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Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development

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A special issue of Catalysts (ISSN 2073-4344). This special issue belongs to the section "Biocatalysis".

Deadline for manuscript submissions: closed (28 February 2019) | Viewed by 63155

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Prof. Dr. Andres R. Alcantara

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Department of Chemistry in Pharmaceutical Sciences, Faculty of Pharmacy, Complutense University, Plaza De Ramon y Cajal, S/N University City, Madrid, Spain
Interests: enzymatic synthesis of drugs and bioactive compounds; sustainable processes; biocatalyst upgrading; pharmaceutical industry; organic chemistry; pharmaceutical chemistry
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Dear Colleagues,

In the last years, the advances in bioinformatics, enzyme evolution or process intensification have enlarged the effectiveness of biotransformations, accelerating the rate at which new enzymes are becoming available, even for promiscuous activities not previously known. Thus, now it is possible to join the exquisite enzymatic precision and inherent sustainability associated to the employ of biocatalysts with the possibility of generating new and more robust biocatalysts, expanding the biocatalytic toolbox, moving inside a time scale more compatible with the demands of pharmaceutical industry. For these reasons, it seems clear that we are entering in a new scenario, in which biocatalysis will play an even more significant role in such a competitive and demanding industry.

This Special Issue aims to gather contributions from research groups, rather original research or up-to-date revisions, to illustrate recent advances in this fascinating area. This includes, but is not restricted to, the discovery of new enzymatic activities, the chemical or genetic modification of known biocatalysts for further application in the development of new drugs, and the implementation of biocatalyzed protocols to increase the sustainability in the synthesis of drugs and bioactive molecules.

Prof. Andres R Alcantara
Guest Editor

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Keywords

Biocatalysis
Biotransformations
Drug synthesis
Sustainable Chemistry
Biocatalyst engineering

Published Papers (12 papers)

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Editorial

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8 pages, 223 KiB

Open AccessEditorial

Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development

by Andrés R. Alcántara

Catalysts 2019, 9(10), 792; https://doi.org/10.3390/catal9100792 - 23 Sep 2019

Cited by 22 | Viewed by 3605

Abstract

Biocatalysis is the term used to describe the application of any type of biocatalyst (enzymes, as isolated preparations of wild-type or genetically modified variants, or whole cells, either as native cells or as recombinant expressed proteins inside host cells) in a given synthetic [...] Read more.

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

Research

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12 pages, 1108 KiB

Open AccessArticle

Tailored Enzymatic Synthesis of Chitooligosaccharides with Different Deacetylation Degrees and Their Anti-Inflammatory Activity

by P. Santos-Moriano, P. Kidibule, N. Míguez, L. Fernández-Arrojo, A.O. Ballesteros, M. Fernández-Lobato and F.J. Plou

Catalysts 2019, 9(5), 405; https://doi.org/10.3390/catal9050405 - 30 Apr 2019

Cited by 30 | Viewed by 3749

Abstract

By controlled hydrolysis of chitosan or chitin with different enzymes, three types of chitooligosaccharides (COS) with MW between 0.2 and 1.2 kDa were obtained: fully deacetylated (fdCOS), partially acetylated (paCOS), and fully acetylated (faCOS). The chemical composition of the samples was analyzed by high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and MALDI-TOF mass spectrometry. The synthesized fdCOS was basically formed by GlcN, (GlcN)₂, (GlcN)₃, and (GlcN)₄. On the contrary, faCOS contained mostly GlcNAc, (GlcNAc)₂ and (GlcNAc)₃, while paCOS corresponded to a mixture of at least 11 oligosaccharides with different proportions of GlcNAc and GlcN. The anti-inflammatory activity of the three COS mixtures was studied by measuring their ability to reduce the level of TNF-α (tumor necrosis factor) in murine macrophages (RAW 264.7) after stimulation with a mixture of lipopolysaccharides (LPS). Only fdCOS and faCOS were able to significantly reduce the production of tumor necrosis factor (TNF)-α at 6 h after stimulation with lipopolysaccharides. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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12 pages, 875 KiB

Open AccessArticle

Synthesis of Ribavirin, Tecadenoson, and Cladribine by Enzymatic Transglycosylation

by Marco Rabuffetti, Teodora Bavaro, Riccardo Semproli, Giulia Cattaneo, Michela Massone, Carlo F. Morelli, Giovanna Speranza and Daniela Ubiali

Catalysts 2019, 9(4), 355; https://doi.org/10.3390/catal9040355 - 12 Apr 2019

Cited by 36 | Viewed by 6346

Abstract

Despite the impressive progress in nucleoside chemistry to date, the synthesis of nucleoside analogues is still a challenge. Chemoenzymatic synthesis has been proven to overcome most of the constraints of conventional nucleoside chemistry. A purine nucleoside phosphorylase from Aeromonas hydrophila (AhPNP) has been used herein to catalyze the synthesis of Ribavirin, Tecadenoson, and Cladribine, by a “one-pot, one-enzyme” transglycosylation, which is the transfer of the carbohydrate moiety from a nucleoside donor to a heterocyclic base. As the sugar donor, 7-methylguanosine iodide and its 2′-deoxy counterpart were synthesized and incubated either with the “purine-like” base or the modified purine of the three selected APIs. Good conversions (49–67%) were achieved in all cases under screening conditions. Following this synthetic scheme, 7-methylguanine arabinoside iodide was also prepared with the purpose to synthesize the antiviral Vidarabine by a novel approach. However, in this case, neither the phosphorolysis of the sugar donor, nor the transglycosylation reaction were observed. This study was enlarged to two other ribonucleosides structurally related to Ribavirin and Tecadenoson, namely, Acadesine, or AICAR, and 2-chloro-N⁶-cyclopentyladenosine, or CCPA. Only the formation of CCPA was observed (52%). This study paves the way for the development of a new synthesis of the target APIs at a preparative scale. Furthermore, the screening herein reported contributes to the collection of new data about the specific substrate requirements of AhPNP. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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11 pages, 1108 KiB

Open AccessArticle

A Photo-Enzymatic Cascade to Transform Racemic Alcohols into Enantiomerically Pure Amines

by Jenő Gacs, Wuyuan Zhang, Tanja Knaus, Francesco G. Mutti, Isabel W.C.E. Arends and Frank Hollmann

Catalysts 2019, 9(4), 305; https://doi.org/10.3390/catal9040305 - 27 Mar 2019

Cited by 19 | Viewed by 4498

Abstract

The consecutive photooxidation and reductive amination of various alcohols in a cascade reaction were realized by the combination of a photocatalyst and several enzymes. Whereas the photocatalyst (sodium anthraquinone-2-sulfonate) mediated the light-driven, aerobic oxidation of primary and secondary alcohols, the enzymes (various ω-transaminases) catalyzed the enantio-specific reductive amination of the intermediate aldehydes and ketones. The system worked in a one-pot one-step fashion, whereas the productivity was significantly improved by switching to a one-pot two-step procedure. A wide range of aliphatic and aromatic compounds was transformed into the enantiomerically pure corresponding amines via the photo-enzymatic cascade. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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15 pages, 3372 KiB

Open AccessArticle

Advantageous Preparation of Digested Proteic Extracts from Spirulina platensis Biomass

by Carlos M. Verdasco-Martín, Lea Echevarrieta and Cristina Otero

Catalysts 2019, 9(2), 145; https://doi.org/10.3390/catal9020145 - 02 Feb 2019

Cited by 12 | Viewed by 4258

Abstract

Spirulina biomass has great nutritional value, but its proteins are not as well adsorbed as animal ones are. New functional food ingredients and metabolites can be obtained from spirulina, using different selective biodegradations of its biomass. Four enzyme-assisted extraction methods were independently studied, and their best operation conditions were determined. Enzymes were employed to increase the yield of easily adsorbed proteic extracts. A biomass pre-treatment using Alcalase^® (pH 6.5, 1% v/w, and 30 °C) is described, which increased the extraction yield of hydrophilic biocomponents by 90% w/w compared to the simple solvent extraction. Alcalase^® gives rise to 2.5–6.1 times more amino acids than the others and eight differential short peptides (438–1493 Da). These processes were scaled up and the extracts were analyzed. Higher destruction of cell integrity in the case of Alcalase^® was also visualized by transmission electron microscopy. The described extractive technology uses cheap, commercial, food grade enzymes and hexane, accepted for food and drug safety. It is a promising process for a competitive biofactory, thanks to an efficient production of extracts with high applied potential in the nutrition, cosmetic, and pharmaceutical industries. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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11 pages, 1280 KiB

Open AccessArticle

Preparation of Sterically Demanding 2,2-Disubstituted-2-Hydroxy Acids by Enzymatic Hydrolysis

by Andrea Pinto, Immacolata Serra, Diego Romano, Martina Letizia Contente, Francesco Molinari, Fabio Rancati, Roberta Mazzucato and Laura Carzaniga

Catalysts 2019, 9(2), 113; https://doi.org/10.3390/catal9020113 - 24 Jan 2019

Cited by 1 | Viewed by 2858

Abstract

Preparation of optically-pure derivatives of 2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid of general structure 2 was accomplished by enzymatic hydrolysis of the correspondent esters. A screening with commercial hydrolases using the methyl ester of 2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid (1a) showed that crude pig liver esterase (PLE) was the only preparation with catalytic activity. Low enantioselectivity was observed with substrates 1a–d, whereas PLE-catalysed hydrolysis of 1e proceeded with good enantioselectivity (E = 28), after optimization. Enhancement of the enantioselectivity was obtained by chemical re-esterification of enantiomerically enriched 2e, followed by sequential enzymatic hydrolysis with PLE. The preparation of optically-pure (S)-2e was validated on multi-milligram scale. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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12 pages, 2745 KiB

Open AccessArticle

Development of Biotransamination Reactions towards the 3,4-Dihydro-2H-1,5-benzoxathiepin-3-amine Enantiomers

by Daniel González-Martínez, Nerea Fernández-Sáez, Carlos Cativiela, Joaquín M. Campos and Vicente Gotor-Fernández

Catalysts 2018, 8(10), 470; https://doi.org/10.3390/catal8100470 - 19 Oct 2018

Cited by 5 | Viewed by 3146

Abstract

The stereoselective synthesis of chiral amines is an appealing task nowadays. In this context, biocatalysis plays a crucial role due to the straightforward conversion of prochiral and racemic ketones into enantiopure amines by means of a series of enzyme classes such as amine dehydrogenases, imine reductases, reductive aminases and amine transaminases. In particular, the stereoselective synthesis of 1,5-benzoxathiepin-3-amines have attracted particular attention since they possess remarkable biological profiles; however, their access through biocatalytic methods is unexplored. Amine transaminases are applied herein in the biotransamination of 3,4-dihydro-2H-1,5-benzoxathiepin-3-one, finding suitable enzymes for accessing both target amine enantiomers in high conversion and enantiomeric excess values. Biotransamination experiments have been analysed, trying to optimise the reaction conditions in terms of enzyme loading, temperature and reaction times. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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9 pages, 1262 KiB

Open AccessArticle

OcUGT1-Catalyzed Glucosylation of Sulfuretin Yields Ten Glucosides

by Shuai Yuan, Yan-Li Xu, Yan Yang and Jian-Qiang Kong

Catalysts 2018, 8(10), 416; https://doi.org/10.3390/catal8100416 - 25 Sep 2018

Cited by 5 | Viewed by 2712

Abstract

Sulfuretin glucosides are important sources of innovative drugs. However, few glucosides of sulfuretin have been observed in nature. Therefore, it is urgent to diversify sulfuretin glycosides. Herein, glycosyltransferase (GT)-catalyzed glycodiversification of sulfuretin was achieved. Specifically, a flavonoid GT designated as OcUGT1 was used as a biocatalyst for the glucosylation of sulfuretin with UDP-Glc. The OcUGT1-assisted glucosylation of sulfuretin yielded ten glycosylated products, including three monoglucosides, five diglucosides and two triglucosides. The three monoglucosides were thus identified to be sulfuretin 3′-, 4′- and 6-glucoside according to HR-ESI-TOFMS data and their coelution with respective standards. A major diglucoside was assigned as sulfuretin 4′,6-diglucoside by HR-ESI-TOFMS in conjunction with NMR analysis. The exact structure of the other four diglucosides was not well characterized due to their trace amount. However, they were reasonably inferred as sulfuretin 3′,6-diglucoside, sulfuretin 3′,4′-diglucoside and two disaccharide glucosides. In addition, the structural identification of the remaining two triglucosides was not performed because of their small amount. However, one of the triglucosides was deduced to be sulfuretin 3′,4′,6-triglucoside based on the catalytic behavior of OcUGT1. Of the ten sulfuretin glucosides, at least six were new compounds. This is the first time to obtain monoglucosides, diglucosides and triglucosides of sulfuretin simultaneously by a single glycosyltransferase. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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15 pages, 1552 KiB

Open AccessArticle

Laccase Activity as an Essential Factor in the Oligomerization of Rutin

by Abel Muñiz-Mouro, Beatriz Gullón, Thelmo A. Lú-Chau, María Teresa Moreira, Juan M. Lema and Gemma Eibes

Catalysts 2018, 8(8), 321; https://doi.org/10.3390/catal8080321 - 06 Aug 2018

Cited by 14 | Viewed by 3986

Abstract

The enzyme-mediated polymerization of bioactive phenolic compounds, such as the flavonoid rutin, has gained interest due to the enhanced physico-chemical and biological properties of the products, which increases their potential application as a nutraceutical. In this work, the influence of enzyme activity on rutin oligomerization was evaluated in reactions with low (1000 U/L) and high (10,000 U/L) initial laccase activities. For both reactions, high molecular weight oligomer fractions showed better properties compared to lower weight oligomers. Products of the reaction with low laccase activity exhibited thermal stability and antioxidant potential similar to control reaction, but led to higher inhibitory activity of xanthine oxidase and apparent aqueous solubility. Oligomers obtained in the reaction with high laccase activity showed better apparent aqueous solubility but decreased biological activities and stability. Their low antioxidant activity was correlated with a decreased phenolic content, which could be attributed to the formation of several bonds between rutin molecules. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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Review

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19 pages, 5085 KiB

Open AccessFeature PaperReview

Chondroitin Sulfate-Degrading Enzymes as Tools for the Development of New Pharmaceuticals

by Raúl Benito-Arenas, Sandra G. Zárate, Julia Revuelta and Agatha Bastida

Catalysts 2019, 9(4), 322; https://doi.org/10.3390/catal9040322 - 01 Apr 2019

Cited by 19 | Viewed by 5203

Abstract

Chondroitin sulfates are linear anionic sulfated polysaccharides found in biological tissues, mainly within the extracellular matrix, which are degraded and altered by specific lyases depending on specific time points. These polysaccharides have recently acquired relevance in the pharmaceutical industry due to their interesting therapeutic applications. As a consequence, chondroitin sulfate (CS) lyases have been widely investigated as tools for the development of new pharmaceuticals based on these polysaccharides. This review focuses on the major breakthrough represented by chondroitin sulfate-degrading enzymes and their structures and mechanisms of function in addition to their major applications. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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32 pages, 2719 KiB

Open AccessReview

Biocatalyzed Synthesis of Statins: A Sustainable Strategy for the Preparation of Valuable Drugs

by Pilar Hoyos, Vittorio Pace and Andrés R. Alcántara

Catalysts 2019, 9(3), 260; https://doi.org/10.3390/catal9030260 - 14 Mar 2019

Cited by 35 | Viewed by 14922

Abstract

Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are the largest selling class of drugs prescribed for the pharmacological treatment of hypercholesterolemia and dyslipidaemia. Statins also possess other therapeutic effects, called pleiotropic, because the blockade of the conversion of HMG-CoA to (R)-mevalonate produces a concomitant inhibition of the biosynthesis of numerous isoprenoid metabolites (e.g., geranylgeranyl pyrophosphate (GGPP) or farnesyl pyrophosphate (FPP)). Thus, the prenylation of several cell signalling proteins (small GTPase family members: Ras, Rac, and Rho) is hampered, so that these molecular switches, controlling multiple pathways and cell functions (maintenance of cell shape, motility, factor secretion, differentiation, and proliferation) are regulated, leading to beneficial effects in cardiovascular health, regulation of the immune system, anti-inflammatory and immunosuppressive properties, prevention and treatment of sepsis, treatment of autoimmune diseases, osteoporosis, kidney and neurological disorders, or even in cancer therapy. Thus, there is a growing interest in developing more sustainable protocols for preparation of statins, and the introduction of biocatalyzed steps into the synthetic pathways is highly advantageous—synthetic routes are conducted under mild reaction conditions, at ambient temperature, and can use water as a reaction medium in many cases. Furthermore, their high selectivity avoids the need for functional group activation and protection/deprotection steps usually required in traditional organic synthesis. Therefore, biocatalysis provides shorter processes, produces less waste, and reduces manufacturing costs and environmental impact. In this review, we will comment on the pleiotropic effects of statins and will illustrate some biotransformations nowadays implemented for statin synthesis. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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10 pages, 1161 KiB

Open AccessReview

Microbial Reduction of Cholesterol to Coprostanol: An Old Concept and New Insights

by Aicha Kriaa, Mélanie Bourgin, Héla Mkaouar, Amin Jablaoui, Nizar Akermi, Souha Soussou, Emmanuelle Maguin and Moez Rhimi

Catalysts 2019, 9(2), 167; https://doi.org/10.3390/catal9020167 - 08 Feb 2019

Cited by 27 | Viewed by 6888

Abstract

The gut microbiota plays a key role in cholesterol metabolism, mainly through the reduction of cholesterol to coprostanol. The latter sterol exhibits distinct physicochemical properties linked to its limited absorption in the gut. Few bacteria were reported to reduce cholesterol into coprostanol. Three microbial pathways of coprostanol production were described based on the analysis of reaction intermediates. However, these metabolic pathways and their associated genes remain poorly studied. In this review, we shed light on the microbial metabolic pathways related to coprostanol synthesis. Moreover, we highlight current strategies and future directions to better characterize these microbial enzymes and pathways. Full article

(This article belongs to the Special Issue Biocatalysis and Pharmaceuticals: A Smart Tool for Sustainable Development)

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