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15 pages, 1563 KB

Open AccessArticle

DERA-Catalyzed Chemoenzymatic Access to Nucleobase-Substituted Candidate Statin Precursors

by Romina Fernández Varela, Eman Abdelraheem, Lautaro Giaimo, Luciano Cortés, Leticia Lafuente, Ana Laura Valino, Peter-Leon Hagedoorn, Ulf Hanefeld, Adolfo Iribarren and Elizabeth Lewkowicz

Biomolecules 2026, 16(2), 321; https://doi.org/10.3390/biom16020321 - 19 Feb 2026

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Abstract

Aldolases are powerful biocatalysts for the stereoselective formation of carbon–carbon bonds and are widely used in the synthesis of chiral intermediates for pharmaceutical applications. Among them, 2-deoxyribose-5-phosphate aldolase (DERA) has been extensively exploited for the preparation of the conserved side chain of statins. In this work, we report a novel chemoenzymatic approach for the synthesis of nucleobase-substituted lactol products as potential precursors of new statin analogues. A C49M variant of DERA from Pectobacterium atrosepticum (PaDERA C49M) was employed to catalyze sequential aldol additions using aldehyde-functionalized nucleobases as non-natural electrophilic substrates. The formation of nucleobase-containing lactols was confirmed, demonstrating for the first time the acceptance of nucleobase-derived aldehydes in DERA-catalyzed aldol reactions. This strategy provides access to structurally novel statin side-chain precursors and expands the synthetic potential of DERA toward the generation of new classes of bioactive compounds. Full article

(This article belongs to the Special Issue Recent Advances in the Enzymatic Synthesis of Bioactive Compounds)

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12 pages, 1547 KB

Open AccessArticle

Rational Designing and Stepwise Cascade for Efficient Biosynthesis of Raspberry Ketone

by Yang Yang, Kangkang Shang, Xiaorui Gao, Xingmiao Zhu, Mengying Ling, Pu Zheng, Shichao Xu and Pengcheng Chen

Catalysts 2025, 15(12), 1148; https://doi.org/10.3390/catal15121148 - 5 Dec 2025

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Abstract

Raspberry ketone (RK) is the primary aromatic compound in raspberry fruit, which is widely utilized in perfume, cosmetics, and food additive industries. Currently, RK is predominantly produced chemically. RK biosynthesis through enzyme or whole cell has garnered significant attention due to the mild reaction conditions and the process being regarded as ‘natural’. This study proposed a ‘dual-microorganism, two-phase’ stepwise cascade strategy to produce RK from an economical precursor, 4-hydroxybenzaldehyde (4-HBD). An acetone-tolerant deoxyribose-phosphate aldolase DERA_Ec (S238D) mutant was obtained through a site-specific rigidification strategy for converting 4-HBD to 4-hydroxybenzylaceton (4-HBA). Then, an engineered E. coli co-expressing isocitrate dehydrogenase and raspberry ketone synthase RiRZS1 with a citrate-sodium citrate buffer to recycle nicotinamide adenine dinucleotide phosphate (NADPH) was constructed for the conversion of 4-HBA to RK. The final concentration of RK was 50.00 ± 1.92 mmol·L⁻¹ with a yield of 86.96%. This strategy provides a scalable coenzyme self-recycling and two-phase catalysis platform for high-value phenolic compounds. Full article

(This article belongs to the Section Biocatalysis)

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13 pages, 6424 KB

Open AccessArticle

Mesocellular Silica Foam as Immobilization Carrier for Production of Statin Precursors

by Dino Skendrović, Mateja Primožič, Tonči Rezić and Ana Vrsalović Presečki

Int. J. Mol. Sci. 2024, 25(4), 1971; https://doi.org/10.3390/ijms25041971 - 6 Feb 2024

Cited by 5 | Viewed by 2786

Abstract

The employment of 2-deoxyribose-5-phosphate aldolase (DERA) stands as a prevalent biocatalytic route for synthesizing statin side chains. The main problem with this pathway is the low stability of the enzyme. In this study, mesocellular silica foam (MCF) with different pore sizes was used as a carrier for the covalent immobilization of DERA. Different functionalizing and activating agents were tested and kinetic modeling was subsequently performed. The use of succinic anhydride as an activating agent resulted in an enzyme hyperactivation of approx. 140%, and the stability almost doubled compared to that of the free enzyme. It was also shown that the pore size of MCF has a decisive influence on the stability of the DERA enzyme. Full article

(This article belongs to the Special Issue Design, Synthesis, and Modification of Efficient Catalyst Materials)

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12 pages, 1843 KB

Open AccessArticle

In Vitro One-Pot 3-Hydroxypropanal Production from Cheap C1 and C2 Compounds

by Su-Bin Ju, Min-Ju Seo and Soo-Jin Yeom

Int. J. Mol. Sci. 2022, 23(7), 3990; https://doi.org/10.3390/ijms23073990 - 3 Apr 2022

Cited by 8 | Viewed by 4345

Abstract

One- or two-carbon (C1 or C2) compounds have been considered attractive substrates because they are inexpensive and abundant. Methanol and ethanol are representative C1 and C2 compounds, which can be used as bio-renewable platform feedstocks for the biotechnological production of value-added natural chemicals. Methanol-derived formaldehyde and ethanol-derived acetaldehyde can be converted to 3-hydroxypropanal (3-HPA) via aldol condensation. 3-HPA is used in food preservation and as a precursor for 3-hydroxypropionic acid and 1,3-propanediol that are starting materials for manufacturing biocompatible plastic and polytrimethylene terephthalate. In this study, 3-HPA was biosynthesized from formaldehyde and acetaldehyde using deoxyribose-5-phosphate aldolase from Thermotoga maritima (DERA_Tma) and cloned and expressed in Escherichia coli for 3-HPA production. Under optimum conditions, DERA_Tma produced 7 mM 3-HPA from 25 mM substrate (formaldehyde and acetaldehyde) for 60 min with 520 mg/L/h productivity. To demonstrate the one-pot 3-HPA production from methanol and ethanol, we used methanol dehydrogenase from Lysinibacillus xylanilyticus (MDH_Lx) and DERA_Tma. One-pot 3-HPA production via aldol condensation of formaldehyde and acetaldehyde from methanol and ethanol, respectively, was investigated under optimized reaction conditions. This is the first report on 3-HPA production from inexpensive alcohol substrates (methanol and ethanol) by cascade reaction using DERA_Tma and MDH_Lx. Full article

(This article belongs to the Special Issue Biocatalysis, a Life Companion for Green Chemistry: Biomolecular Aspects of Bioprocesses 2.0)

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10 pages, 1504 KB

Open AccessFeature PaperArticle

Discovery and Engineering of an Aldehyde Tolerant 2-deoxy-D-ribose 5-phosphate Aldolase (DERA) from Pectobacterium atrosepticum

by Meera Haridas, Carolin Bisterfeld, Le Min Chen, Stefan R. Marsden, Fabio Tonin, Rosario Médici, Adolfo Iribarren, Elizabeth Lewkowicz, Peter-Leon Hagedoorn, Ulf Hanefeld and Eman Abdelraheem

Catalysts 2020, 10(8), 883; https://doi.org/10.3390/catal10080883 - 5 Aug 2020

Cited by 9 | Viewed by 5888

Abstract

DERA (2-Deoxy-D-ribose 5-phosphate aldolase) is the only known aldolase that accepts two aldehyde substrates, which makes it an attractive catalyst for the synthesis of a chiral polyol motif that is present in several pharmaceuticals, such as atorvastatin and pravastatin. However, inactivation of the enzyme in the presence of aldehydes hinders its practical application. Whole cells of Pectobacterium atrosepticum were reported to exhibit good tolerance toward acetaldehyde and to afford 2-deoxyribose 5-phosphate with good yields. The DERA gene (PaDERA) was identified, and both the wild-type and a C49M mutant were heterologously expressed in Escherichia coli. The purification protocol was optimized and an initial biochemical characterization was conducted. Unlike other DERAs, which show a maximal activity between pH 4.0 and 7.5, PaDERA presented an optimum pH in the alkaline range between 8.0 and 9.0. This could warrant its use for specific syntheses in the future. PaDERA also displayed fourfold higher specific activity than DERA from E. coli (EcDERA) and displayed a promising acetaldehyde resistance outside the whole-cell environment. The C49M mutation, which was previously identified to increase acetaldehyde tolerance in EcDERA, also led to significant improvements in the acetaldehyde tolerance of PaDERA. Full article

(This article belongs to the Special Issue Biocatalysis and Whole-Cell Biotransformation in Biomanufacturing)

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15 pages, 4897 KB

Open AccessArticle

DERA in Flow: Synthesis of a Statin Side Chain Precursor in Continuous Flow Employing Deoxyribose-5-Phosphate Aldolase Immobilized in Alginate-Luffa Matrix

by Bianca Grabner, Yekaterina Pokhilchuk and Heidrun Gruber-Woelfler

Catalysts 2020, 10(1), 137; https://doi.org/10.3390/catal10010137 - 18 Jan 2020

Cited by 17 | Viewed by 6498

Abstract

Statins, cholesterol-lowering drugs used for the treatment of coronary artery disease (CAD), are among the top 10 prescribed drugs worldwide. However, the synthesis of their characteristic side chain containing two chiral hydroxyl groups can be challenging. The application of deoxyribose-5-phosphate aldolase (DERA) is currently one of the most promising routes for the synthesis of this side chain. Herein, we describe the development of a continuous flow process for the biosynthesis of a side chain precursor. Design of experiments (DoE) was used to optimize the reaction conditions (pH value and temperature) in batch. A pH of 7.5 and a temperature of 32.5 °C were identified to be the optimal process settings within the reaction space considered. Additionally, an immobilization method was developed using the alginate-luffa matrix (ALM), which is a fast, simple, and inexpensive method for enzyme immobilization. Furthermore, it is non-toxic, biodegradable, and from renewable resources. The final continuous process was operated stable for 4 h and can produce up to 4.5 g of product per day. Full article

(This article belongs to the Special Issue Biocatalytic Process Optimization)

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