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Introduction to Pharmaceutical Biotechnology, Volume 2 (Second Edition)
particularly suitable for application in specialized domains such as bio-stoning and
fading of denim fabric (often found in blue jeans) and laundry detergents [78].
Current endeavors are being made to acquire cellulase-generating mutants and/or
recombinants that exhibit enhanced efficiency. To achieve these objectives, the
United States Department of Energy (DOE) has provided money to two prominent
manufacturers specializing in enzymes. In the year 2000, Genencor International
received a grant of USD 17.1 million from the National Renewable Energy
Laboratory, located in Golden, Colorado, and operated by the DOE. The purpose
of this funding was to support Genesco International’s efforts in developing costeffective cellulases and other enzymes that can be utilized to synthesize ethanol from
biomass [79]. The aim of this study is to investigate and create enzyme systems that
have the potential to signifi cantly improve the cost-effectiveness of decomposing
cellulosic material and other complex carbohydrates into fermentable sugars, with a
target enhancement of tenfold. The DOE has provided money for USD 14.8 million
to Novozymes Inc. over three years from 2001 to 2003. This financial support was
allocated to facilitate the development of cellulase enzymes that are more economically viable for manufacturing bioethanol. Currently, the expenditure associated
with the enzyme totals USD 0.50 for every gallon of ethanol generated [80].
3.12.2.2 Production
Multiple businesses industrially manufacture cellulases using SmF methodology. The
selection of production technology is contingent upon the intended application of the
cellulase preparation [81]. In specific applications within the textile industry, pulp and
paper industry, and specific sectors of the food business, there is a requirement for
cellulases that have been partially or extensively purified or particular components of
the cellulase enzyme complex. A crude enzyme complex comprising cellulases, hemicelluloses, and pectinases may be deemed appropriate for agro-biotechnological
purposes. Ongoing endeavors are being made to decrease production costs due to
the comparatively elevated expenses associated with cellulases. The existing hypercellulolytic fungal mutants utilized for cellulase production through SmF exhibit much
lower yields than antibiotics or other high-quality biochemical compounds [82]. The
exorbitant cost associated with commercial cellulases poses a significant barrier for the
majority of agrobiotechnology applications, hence rendering them commercially
unviable. The potential reduction in application costs can be achieved by implementing
on-site or in situ production methods. The aforementioned techniques encompass the
inclusion of substrate residue in the enzymatic production process, wherein it is utilized
in the synthesis of end products like feed additives or the saccharification of pretreated
lignocellulose for the purpose of bio-alcohol production. [83].
3.13 The role of enzymes in the synthesis of functional foods
Considerable investigation has examined the utilization of enzymes in bioprocessing
to produce components and functional foods. The phenomenon can be principally
ascribed to the enzymes’ capacity to augment the occurrence of bioactive chemicals
in food, promote solubility and stability, and mitigate specific unfavorable
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Introduction to Pharmaceutical Biotechnology, Volume 2 (Second Edition)
Figure 3.8. Biotechnological production pipeline: from culture initiation to fermentation and final product
formulation.
nutritional characteristics in food items [84]. Using commercial enzymes from
various sources, scientists have created procedures for microbial fermentation and
enzymatic breakdown or conversion to create functional foods. A fermentation
pipeline was described in figure 3.8. These functional foods provide one or more
beneficial benefits to one’s health. Enzymes, including the peptidases tannases,
lipases, L-asparaginase, carbohydrate modifying enzymes, and phytases, are vital
components in producing functional meals [85].
3.13.1 Lipases
Hydrolases, of which lipases are members, catalyze the hydrolysis of triacylglycerols
(TAGs) into glycerol and fatty acids (FAs). Lipases are a class of enzyme catalysts
that play crucial roles in the biochemical process of lipid metabolism [86].
Triacylglycerol (TAG) hydrolases are a class of enzymes that can catalyze the
hydrolysis of triacylglycerol molecules. Biocatalysts, like enzymes, have been used
increasingly in the last few decades to help make esters, polyunsaturated fatty acids
(PUFAs), and long-chain FAs. In these processes, enzymes are used more often
because they can be used in many ways. The functional classification of meals
formulated from lipases is attributed to the diverse qualities of oils and fats because
of their enzymatic action. The sources of this enzyme exhibit significant variability,
encompassing a wide range of species such as plants, animals, fungi, and bacteria
[87]. Microbial-derived lipases are favored due to their cost-effectiveness in procurement, genetic manipulability, straightforward isolation and production processes,
and various biochemical functionalities. In contrast, previous studies have demonstrated that enzymes produced from plants and animals have comparatively lower
stability when compared to their counterparts. This proposal introduces a possible
replacement approach and has been utilized for the production of enzymes using
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biologic procedures that are financially and energy viable [88]. Nevertheless, a
significant hurdle that persists is the disparity in the number and quality of molecules
that can be extracted compared to alternative technologies. Lipases are frequently
employed in food processing to enhance and formulate various dairy products and
derivatives, including cheeses. They are also utilized in bakery products, the
processing of fats and oils to produce modified acylglycerols, and in the fruit juice
business. Lipase is employed in the dairy industry to alter the lengths of FA chains,
augmenting the flavor of cheeses by the hydrolysis of milk fat. Furthermore, this
technique can be utilized to expedite the aging process of cheese and impart distinct
flavors primarily to varieties of soft cheeses. The functional characteristics of lipases
have contributed to their widespread use in various industrial applications, particularly in the food industry, as well as in the creation of pharmaceuticals and
cosmetics, among other commercial products. The multifunctionality and potential
applications of these enzymes constitute compelling reasons to advance further
cutting-edge technologies that facilitate the generation and utilization of lipases as a
valuable resource for ingredient sourcing and the development of functional food
products [89].
3.13.2 Proteases
Proteases are a diverse group of enzymes that are capable of the ability to catalyze
the hydrolysis of bonds made up of peptides. The categorization of enzymes is
contingent upon several variables, encompassing the characteristics and chemical
qualities of the active site, the specific process in which the molecule functions as a
catalyst, and the development of a protease shape along with its associated
relationships [90]. An alternative and captivating classification may be derived by
analyzing the active site of the molecule, resulting in the categorization of several
types, such as cysteine, serine, aspartic, asparagine peptide lyases, threonine,
glutamic, and metalloproteases. Proteases can be derived from several sources,
including plants, animals, and microbes, and exhibit considerable potential in
functional food manufacturing. Proteases have been employed in food to facilitate
protein modification, enhance flavor profiles, extend the shelf life of protein sources,
optimize digestibility, and reduce allergenic potential [91]. Protease is employed in
several food production processes, such as manufacturing cheese, bread goods,
hydrolyzed soybeans, and meat tenderization. The generation of proteases by
microbes and their application in the food industry have been extensively studied.
One instance that exemplifies this phenomenon is the Flavoenzyme enzyme, which is
synthesized by specifically chosen strains of Aspergillus oryzae. The utilization of this
enzyme, in conjunction with Protamex, serves the purpose of transforming meat byproducts into a broth imbued with flesh-like flavor [92]. This broth is subsequently
incorporated into meat processing procedures, diminishing the salt required in the
ultimate products. Neutrase is employed in the context of drinks to ensure consistent
yeast proliferation, leading to enhanced beer performance and quality. However, it
is crucial to do a safety evaluation of the generating strain when considering
enzymes derived from microbes. In addition to meeting safety requirements for
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Introduction to Pharmaceutical Biotechnology, Volume 2 (Second Edition)
consumer health, the microbe resulting from the enzyme must be the intended
product. The Joint FAO/WHO Experts Committee on Food Additives (JECFA) is
recognized as one of the entities within the regulatory framework that offers
certification. Certain plant-derived enzymes, such as papain, have acquired significant commercial significance due to their exceptional performance under diverse
operational circumstances. Furthermore, these enzymes have demonstrated noteworthy proteolytic activity against various protein substrates [93]. One illustration of
this phenomenon is the utilization of papain as a substitute in the process of cheese
production since it has demonstrated efficacy in developing semisoft and creamy
cheese varieties. Nevertheless, it is crucial to consider that the coagulation rate of
this enzyme exhibits variability when employed with various milk variants [94].
3.13.3 Carbohydrate-modifying enzyme
Carbohydrates refer to a class of enzymes that play a crucial role in catalyzing the
breakdown of carbohydrates. Enzymes, including amylases, indulines, galactosidases, glucosidases, pectinases, glucosyltransferases, and fructosyltransferases, play
a significant role in the food industry by producing advantageous biological
substances that contribute to the development or enhancement of functional foods
[95]. Extensive research has been conducted on lactic acid bacteria due to its
advantageous characteristics in promoting human health. One illustrative instance is
the b-galactosidase enzyme, which is notable for its utilization in the dairy sector due
to its ability to enhance the breakdown of lactose, thereby ameliorating the
manifestations seen by lactose-intolerant individuals. The utilization of b-galactosidase has been employed in the manufacturing and retrieval of galacto-oligosaccharides (GOSs). The intake of GOS has been associated with immunomodulatory
effects because of its direct interaction with immune cells, enhancing the abundance
of beneficial bacteria. The utilization of microorganisms as a source for enzymes
with carbohydrate activity offers a cost-effective alternative and a more sustainable
technique from an environmental standpoint [96]. The utilization of Lactobacillus
paracasei BGP1 in the fermentation process of GOS derived from diverse plant
species has demonstrated promise as a viable substitute for generating valuable
prebiotic components in the formulation of functional food products. An illustration
of functional foods can be observed in developing beverage prototypes forti fi ed with
GOS and possessing antibacterial qualities. These prototypes are created through
fermentation involving lactic acid bacteria and apple by-products. The findings
indicate a favorable level of acceptability in the end product and the proposition of
novel beverage prototypes that possess prebiotic and antibacterial properties. The
utilization of sustainable materials in the development of food packaging, which
serves the dual purpose of preserving food and minimizing environmental impact,
has garnered significant attention and widespread adoption. This study focused on
investigating the production of edible prebiotic films using whey protein that was
enhanced with GOS and XOSs. The objective was to develop semipermeable
packaging materials that could be used for coating fresh fruits and vegetables and
bakery foods. This hypothesis elucidates the extensive research that pertains to the
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development and enhancement of functional foods through the utilization of
enzymes derived from various biotechnological sources. Glycosaminoglycans
(GAGs) and xyloglucans (XGs) constitute a significant proportion of the oligosaccharides that are widely present [97]. Cross-linked oligosaccharides (XOSs) hold
significant importance in commercial oligosaccharide development. The enzymatic
synthesis of these compounds is exceptionally viable as it effectively reduces the
occurrence of undesired reactions and the formation of secondary products during
enzymatic hydrolysis. Xylo oligosaccharides (XOSs) can be found in various natural
sources, including fruit, vegetables, honey, and milk. Furthermore, many agroindustrial by-products, such as wheat oat bran, rice straw, wheat, and maize, have
the potential to serve as abundant sources for the synthesis of X. oligosaccharides
(XOSs). Utilizing X. oligosaccharides in the improvement of efficient foods enhances
the presence of functional and nutritional components within traditional food
products. One instance of this phenomenon can be observed using symbiotic soy
milk supplemented with X. oligosaccharides and an inoculum of Weissella cibaria
FB069. This specific formulation has been developed to investigate its impact on the
spread of malignant cells within the colon in comparison to alternative agitated
soybean stuffs [98].
3.13.4 Tannase
Like other enzymes, tannase exhibits a broad distribution across several ecosystems,
encompassing plants, animals, and microbes. The mechanism by which it operates
involves the cleavage of ester and depside linkages present in hydrolyzable tannins,
resulting in the liberation of glucose and gallic acid. Consequently, tannase
significantly contributes to the production of gallic acid [99]. Within the realm of
the food business, this substance finds application in the manufacturing process of
instant tea and serves as an enhancer for the overall quality of various beverages,
including fruit juices, beer, and wine. The utilization of microorganisms to
manufacture tannase is a highly prevalent and extensively researched approach
due to its widespread availability. Fungal species, including Aspergillus fumigatus,
Aspergillus sp., and Aspergillus versicolor, as well as bacterial strains such as
Lactobacillus para Plantarum, Lactobacillus plantarum, and Klebsiella pneumoniae,
Pseudomonas aeruginosa, have demonstrated promising capabilities in the produc-
tion of this enzyme to a satisfactory extent. The utilization of tannase derived from
microorganisms in food production has been documented. This pertains specifically
to the enzymatic extraction of tannase from green tea, employing tannase sourced
from A. niger [100].
3.13.5 Asparaginase
L-asparaginase, an enzyme, is ubiquitous in many organisms, including algae,
plants, microorganisms (such as bacteria and fungi), and certain animal species.
Extensive research has been conducted to investigate its efficacy as a potent
anticancer agent. Several microbes have been reported to produce L-asparaginase,
including Erwinia aroideae, P. aeruginosa, Aspergillus tamari, Vibro succinogenes,
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Aspergillus terreus, Pseudomonas stutzeri, and Staphylococcus sp. In food science,
this method is notable for its efficacy in the mitigation or diminishment of
acrylamide, a chemical molecule found in carbohydrate-rich foods that have
undergone high-temperature cooking processes. This compound is known to
potentially exhibit carcinogenic properties when consumed by individuals [101].
3.13.6 The phytases
Phytase functions as an enzymatic catalyst in the hydrolysis of phytate, a compound
indigestible by the human body. It is predominantly present in non-plant-based
meals in higher concentrations. Fortifying food items with phytase can enhance
components’ and functional foods’ performance and nutritional quality. Like other
enzymes, phytase can be found in various organisms such as herbs, mammals,
fungus, bacteria, and yeast. The categorization of enzymes is contingent upon
several variables, encompassing the characteristics and chemical qualities of the
active site, the specific process in which the molecule functions as a catalyst, and the
development of a protease shape along with its associated relationships. The enzyme
in question plays a crucial part in the digestive process by mitigating the antinutritional effects of phytates and phytic acid [102]. Furthermore, it facilitates the
improved absorption of minerals and proteins, contributing to better health. Phytase
has been employed in several applications within the food sector, such as bread
preparation, which enhances plant-based products’ nutritional composition.
Additionally, it is utilized in cereal bran fractionation, grain wet milling, and the
isolation of plant proteins [103].
3.14 Enzymes used as additives to food
Food manufacturing enzymes are subjected to the same regulations as other food
additives because of their role in food production. According to projections, the
global market for food enzymes is anticipated to reach US$ 3.23 billion by 2023
[104]. Enzymes are presently employed as food additives in various food applications. The applications that garner the highest level of popularity are observed in the
bakery field, wherein they modify the rheology of dough, enhance crumb softness,
and improve gas retention. Similarly, these applications find extensive use in brewing
and winemaking processes, effectively mitigating the Influence of long-chained
molecules such as pectins and enhancing fermentation. Furthermore, these applications are also employed in producing fruit. Enzymes intended for utilization in food
applications must satisfy the following criteria [105].
3.14.1 The enzymatic synthesis of dietary antioxidants
The use of antioxidants helps keep the food fresh and extends its shelf life. The food
and edible oil industries have widely adopted synthetic antioxidants such as
butylated hydroxytoluene (BHT) and butylated hydroxy anisole. However, concerns
have arisen regarding their potential toxicity or the formation of carcinogenic
components during their degradation [106]. As a result, manufacturers have started
to focus on natural antioxidants as an alternative. Their inadequate solubility
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Introduction to Pharmaceutical Biotechnology, Volume 2 (Second Edition)
hinders the efficacy of most natural antioxidants in lipid-based dietary products. To
address this issue, many enzymatic approaches have been devised to enhance the
solubility characteristics of these compounds through the attachment of FAs, hence
augmenting their hydrophobic nature [107].
3.14.2 The use of ascorbyl esters
Vitamin C ascorbyl esters are a popular form of this vitamin because they are fatsoluble and may effectively fight free radicals due to their improved solubility and
ability to mix with other substances. These lipophilic derivatives exhibit exceptional
antioxidant properties and are commonly employed to inhibit the process of lipid
peroxidation [108]. According to Pohanka et al [109], the utilization of ascorbyl
stearate (E305) and ascorbyl palmitate (E304) as antioxidants is authorized in
accordance with the food additives regulations established by the European Union.
Enzymatic methods are often favored over chemical production methods due to
their ability to avoid the generation of by-products, their operation under mild
experimental settings, and their capacity to generate 6-O-ascorbyl esterLipases
derived from Thermomyces lanuginosus, Rhizomucor miehei and Candida antarctica,
that are extensively employed in the production of ascorbyl esters [110]. The
enzymes have the ability to facilitate esterification that results in transesterification
processes that involve ascorbic acid and various acyl donors. These acyl donors
encompass free FAs, such as oleic, stearic, palmitic, and omega-3 FAs, as well as
triacylglycerol, including olive oil, palm oil, and soybean oil, and FA esters, such as
methyl, ethyl, and vinyl esters. In order to mitigate the substantial expenses
associated with enzymatic procedures, it is possible to immobilise enzymes for the
purpose of repeated utilization. Multiple investigations have demonstrated that the
immobilization of lipases enhances their catalytic performance and significantly
increases the production yield of ascorbyl esters, reaching up to 80% within a time
frame of less than 24 h. The antioxidant effects of ascorbyl oleate and ascorbyl
palmitate, synthesized by the utilization of immobilized lipases derived from C.
antarctica and T. lanuginosus, utilizing olive oil and triolein as substrates, were
found to be highly effective in soybean oil [111]. The researchers discovered that the
application of ascorbyl esters had a notable inhibitory effect on the formation of
peroxides in soybean oil. Ascorbyl esters have also been employed for the purpose of
oxidative inhibition in lipid-based food products, such as mayonnaise, salad
dressing, milk, and dairy derivatives. A prior investigation similarly discovered
that the inclusion of ascorbic palmitate effectively inhibited primary oxidation and
hexanal generation in the process and preservation of cookies containing chocolate
cream and milk.
3.14.3 Polyphenolic esters
Polyphenols encompass a diverse group of naturally occurring organic chemicals
originating from plants, exhibiting notable antioxidant properties, and conferring
various health advantages. Dietary sources rich in these substances are prevalent
and renowned for their capacity to mitigate the onset of degenerative ailments,
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Introduction to Pharmaceutical Biotechnology, Volume 2 (Second Edition)
including cancer and cardiovascular disorders [112]. Polyphenols may be classified
into many categories, including hydroxybenzoic acid, hydroxycinnamic acids,
flavonoids, which contain acid chlorogenic, stilbenes, and the lignans. The utilization of polyphenols as food additives in the food industry is a common practice.
However, their application in lipid-based food products presents a significant
challenge due to their extremely limited solubility in oil. One effective strategy for
addressing this challenge involves enhancing hydrophobicity through the enzymatic
esterification step catalyzed by lipase, wherein an FA is attached [113]. The
utilization of lipases has been employed in the synthesis of several lipophilic esters
derived from polyphenols. The synthesis of acyl esters of quercetin-3-O-glucoside
was conducted with immobilized lipase B from Candida antarctica (Cal B). The
chemicals show the ability to impede the initial oxidation process in both fish oil and
fish oil emulsion. It has been shown that lipase is responsible for the esterification
process that occurs during the production of esters between epigallocatechin gallate
‘EGCG’ and polyunsaturated FAs, more especially eicosatetraenoic acid (EPA) and
docosahexaenoic acid ‘DHA’. The antioxidant activity of these EGCG esters was
observed to be greater in comparison to that of EGCG alone. Furthermore, the
integration of EPA and DHA into the EGCG molecule has the potential to provide
supplementary health advantages, hence making them suitable for utilization in food
and natural health commodities. A series of lipophilic esters of hydroxy-tyrosyl were
synthesized utilizing the enzyme Cal B [114]. The research revealed that the EPA
ester of hydroxy-tyrosyl had superior antioxidant properties compared to BHT and
α-tocopherol in various forms of fish oil, including bulk fish oil, fish-oil-in-water
emulsion, and microencapsulated fish oil. The stability of the substance was seen to
persist for a duration of one year when subjected to storage conditions of −20 °C.
Additionally, a separate study discovered that the process of esterification of tyrosyl
resulted in an increased antioxidant efficacy when applied to infant formula.
Previous studies have documented the existence of lipophilic esters of polyphenols
generated by lipase, which possess food-grade properties.
3.14.4 Synthesis of sugars esters surfactants by enzymes
Glucose esters of FAs are non-ionic surfactants that are widely used in the dietary
supplement, pharmaceuticals, and cosmetics sectors due to their advantageous
characteristics, including low toxicity, biodegradability, and sustainable sourcing
from natural resources [115]. Sugar esters are used extensively in the food sector, and
the most common types used are sucrose esters, alkyl polyglycolide esters, and
sorbitan esters. The chemicals discussed in this context are synthesized by the
esterification process, which involves the combination of sugar molecules with
different FA chains. The synthesis of sugar esters with diverse lipophilic and
hydrophilic properties may be achieved by the manipulation of both the sugar
moiety and the length of the FA chain. The user’s text is too short to be rewritten
academically. In industrial settings, the production of sugar esters involves chemical
synthesis utilizing homogenous acid or base catalyst systems. Nevertheless, there are
certain limitations involved with these approaches, such as their substantial financial
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Introduction to Pharmaceutical Biotechnology, Volume 2 (Second Edition)
implications, the potential for soap creation, and the environmental implications
that need to be considered [115]. The enzymatic synthesis of sugar esters has been
extensively documented in literature. Sugar esters can be synthesized through two
different methods: direct esterification of sucrose with an FA chain, or transesterification of sucrose with FA methyl esters using lipases. These techniques have
resulted in the synthesis of sugar esters characterized by elevated levels of purity and
reduced formation of by-products. The lipases derived from C. antarctica, R. miehei,
and Candida rugosa are the most employed enzymes in the production of sugar
esters. Sugar esters have been granted approval for utilization as food additives in
numerous countries. Sucrose esters of FAs have received international approval and
are authorized for use in several regions, including the European Union, the United
Kingdom, and the United States. E473 is a food additive that fi nds applications in
many food products such as ice cream, soup, and mayonnaise [116]. A prior
investigation revealed that sugar esters generated by lipase, namely fructose laurate,
exhibited inhibitory effects on the proliferation of Streptococcus mutans, a pathogenic bacterium commonly associated with food-borne illnesses. In a separate
investigation, the application of a diluted solution containing sucrose Mon myristate
and Mon palmitate at a concentration of 0.05% showed significant inhibitory
properties against the proliferation of S. aureus, Escherichia coli, and Salmonella
enteritidis. These findings indicate that sugar esters of FAs possess potential as
antimicrobial agents in the context of food applications. Additional applications of
sugar esters in the food sector encompass the facilitation of cheese maturation,
enhancement of flavour profiles, and incorporation into the manufacturing processes
of cakes, biscuits, sauces, sausages, wine, and dairy goods [117].
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