Microbial Steroid Production Technologies: Current Trends and Prospects

Donova, Marina V.

doi:10.3390/microorganisms10010053

Cited by 24 publications

(21 citation statements)

References 30 publications

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“…The hydroxylation of C7, C11, C14 has great significance in the pharmaceutical industry (Chen et al 2019 ; Milecka-Tronina et al 2014 ; Schiffer et al 2015 ). To extend the steroidal bioconversion pathway, exploration and screening of hydroxylase with higher activity and selectivity towards more active steroids and their functional expression in Mycobacterium is regarded as novel direction for the rational development of mycobacteria cells in the future (Donova 2021 ). Therefore, it is of great significance that we carry out more research on steroid oxidation by CYP enzymes, which will help to expand the application of cholesterol derivatives.…”

Section: Significance Of Monooxygenase Resources For Steroid Modifica...mentioning

confidence: 99%

Rational development of mycobacteria cell factory for advancing the steroid biomanufacturing

Wang

Liu

et al. 2022

World J Microbiol Biotechnol

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Steroidal resource occupies a vital proportion in the pharmaceutical industry attributing to their important therapeutic effects on fertility, anti-inflammatory and antiviral activities. Currently, microbial transformation from phytosterol has become the dominant strategy of steroidal drug intermediate synthesis that bypasses the traditional chemical route. Mycobacterium sp. serve as the main industrial microbial strains that are capable of introducing selective functional modifications of steroidal intermediate, which has become an indispensable platform for steroid biomanufacturing. By reviewing the progress in past two decades, the present paper concentrates mainly on the microbial rational modification aspects that include metabolic pathway editing, key enzymes engineering, material transport pathway reinforcement, toxic metabolic intermediates removal and byproduct reconciliation. In addition, progress on omics analysis and direct genetic manipulation are summarized and classified that may help reform the industrial hosts with more efficiency. The paper provides an insightful present for steroid biomanufacturing especially on the current trends and prospects of mycobacteria.

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Section: Significance Of Monooxygenase Resources For Steroid Modifica...mentioning

confidence: 99%

Rational development of mycobacteria cell factory for advancing the steroid biomanufacturing

Wang

Liu

et al. 2022

World J Microbiol Biotechnol

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“…One of the most attractive and efficient strategies for producing steroid precursors useful for the synthesis of steroid pharmaceutical drugs is to utilize mycobacterial strains to transform naturals sterols into useful intermediates or synthons as building blocks (Fernández-Cabezón et al ., 2018; Donova, 2021; Nunes et al ., 2022). Currently, three main C19 synthons are produced at industrial scale by different mycobacterial strains, i.e., 4-androstene-3,17-dione (AD), 1,4-androstadiene-3,17-dione (ADD) and 9α- hydroxy-4-androstenedione (9OH-AD) using phytosterols as natural precursors.…”

Section: Introductionmentioning

confidence: 99%

Identification of the aldolase responsible for the production of 22-hydroxy-23,24-bisnorchol-4-ene-3-one from natural sterols inMycolicibacterium smegmatis

Hernández‐Fernández

Acedos

García

et al. 2023

Preprint

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The production of 4-androstene-3,17-dione (AD) from natural sterols has been improved by deleting the MSMEG_6561 gene ofMycolicibacterium smegmatiswhich encodes an aldolase. The deletion of this gene increases the AD production yield avoiding the production of 22-hydroxy-23,24-bisnorchol-4-ene-3-one (4-HBC) as by-product and the drawbacks in the AD purification. TheMSMEG_6561gene encodes the only enzyme within theM. smegmatisgenome responsible for the aldolytic activity transforming 22-hydroxy-3-oxo-cholest-4-ene-24-carboxyl-CoA (22-OH-BCN-CoA) into the 4-HBC precursor (20S)-3-oxopregn-4-ene-20-carboxaldehyde (3-OPA). The molar yield of AD production using the MS6039-5941-6561 triple mutant strain was checked in flasks and bioreactor improving very significantly compared with the previously described MS6039-5941 strain.

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“…However, the production of steroidal C7β alcohols is still a challenge due to the lack of cheap 7β -hydroxy precursor. For most of the common steroidal molecules, C7 is usually not an active site and thus the hydroxylation at C7β in a regio- and stereo-selective way is not easily accessible in the industry [ 6 , 7 ]. Therefore, it is necessary to develop a feasible way to produce commodifiable and universal 7β-hydroxylated synthons for the synthesis of 7β-OHSt.…”

Section: Introductionmentioning

confidence: 99%

One-pot biosynthesis of 7β-hydroxyandrost-4-ene-3,17-dione from phytosterols by cofactor regeneration system in engineered mycolicibacterium neoaurum

Zhao

Liu

et al. 2022

Microb Cell Fact

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Background 7β-hydroxylated steroids (7β-OHSt) possess significant activities in anti-inflammatory and neuroprotection, and some of them have been widely used in clinics. However, the production of 7β-OHSt is still a challenge due to the lack of cheap 7β-hydroxy precursor and the difficulty in regio- and stereo-selectively hydroxylation at the inert C7 site of steroids in industry. The conversion of phytosterols by Mycolicibacterium species to the commercial precursor, androst-4-ene-3,17-dione (AD), is one of the basic ways to produce different steroids. This study presents a way to produce a basic 7β-hydroxy precursor, 7β-hydroxyandrost-4-ene-3,17-dione (7β-OH-AD) in Mycolicibacterium, for 7β-OHSt synthesis. Results A mutant of P450-BM3, mP450-BM3, was mutated and engineered into an AD producing strain for the efficient production of 7β-OH-AD. The enzyme activity of mP450-BM3 was then increased by 1.38 times through protein engineering and the yield of 7β-OH-AD was increased from 34.24 mg L− 1 to 66.25 mg L− 1. To further enhance the performance of 7β-OH-AD producing strain, the regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) for the activity of mP450-BM3-0 was optimized by introducing an NAD kinase (NADK) and a glucose-6-phosphate dehydrogenase (G6PDH). Finally, the engineered strain could produce 164.52 mg L− 1 7β-OH-AD in the cofactor recycling and regeneration system. Conclusions This was the first report on the one-pot biosynthesis of 7β-OH-AD from the conversion of cheap phytosterols by an engineered microorganism, and the yield was significantly increased through the mutation of mP450-BM3 combined with overexpression of NADK and G6PDH. The present strategy may be developed as a basic industrial pathway for the commercial production of high value products from cheap raw materials.

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Microbial Steroid Production Technologies: Current Trends and Prospects

Abstract: This Special Issue aims to collect articles and reviews on new methodologies, research, and achievements in the field of steroid microbial biotechnologies [...]

Cited by 24 publications

References 30 publications

Rational development of mycobacteria cell factory for advancing the steroid biomanufacturing

Rational development of mycobacteria cell factory for advancing the steroid biomanufacturing

Identification of the aldolase responsible for the production of 22-hydroxy-23,24-bisnorchol-4-ene-3-one from natural sterols inMycolicibacterium smegmatis

One-pot biosynthesis of 7β-hydroxyandrost-4-ene-3,17-dione from phytosterols by cofactor regeneration system in engineered mycolicibacterium neoaurum

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