredients (APIs) have been produced via partial synthetic processes first mainly from sapogenins, which was converted into 16‐dehydropregnenolone by the famous “Marker Degradation”. Traditional mutation and screening, and process engineering have resulted in the industrial production of 4‐androstene‐3,17‐dione (AD), androst‐1,4‐diene‐3,17‐dione (ADD), 9α‐hydroxy‐androsta‐4‐ene‐3,17‐dione (9α‐OH‐AD), and so on, which serve as the key intermediates for the synthesis of steroidal APIs. Recently, genetic and metabolic engineering have generated highly efficient microbial strains for the production of these precursors, leading to the replacement of sapogenins with phytosterols as the starting materials. Further advances in synthetic biology hold promise in the design and construction of microbial cell factories for the industrial production of steroidal intermediates and/or APIs from simple carbon sources such as glucose. Integration of biotransformation into the synthesis of steroidal APIs can greatly reduce the number of reaction steps, achieve lower waste discharge and higher production efficiency, thus enabling a greener steroidal pharmaceutical industry.

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Enhancing production of 9α-hydroxy-androst-4-ene-3,17-dione (9-OHAD) from phytosterols by metabolic pathway engineering of mycobacteria

Cited by 15 publications

References 45 publications

Biotransformation of Phytosterols into Androstenedione—A Technological Prospecting Study

Biotransformation of Phytosterols into Androstenedione—A Technological Prospecting Study

Correlation Relationship between Phase Inversion of Pickering Emulsions and Biocatalytic Activity of Microbial Transformation of Phytosterols

Biotransformation Enables Innovations Toward Green Synthesis of Steroidal Pharmaceuticals

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