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Download This Article PDF Format Catalysis Science & Technology View Article Online MINI REVIEW View Journal | View Issue Novozym 435: the “perfect” lipase immobilized Cite this: Catal. Sci. Technol.,2019, biocatalyst? 9,2380 Claudia Ortiz,a María Luján Ferreira,b Oveimar Barbosa,c José C. S. dos Santos, d Rafael C. Rodrigues,e Ángel Berenguer-Murcia, f Laura E. Briand *g and Roberto Fernandez-Lafuente *h Novozym 435 (N435) is a commercially available immobilized lipase produced by Novozymes. It is based on immobilization via interfacial activation of lipase B from Candida antarctica on a resin, Lewatit VP OC 1600. This resin is a macroporous support formed by polyIJmethyl methacrylate) crosslinked with divinyl- benzene. N435 is perhaps the most widely used commercial biocatalyst in both academy and industry. Here, we review some of the success stories of N435 (in chemistry, energy and lipid manipulation), but we focus on some of the problems that the use of this biocatalyst may generate. Some of these problems are just based on the mechanism of immobilization (interfacial activation) that may facilitate enzyme desorp- Creative Commons Attribution-NonCommercial 3.0 Unported Licence. tion under certain conditions. Other problems are specific to the support: mechanical fragility, moderate Received 1st March 2019, hydrophilicity that permits the accumulation of hydrophilic compounds (e.g., water or glycerin) and the Accepted 12th April 2019 most critical one, support dissolution in some organic media. Finally, some solutions (N435 coating with silicone, enzyme physical or chemical crosslinking, and use of alternative supports) are proposed. However, DOI: 10.1039/c9cy00415g the N435 history, even with these problems, may continue in the coming future due to its very good prop- rsc.li/catalysis erties if some simpler alternative biocatalysts are not developed. of them. In this environment, the use of enzymes as indus- This article is licensed under a 1. Introduction – trial catalysts is rising.5 7 Enzymes have many properties that 1.1. Lipases in biocatalysis make them very interesting: they are the most efficient cata- Chemistry is being continuously (and vigorously) pushed to lysts in nature, performing their function under very mild Open Access Article. Published on 12 April 2019. Downloaded 9/30/2021 7:46:38 AM. become more environmentally friendly and compatible, there- conditions (at low pressure and temperature) in aqueous me- fore green chemistry is nowadays the final goal in most chem- dia. Moreover, they are very selective and specific, saving – – ical industry developments.1 4 This is coupled with an ever- many protection/deprotection steps.8 13 However, enzymes increasing demand for products with growing complexity, in are catalysts with a biological origin, and they have evolved many instances with multiple functions and chirality in many under natural selection to be able to respond under stress conditions. Thus, enzymes are inhibited by diverse compo- a Escuela de Microbiología, Universidad Industrial de Santander, Bucaramanga, nents, their stability is moderate even under physiological Colombia conditions and their excellent properties are only exhibited in b – Planta Piloto de Ingeniería Química PLAPIQUI, CONICET, Universidad physiological reactions and substrates.14 Besides, they are Nacional del Sur, Camino La Carrindanga km 7, 8000 Bahía Blanca, Argentina c usually water soluble. These properties, although physiologi- Departamento de Química, Facultad de Ciencias, Universidad del Tolima, Ibagué, 730006299, Colombia cally necessary, are a problem if they are going to be used as d Instituto de Engenharias e Desenvolvimento Sustentável, Universidade da industrial biocatalysts, where they are expected to perform Integração Internacional da Lusofonia Afro-Brasileira, CEP 62790-970, Redenção, their function under standardized conditions. In this respect, CE, Brazil maximal stability and activity will always be desired, and the e Biotechnology, Bioprocess, and Biocatalysis Group, Food Science and Technology substrates, as well as reaction conditions, may be quite far Institute, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, P. O. Box 15090, Porto Alegre, RS ZC 91501-970, Brazil from the physiological ones. f Instituto Universitario de Materiales, Departamento de Química Inorgánica, As a result, enzymes normally need to be improved in Universidad de Alicante, Ap. 99-03080, Alicante, Spain many instances before their industrial implementation. g Centro de Investigación y Desarrollo en Ciencias Aplicadas-Dr. Jorge J. Ronco, Thanks to the development of many different scientific areas, Universidad Nacional de La Plata, CONICET, CCT La Plata. Calle 47N 257, B1900AJK La Plata, Buenos Aires, Argentina. E-mail: [email protected] there are several ways of improving these enzyme limitations. 15–20 h Department of Biocatalysis, ICP-CSIC, Campus UAM-CSIC, Cantoblanco, Microbiological (metagenomics) and genetic (site-di- 21–23 24–28 Madrid, ZC 28049, Spain. E-mail: [email protected] rected mutagenesis, directed evolution, etc.) tools 2380 | Catal. Sci. Technol.,2019,9, 2380–2420 This journal is © The Royal Society of Chemistry 2019 View Article Online Catalysis Science & Technology Mini review may provide high enzyme production with improved proper- ties compared to the native enzyme. Immobilization was first a requirement to solve the issue of enzyme solubility, but it has recently become a powerful tool to improve many other enzyme properties like stability, activity, selectivity, specific- – ity, purity, inhibition, or resistance to chemicals.29 39 As such, enzyme immobilization has evolved from a require- ment to use these expensive catalysts to a tool to greatly en- hance enzyme features. Lipases are among the most widely used enzymes in bioca- talysis.40,41 The biological function of lipases is the hydrolysis of triglycerides to produce free fatty acids and glycerol.42 The – heterogeneity of the natural substrate43 48 has converted lipases in enzymes with a very broad specificity, accepting substrates very different from glycerides (even amides). Thus, lipases are used in vitro to catalyze reactions different from those of the – – natural hydrolase function,49 54 such as esterification,55 61 Fig. 1 Conformational equilibrium and interfacial activation of lipases. – – – acidolysis,62 67 interesterificaton,68 71 transesterification,72 76 – aminolysis,77 81 perhydrolysis,82,83 etc., together with a collec- – tion of the so-called promiscuous reactions.84 92 This catalytic mechanism may be a problem for lipase 116 Lipases are usually quite stable, and so they have been handling. Lipases are adsorbed on any hydrophobic sur- used in diverse media, like aqueous media, organic face. As an example, lipases tend to form dimeric aggregates 93–95 96–99 100–102 by interaction between two open forms of lipases (giving al- Creative Commons Attribution-NonCommercial 3.0 Unported Licence. solvents, ionic liquids, supercritical fluids, and – – 117 119 deep eutectic solvents.103 106 This way, lipases have a huge tered properties) (Fig. 2) or may interact with hydro- range of possibilities in industrial biocatalysis. Besides, they phobic proteins on the crude extract (also altering enzyme 120 have a peculiar mechanism of action called “interfacial acti- properties). This may also be a problem when vation”, which will be explained below. immobilizing a lipase on a solid support, as the lipase mole- 1.1.1. Interfacial activation of lipases: drawbacks and new cules will be isolated from the external medium and external opportunities. As previously stated, the natural substrates of drops of the hydrophobic substrate can hardly interact with – lipases are glycerides.49 54 These molecules have low solubility the enzyme, making their interfacial activation impossible. in water, therefore they form insoluble drops, where the li- However, once this phenomenon is known, it can be uti- This article is licensed under a pase must act. For this purpose, lipases have a peculiar mech- lized for some purposes. For example, properly oriented anism of action, called interfacial activation, which permits li- immobilized lipases have been used as a chromatography pases to become adsorbed on the hydrophobic surface of the matrix to purify other lipases via interaction between the 120,121 Open Access Article. Published on 12 April 2019. Downloaded 9/30/2021 7:46:38 AM. glyceride drops and act in the interface (this is why lipases open forms of two lipase molecules (Fig. 3). are called “interfacial enzymes”).107 This mechanism is based Moreover, as described later, this allowed development of on the existence of a large hydrophobic pocket surrounding one of the most utilized protocols for lipase immobilization: – the active center.108 115 An enzyme molecule with this large the immobilization of lipases on hydrophobic supports via 122 hydrophobic pocket will be very unstable and will have low interfacial activation. solubility in aqueous media. However, this problem is avoided because this hydrophobic pocket it is covered by a 1.2. Lipase B from Candida antarctica polypeptide chain called lid, which generally isolates the ac- CALB has a molecular weight of 33 kDa, with a pI of 6.0. “ ” tive center from the reaction medium (in this closed form, CALB is an α/β protein with many features similar to those of the lipase is inactive). The lid also has an internal hydropho- bic face that interacts with the hydrophobic areas of the active center and a hydrophilic external face,
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