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Microorganisms as Biocatalysts and Enzyme Sources

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Arturo Cano-Flores, Javier Gómez, Iker S. Escalona-Torres and Benjamín Velasco-Bejarano

Submitted: 08 October 2019 Reviewed: 31 October 2019 Published: 16 January 2020

DOI: 10.5772/intechopen.90338

From the Edited Volume

Microorganisms

Edited by Miroslav Blumenberg, Mona Shaaban, Abdelaziz Elgaml

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Abstract

Microbial-catalyzed biotransformations have considerable potential for the generation of an enormous variety of structurally diversified organic compounds, especially natural products with complex structures like triterpenoids, flavonoids, steroids, steroidal saponins, and sesquiterpenoids. They offer efficient and economical ways to produce semisynthetic analogues and novel lead molecules. Microorganisms such as bacteria and fungi could catalyze chemo-, regio-, and stereospecific hydroxylations of diverse substrates that are extremely difficult to produce by chemical routes. During recent years, considerable research has been performed on the microbial transformation of bioactive compounds, in order to obtain biologically active molecules with diverse structural features. In green chemistry, biotransformations are an important chemical methodology toward more sustainable industrial processes.

Keywords

  • microorganisms
  • fungi
  • bacteria
  • microbial transformation
  • natural products
  • enzymes

1. Introduction

Microbial transformation is regarded as an enzymatic reaction by using the metabolic activities of microorganisms to modify the chemical structures of bioactive substrates for finding the new chemical derivatives with the potent bioactivities and physical-chemical characteristics. It has a number of advantages over chemical synthesis such as higher stereo- and regioselectivity but is also enantiospecific, allowing the production of chiral products from racemic mixtures. The conditions for biotransformations are mild, and in the majority of cases, they do not require the protection of pre-existing functional groups. Furthermore, some reactions that do not occur when using chemical approaches are easily carried out by microbial transformation. Microbial factories show advantages, for instance, growing rapidly and ease of large-scale production [1, 2, 3].

The use of microorganisms may be a highly efficient method of production of these compounds. The reactions involved in biotransformation of organic compounds by whole cells of various microorganisms include oxidation, reduction, hydroxylation, esterification, methylation, demethylation, isomerization, hydrolysis, glycosylation, and hydrogenation [4, 5].

Biotransformation may be carried out with isolated enzyme systems or with intact organism. Although isolated enzyme systems may be more specific and efficient for certain biotransformation, these reactions may involve isolating the enzyme system, and, for some classes of enzyme-catalyzed reaction, a recycling sequence may be required to regenerate the enzyme [6].

Fungi are playing a prominent role in the catalysis of organic compounds and in the production of commercially and industrially important compounds, because of their ability to catalyze novel reactions [7]. Fungi are commonly used in the industry for production of fermented beverages, foods, physiologically active substances, solvents, organic acids, polysaccharides, antibiotics, etc. Of the zygomycota, Mucor and Rhizopus are commonly used in the industry. Rhizopus strains are important in citric acid production. Mucor strains make a significant number of important lipases and catalyze the hydroxylation of a wide range of chemical compounds [2, 3, 4].

The use of the microbial model offers a number of advantages over the use of animals in metabolism studies, mainly: (1) simple, easy, and can be prepared at low cost; (2) screening for a large number of strains is a simple repetitive process; (3) the large number of metabolites formed allows easier detection, isolation, and structural identification; (4) newer metabolites can be isolated; (5) utilized for synthetic reactions involving many steps; (6) useful in cases where regio- and stereospecificity is required; (7) maintenance of stock cultures of microorganisms is simpler and cheaper than the maintenance of cell or tissue cultures or laboratory animals; (8) ease of setup and manipulation; and (9) more reliable and reproducible [8, 9].

The objective of this review is to highlight the importance of microorganisms or enzymes isolated from them in the biotransformation process of natural products or xenobiotic compounds, according to green chemistry or white biotechnology.

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2. Microbiological transformations of some selected natural products with different microorganisms

2.1 Sesquiterpene lactone

Artemisinin (1), a sesquiterpene lactone endoperoxide and an antimalarial drug, is effective against chloroquine-resistant parasites; but its toxicities and low solubility in water hamper its therapeutical use. Studies on modification of 1 through biological and chemical methodologies have been reported to yield more effective and water-soluble derivatives. A wide array of microbial transformations of 1 involve oxidation, reduction, and degradation reactions by different microorganisms, such as Aspergillus niger, A. flavus, A. adametzi (ATCC 10407), Cunninghamella echinulata, Caenorhabditis elegans, Mucor polymorphous, M. rammanianus, Streptomyces griseus, Penicillium simplicissimum, P. chrysogenum, P. purpuresceus, Pestalotiopsis guepini (P-8), Eurotium amstelodami, Trichoderma viride (T-58), Saccharomyces cerevisiae, and Pichia pastoris. Biotransformation of 1 usually includes the processes such as hydroxylation of methyl, methine and methylene groups, deoxidation reactions, hydration and acetylation reactions, epimerization, and breakdown of heterocyclic rings (Table 1).

MicroorganismProductsActionReference
A. niger3β-hydroxy-4,12-epoxy-1-deoxyartemisinin
Artemisinin G
3,13-epoxyartemisinin
4α-hydroxy-1-deoxyartemisinin
Epoxidation, hydroxylation C-3β site
Endoperoxide function reduction
Breakdown of heterocyclic rings
Epoxidation C-3 and C-13
Hydroxylation C-4, endoperoxide function reduction
[10]
A. flavus (MTCC 9167)14-hydroxyartemisinin
Artemisinin G
4α-hydroxydeoxyartemisinin
Deoxyartemisinin
Hydroxylation of C-14 site
Breakdown of heterocyclic rings
Hydroxylation of C-4α site
Endoperoxide function reduction
[11, 12]
C. elegans (ATCC 9245)7β-hydroxy-9α-artemisinin
4α-hydroxy-1-deoxoartemisinin
7β-hydroxyartemisinin
6β-hydroxyartemisinin
7α-hydroxyartemisinin
6β,7α-dihydroxyartemisinin
Hydroxylation C-7β site
Epimerization C-9
Hydroxylation C-4α site
Hydroxylation C-7β site
Hydroxylation C-6β site
Hydroxylation C-7α site
Hydroxylation C-6β and C-7α sites
[13, 14]
P. simplicissimum9β-acetoxyartimisinin
9α-hydroxyartemisinin
Acetylation of C-9β site
Hydroxylation of C-9α site
[15]
R. stoloniferDeoxyartemisinin
1α-hydroxyartemisinin
10β-hydroxyartemisinin
Endoperoxide function reduction
Hydroxylation of C-1 site
[16]
S. griseus (ATCC 13273)9-artemisitone
9α-hydroxyartemisinin
9β-hydroxyartemisinin
3α-hydroxyartemisinin
Oxidation of C-9 site
Hydroxylation of C-9α site
Hydroxylation of C-9β site
Hydroxylation of C-3α site
[17]
N. corallinaDeoxyartemisininEndoperoxide function reduction[11]

Table 1.

Products obtained from the biotransformation of artemisinin (1) by different microorganisms.

2.2 Triterpene

Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid, UA, 2), a natural pentacyclic triterpene, is broadly used in food, cosmetics, and biomedical industries. As a ubiquitous constituent in the plant kingdom and the major component of many traditional medicine herbs, ursolic acid remarkably exhibits a lot of biological activities, such as antibacterial, anti-allergic, antioxidative, anti-inflammation, and antitumor activities [18].

Microbial transformation of ursolic acid (2) by Bacillus megaterium CGMCC 1.1741 yielded five metabolites identified as 3-oxo-urs-12-en-28-oic acid (3, 6.2%); 1β,11α-dihydroxy-3-oxo-urs-12-en-28-oic acid (4, 13.5%); 1β-hydroxy-3-oxo-urs-12-en-28,13-lactone (5, 5.0%); 1β,3β,11α-trihydroxy-urs-12-en-28-oic acid (6, 26.9%); and 1β,11α-dihydroxy-3-oxo-urs-12-en-28-O-β-d-glucopyranoside (7, 8.6%) [19]. The biotransformation studies of 2 by Alternaria longipes AS 3.2875 have led to the isolation of six products of hydroxylation or glycosylation. Their structures were identified as 3-carbonyl-ursolic acid-28-O-β-d-glucopyranosyl ester (8), ursolic acid-3-O-β-d-glucopyranoside (9), ursolic acid-28-O-β-d-glucopyranosyl ester (10), 2α,3β-dihydroxy-ursolic acid-28-O-β-d-glucopyranosyl ester (11), 3β,21β-dihydroxy-ursolic acid-28-O-β-d-glucopyranosyl ester (12), and 3-O-(β-d-glucopyranosyl)-ursolic acid-28-O-(β-d-glucopyranosyl) ester (13). Glycosylation reaction on pentacyclic triterpenoid fulfilled with difficulty in the process of chemical synthesis is facile by microbial transformation [20]. Biotransformation of 2 by A. alternata eight metabolites were found to be 2α,3β-dihydroxyurs-12-en-28-oic acid (corosolic acid, 14), urs-12-en-2α,3β,28-triol (15), 3β,23-dihydroxyurs-12-en-28-oic acid (16), 2α,3β,23-trihydroxyurs-12-en-28-oic acid (17), 2α,3β,23,24-tetrahydroxyurs-12-en-28-oic acid (18), 3β,28-dihydroxy-12-ursene (19), urs-12-en-3β-ol (20), and urs-12-en-2α,3β-diol (21). The reduction of the C-28 carboxyl group and hydroxylation at C-2, 23, and 24 are steps in the metabolic pathway of 2 [21].

Biotransformation of UA by S. racemosum (3.2500) yielded five metabolites 3β,7β,21β-trihydroxy-urs-12-en-28-oic acid (22); 3β,21β-dihydroxy-urs-11-en-28-oic acid-13-lactone (23); 1β,3β,21β-trihydroxy-urs-12-en-28-oic acid (24); 3β,7β,21β-trihydroxy-urs-1-en-28-oic acid-13-lactone (25); and 1β,3β-dihydroxy-urs-12-en-21-oxo-28-oic acid (26) which were afforded [22]. Additionally, of the biotransformation of 2 with by S. racemosum compounds 27–30 and 11,26-epoxy-3β-21β-dihydroxy-urs-12-en-28-oic acid were obtained (31), (Figure 1) [23].

Figure 1.

Biotransformation products of ursolic acid (2).

The endophytic fungi Pestalotiopsis microspora isolated from medical plant Huperzia serrata can transform 1 to afforded 3-oxo-15β,30-dihydroxy-urs-12-en-28-oic acid (32), 3β,15β-dihydroxy-urs-12-en-28-oic acid (33), 3β,15β,30-trihydroxy-urs-12-en-28-oic acid (34), and 30 [24].

Microbial transformation of ursolic acid by Mucor spinosus AS 3.3450 were isolated and their structures were identified as 9, 22 and 3β,7β-dihydroxy-ursolic acid-28-ethanone (35) (Figure 1) [25].

Figure 2.

Biotransformation products of 11-keto-b-boswellic acid (36).

The gum resin Boswellia serrata has been used for the treatment of inflammatory and arthritic diseases. Its major active constituents are ursane triterpenoids, which include 11-keto-β-boswellic acid (KBA, 36), β-boswellic acid (BA), and acetyl-β-boswellic acid (ABA). Microbial transformation 36 by Cunninghamella blakesleeana (AS 3.970) yielded ten regioselective transformed products: 7β-hydroxy-11-keto-β-boswellic acid (37), 7β,15α-dihydroxy-11-keto-β-boswellic acid (38), 7β,16β-dihydroxy-11-keto-β-boswellic acid (39), 7β,16α-dihydroxy-11-keto-β-boswellic acid (40), 7β,22β-dihydroxy-11-keto-β-boswellic acid (41), 7β,21β-dihydroxy-11-keto-β-boswellic acid (42), 7β,20β-dihydroxy-11-keto-β-boswellic acid (43), 7β,30-dihydroxy-11-keto-β-boswellic acid (44), 3α,7β-dihydroxy-11-oxours-12-en,24,30-dioic acid (45), and 3α,7β-dihydroxy-30-(2-hydroxypropanoyloxy)-11-oxours-12-en, 24-oic acid (46). Bioconversion of 36 with Bacillus megaterium based on a recombinant cytochrome P450 system yielded regio- and stereoselective 15α-hydroxylation (47) of substrate (Figure 2) [26].

Figure 3.

Biotransformation products of 18β-glycyrrhetinic acid (48).

18β-glycyrrhetinic acid (48) is the active form of glycyrrhizin which is the major pentacyclic triterpene found in licorice (Glycyrrhiza glabra L.). Glycyrrhetinic acid has been shown to possess several pharmacological activities, such as antiulcerative, anti-inflammatory, immunomodulating, antitumor, antiviral, antihepatitis effects, and anticancer. Biotransformation 48 with a fungus C. blakesleeana (AS 3.970) yielded 3-oxo-7β-hydroxyglycyrrhetinic acid (49) and 7β-hydroxyglycyrrhetinic acid (50) [27], while of 48 using Absidia pseudocylindrospora (ATCC 24169), Gliocladium viride (ATCC 10097) and Cunninghamella echinulata (ATCC 8688a) afforded seven derivatives: 51, 52, 7β,15α-dihydroxy-18β-glycyrrhetinic acid (53), 15α-hydroxy-18β-glycyrrhetinic acid (54), 1α-hydroxy-18β-glycyrrhetinic acid (55) and 13β-hydroxy-7α,27-oxy-12-dihydro-18β-glycyrrhetinic acid (56), and the epimer of compound 53 on C-17 (Figure 3) [28].

Figure 4.

Triterpenic acid: ginsenoside Rb1 (61), oleanolic acid (62), betulinic (63) and betulonic acid (64).

Ginsenoside Rb1 (61) is the most predominant protopanaxadiol-type ginsenoside in Panax species (ginseng). Several microbial transformations of this substrate (Ginsenoside Rb1) have been accomplished with an ample and varied group of microorganisms, all of these having β-glucosidase activities. Deglycosylation appears to be the major transformation pathway, and the intermediate and the final hydrolysis products of 61 depended on the microorganisms used. The biotransformation of various triterpenes, such as 61–64, has been described in the literature. For each triterpenoid, the transforming microorganism together with the type and site of the reaction catalyzed is given in Table 2 (Figure 4) [29].

TriterpenoidMicroorganismReactionReference
Ginsenoside Rb1 (61)A. niger (KTC 6909)Deglycosylation at the C-3 and C-20 sites[30]
A. niger (AS 3.1858)Deglycosylation at the C-3 and C-20 sites[30]
A. usamii (KTC 6956)Deglycosylation at the C-3 and C-20 sites[30]
F. sacchariDeglycosylation at the C-3 and C-20 sites[31]
P. oxalicumDeglycosylation at the C-3 site[32]
C. lunata (AS 3.1109)Deglycosylation at the C-20 site, hydration Δ24(25)
Formation of tertiary alcohol
[33]
R. stolonifer (AS 3.822)Deglycosylation at the C-3 and C-20 sites[33]
Oleanolic acid (62)C. blakesleeanaDiverse hydroxylation at the C-1β, C-7β, C-13β sites[4]
F. liniDehydrogenation C-13 and C-18. oleanderolide formation[4]
P. chrysogenumHydroxylation on C-21. Oxidation of the hydroxyl group in C-3[4]
C. phomoidesHydroxylation in C-6β[4]
A. ochraceus (NG 1203)Hydroxylation in C-11α[4]
Chaetomium longirostreOxidative ring A cleavage, hydroxylation at the C-21β sites[34]
Nocardia sp. (NRRL 5646)Methyl esterification of the C-28 carboxyl group[4]
R. miehei (CECT 2749)Hydroxylation of the C-7β, C-15α and C-30 sites
Deshidrogenation Δ9(11)
[35]
Betulinic acid (63)B. megaterium (ATCC 14581)Dehydrogenation of the C-3 secondary alcohol group, hydroxylation at the C-6α and C-7β sites[36]
B. megaterium (ATCC 13368)Dehydrogenation of the C-3 secondary alcohol group, hydroxylation at the C-7β and C-15α sites[37]
C. elegans (ATCC 9244)Hydroxylation at the C-1β and C-7β sites[4]
Cunninghamella sp.Introduction of a β-glucopyranosyl at the C-28 carboxylic acid group[38]
Betulonic acid (64)B. megaterium (ATCC 13368)Ketone α-hydroxylation at the C-2 site[37]
Ch. longirostrisOxidative ring A cleavage, hydroxylation, decarboxylation[39]
C. lunata (ATCC 13432)Hydroxylations at the C-7β and (or) C-15β sites[4, 40]

Table 2.

Examples of biotransformed triterpenes (61–64) with different microorganisms.

Figure 5.

Biotransformation products of oleanolic acid (62), echnocystic acid (68) and betulinic acid (63).

Biotransformation of oleanolic acid (62) with Bacillus subtilis (ATCC 6633) resulted in five more polar metabolites as 28-O-β-d-glucopyranosyl oleanic acid (63), 3β-O-β-d-glucopyranosyl oleanic acid (64), 3-O-(β-d-glucopyranosyl)-oleanic acid-28-O-β-d-glucopyranoside (61), 24-hydroxyl-oleanolic acid (62), and 3β-24-dihydroxy-olean-12-en-28-O-β-d-glucopyranosyl-oic acid (63), while echinocystic acid (64, 250 mg) was metabolized to three more polar metabolites as 28-O-β-d-glucopyranosyl echinocystic acid (65), 3-O-(β-d-glucopyranosyl)-echinocystic acid-28-O-β-d-glucopyranoside (66), and 24-hydroxyl-28-O-β-glucopyranosyl echinocytic acid (67), and then biotransformation of betulinic acid (68) contributed four metabolites as 28-O-β-d-glucopyranosyl betulinic acid (69), 3-O-(β-d-glucopyranosyl)-betulinic acid-28-O-β-d-glucopyranoside (70), 23-hydroxy-betulinic acid (71), and 23-hydroxy-28-O-d-β-glucopyranosyl betulinic acid (72). In this way there were two types of reactions in the biotransformation of triterpenic acids 58, 64, and 68: hydroxylation and glycosylation [41]. Biotransformation of 58 by C. muscae yielded nine hydroxylated and glycosylated metabolites. The specific hydroxylation (7β, 15α, and 21β) was main reaction type. In addition, the selective glycosylation at C-28 was another main reaction type. It was also observed that the 3β-OH group was selectively dehydrogenated into carbonyl group [42].

A C-3 oxidized derivative of oleanolic acid 73 (3-oxoolean-12-en-28-oic acid) was transformed by the Chaetomium longirostre (RF-1095) into 4-hydroxy-3,4-seco-olean-12-ene-3,28-dioic acid (74) and the corresponding 21-hydroxylated derivative (75). Analogous ring-A cleavage oxidation reactions have been observed in the biotransformation of triterpenoid substrates with the fungi Septomyxa affinis ATCC 6737 and Glomerella fusarioides ATCC 9552. (Figure 5) [4, 43].

2.3 Steroidal saponins

Diosgenin [(25R)-spirost-5-en-3β-ol, 76] is an important natural starting material in the pharmaceutical industry to produce steroid drugs and hormones since the last century. In recent years, a wide array of new biological activities of 76 has been disclosed. Diosgenin was subjected to several structural modification studies to secure new derivatives via microbial transformation. Several microorganisms have been found to be capable of degrading 76, Bacillus megaterium, Corynebacterium mediolanum, Mycobacterium fortuitum, M. phlei, Nocardia rhodochrous, and F. solani. Three major products were accumulated, diosgenone (77), 1-dehydrodiosgenone (78), androst-4-en-3,17-dione (AD, 79), and androsta-1,4-diene-3,17-dione (ADD, 80) (Table 3) [44, 45]. In addition, two side-chain cleavage intermediates of 76 were produced by C. elegans and Aspergillus nidulans. Microbial transformation of 76 using white-rot fungus Coriolus versicolor afforded eight polyhydroxylated steroids, 7β-hydroxydiosgenin (81), (25R)-spirost-5-en-3β,7β,21-triol (82), (25R)-spirost-5-en-3β,7β,12β-triol (83), (25R)-spirost-5-en-3β,7α,15α,21-tetraol (84), (25R)-spirost-5-en-3β,7β,12β,21-tetraol (85), (25R)-spirost-5-en-3β,7α,12β,21-tetraol (86), and (25R)-spirost-5-en-3β,7β,11α,21-tetraol (87). The 3β-hydroxyl group and double bond in the B-ring of 76 were found to be important structural determinants for their activity [46].

FungiDiosgenona (77)AD (79)ADD (80)Progesterone (102)16-AD
A. nidulans++++++++
C elegans++++
F. solani++++
Rhizopus sp.++++++

Table 3.

The ability of different fungi to transform diosgenin (76).

AD androst-4-ene-3,17-dione; ADD androsta1,4-diene-3,17-dione; 16-AD androst-4-ene-3,16-dione.

Microbial transformation of 76 using Cunninghamella blakesleeana AS 3.970 afforded polyhydroxylated derivatives, such as (25R)-spirost-5-en-3β,7α,12β-triol (88), (25R)-spirost-5-en-3β,7α,12β,15α,21-pentaol (89), (25R)-spirost-5-en-3β,7α,12β,18-tetraol (90), (25R)-spirost-5-en-3β,7α,12β,15α-tetraol (91), (25R)-spirost-5-en-3β,7α,11α,21-tetraol (92), (25R)-spirost-5-en-3β,7β,15α,21-tetraol (93), and (25R)-spirost-5-en-3β,7β,12β,18-tetraol (94) [47], specifically, the hydroxylation, ketonization, and methoxylation by Cunninghamella blakesleeana, C. elegans, Helicostylum piriforme, and Streptomyces virginiae, at C-7, C-9, C-11, C-12, and C-25 positions of 76. Biotransformation of 76 by Syncephalastrum racemosum afforded (25R)-spirost-5-en-3β,7α,9α-triol (95, 1%), (25R)-spirost-5-en-3β,9α,12α-triol-7-one (96, 2%), (25R)-spirost-5-en-3β,9α-diol-7,12-dione (97, 1.5%), (25R)-spirost-4-en-9α,12β,14α-triol-3-one (98, 0.66%), and (25S)-spirost-4-en-9α,14α,25β-triol-3-one (99, 0.66%) [48]. C. echinulata (CGMCC3.2716) metabolized 76 to afford 81 (0.9%), 83 (7.7%), (25R)-spirost-5-en-3β,7β-diol-11-one (100, 7, 1.5%), and (25R)-spirost-5-en-3β,7β,11α-triol (101, 6.2%) (Figure 6) [49].

Figure 6.

Biotransformation products of diosgenin (76).

2.4 Steroids

Microorganisms are able to hydroxylate steroids in different positions C-1 to C-21. These represent the most widespread type of steroid bioconversion carried out by fungi. The commercialized microbial process in the steroid field was in the production of 11α-hydroxyprogesterone. This process was realized for the first time by Peterson and Murray (1952), which patented this process of 11α-hydroxylation of progesterone (102) by Rhizopus species [50]. Microbial hydroxylation of 102 by A. griseola produced two hydroxylated pregnane identified as 6β,14α-dihydroxyprogesterone (103) and 7α,14α-dihydroxyprogesterone (104). R. pusillus produced 6β,11α-dihydroxyprogesterone (105) with excellent yield (65.5%) and 7α,14α-dihydroxyprogesterone (106) (Figure 7) [51].

Figure 7.

Biotransformation products of progesterone (102).

Industry, which is carried by different microorganisms, such as different species of Curvularia spp., Cunninghamella spp. and fungi Trichoderma hamatum, Cochliobolus lunatus. Structural transformation of steroidal compounds through microorganisms has emerged as an important application in the steroidal drug industry. Microbial conversions of steroids generally involve dehydrogenation, esterification, halogenation, isomerization, methoxylation, and side-chain modification of steroidal skeleton. Recently, Mucor circinelloides lusitanicus transformed 5-en-3β-ol steroids (108 and 109) into di- and trihydroxy products. The compound 108 yielded 3β,7α,11α-trihydroxypregna-5-en-20-one (110, 46.4%), and 109 afforded 111 (3β,7α-dihydroxyandrost-5-en-17-one, 43.6%) (Figure 8) [52].

Figure 8.

Biotransformation products of 5-en-3β-ol steroids.

Microbial transformation of (20S)-20-hydroxymethylpregna-1,4-dien-3-one (112) is by four filamentous fungi, Cunninghamella elegans (113119), Macrophomina phaseolina (115, 117, 120122), Rhizopus stolonifer (113, 123), and Gibberella fujikuroi (115117, 123). These metabolites were obtained as a result of biohydroxylation of 112 at C-6β, 7β, 11α, 14α, 15β, 16β, and 17α positions (Figure 9) [53].

Figure 9.

Biotransformation products of (20S)-20-hydroxymethylpregna-1, 4-dien-3-one (112).

The 11α-, 11β-, 15α, and 16α-hydroxylations are currently established processes in the steroid industry mainly for the production of adrenal cortex hormones and their analogues. 11α-, 11β-, and 16α-hydroxylations are usually performed using Rhizopus spp. or Aspergillus spp., Curvularia spp. or Cunninghamella spp. and Streptomyces spp., respectively (Figure 10) (Table 4) [54].

Figure 10.

The ability of different microorganism to transform progesterone (102).

Hydroxylation sitesMicroorganismsApplicationsReference
C-7αFusarium sp., Gibberella sp., Nigrospora sp., Acremonium sp., Phycomyces sp.Production of bile acids and drugs for neuropsychiatry and immunology[55, 56]
C-7βMortierella sp.Obtaining drugs for prostate cancer[56, 57]
11βCurvularia sp., Absidia sp., Cunninghamella sp., Trichoderma sp., Cochliobolus sp.Obtaining anti-inflammatory drugs, like hydrocortisone, prednisone acetate, dexamethasone[56, 57, 58, 59, 60]
11αAspergillus sp., Rhizopus sp.Obtaining of anti-inflammatory, immunosuppressive, anti-allergic drugs, and production of contraceptive drugs[56, 61]
14αMucor sp.[56]
15βBacillus sp.[56, 62]
16αStreptomyces sp.[63, 64]

Table 4.

Some examples of steroid hydroxylation reactions promoted by microorganisms and their applications.

Boldenone (124) is an important steroid hormone drug which is the derivative of testosterone. Biotransformation of 124 by Arthrobacter simplex and recombinant Pichia pastoris with 17β-hydroxysteroid dehydrogenase from Saccharomyces cerevisiae produces BD (124) from androst-4-ene-3,17-dione (79, AD) efficiently [65]. Many microorganisms such as Mucor racemosus, Nostoc muscorum, and Arthrobacter oxydans can utilize androst-1,4-diene-3,17-dione (80, ADD) as substrate to produce testosterone through 17β-carbonyl reduction reactions (Table 5). The ability of microorganisms to reduce 17-keto- to 17β-hydroxysteroids was evidenced for a wide variety of substrates and microorganisms of different taxonomy: bacteria, fungi, and yeast [54, 56, 57, 66].

FungiYeastBacteria
Actinomucor elegans
Agaricus silvaticus
A. pantherina
A. spissa
Armillaria mellea
Corticium centrifugum Fusarium spp.
Gibberella saubinetti
Mucor spp.
Penicillium spp.
Aphanocladium album
Aspergillus chevalieri
A. flavus
A. oryzae
A. tamarii
B. obtusa
C. aphidicola
Ceratocystis paradoxa
C. lunatus
Colletotrichum musae
C. radicicola
Exophiala jeanselmei var. lecaniicorni
Fusarium culmorum
F. oxysporum var. cubense
F. solani
Mucor piriformis
M. spinosus
P. chrysogenum
P. crustosum
P. blakesleeanus
R. stolonifer
Septomyxa affinis
T. piriforme
Trichoderma viride
Zygodesmus sp.
Candida albicans
C. pelliculosa
C. pseudotropicalis
C. robusta
C. tropicalis
C. utilis
Cryptococcus albidus
C. laurentii
C. tsukubaensis
Debaryomyces hansenii
D. kloeckeri
D. nicotianae
D. subglobosus
D. vini
Hansenula anomala
H. califórnica
H. schnegii
H. suaveolens
Kloeckera jensenii
Saccharomyces carlsbergensis
S. cerevisiae
S. fragilis
S. lactis
S. oviformis
S. turbidans
S. validus
Pichia farinosa
P. membranaefaciens
Torulopsis spp.
Hortaea werneckii
Phaeotheca triangularis
P. herbarum
P. ostreatus
Rhodotorula aurantiaca
R. mucilaginosa
B. stearothermophilus
Bacteroides fragilis
Brevibacterium sterolicum
Clostridium paraputrificum
Comamonas testosteroni
Lactobacillus bulgaricus
Mycobacterium spp.
B. stearothermophilus
Bacteroides fragilis
Brevibacterium sterolicum
Clostridium paraputrificum
Comamonas testosteroni (syn. Pseudomonas testosteroni)
Lactobacillus bulgaricus
Pediococcus cerevisiae
Sarcina lutea
Staphylococcus aureus
Streptomyces globisporus
S. sphaeroides
S. viridochromogenes
S. hydrogenans
S. lavendulae

Table 5.

Reduction of the C-17 carbonyl group of steroids by (17βHSDs) different microorganisms.

The oxidation of 17β-hydroxyl group was observed along with hydroxylation of steroids at C5 (Penicillium crustosum, P. chrysogenum), C6 (Bacillus stearothermophilus, B. obtusa, P. blakesleeanus), C7 (α/β) (A. coerulea, Botrytis cinerea, B. obtusa, P. blakesleeanus, Rhizopus stolonifer), C10 (Absidia glauca), C11 (α/β) (A. coerulea, B. obtusa, Cephalosporium aphidicola, R. stolonifer), C12 (A. glauca, B. obtusa), C14 (Bacillus sp.), and C15 (A. glauca, Aspergillus fumigatus, B. obtusa) [54, 56, 57, 67, 68, 69]. The biotransformation of 79 with different microorganisms is shown. Compound 79 is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepiandrosterone (DHEA) [70]. DHEA is an endogenous steroid hormone. It functions as a metabolic intermediate in the biosynthesis of the androgen and estrogen sex steroids. Various microorganisms have had the ability to biotransform steroidal compounds such as AD (79) [54], DHEA (125) [54, 55, 70, 71, 72, 73, 76, 77, 80, 81], testosterone [54, 55, 74, 75, 76, 81], cortexolone (126) [78, 79], and prednisone (127) (Figure 11ad) [54, 55, 82].

2.5 Diterpene

Figure 11.

The ability of different fungi to transform DHEA (125), testosterone, cortexolone (126) and prednisone (127). (a) Hydroxilation of 3β-hydroxy-5-androsten-17-one (DHEA) by various microorganisms. (b) Reduction of C-17 and hydroxilation of testosterone by various microorganisms. (c) Hydroxylation of cortexolone (123) by various microorganisms. (d) Reduction and hydroxylation of prednisone (126) microorganisms.

Sclareolide (128) is a natural product isolated from several plant species which displays phytotoxic and cytotoxic activities against several human tumor cells lines. This compound has also been used as starting material for the synthesis of various bioactive products. Regarding the biotransformation of the 128 with different microorganisms, mono- (130, 131, 135, 140142) and dihydroxylation (132134, 136, 139, 143, 146), oxidation (129, 144), hydroxylation/oxidation (145), epimerization (137), and cyclization (138) products have been obtained [83]. The microbial transformation of 128 by Curvularia lunata yielded 3-ketoesclareolide (129), 1β-hydroxysclareolide (130), 3β-hydroxysclareolide (131), 1α,3β-dihydroxysclareolide (133), and 1β,3β-dihydroxysclareolide (134) [84]. The incubation of 128 with Cunninghamella elegans afforded 129, 131, 133, and 135137 [85]. C blakesleeana metabolized 128 to afford 129, 135, 134, and 138140. Biotransformation of 128 with C. echinulata yielded 5-hydroxysclareolide (141) and 7β-hydroxysclareolide (142) [86]. Fermentation of 148 with A. niger using a nutrient-rich culture medium yielded 141 and 144146 (Figure 12) [83].

Figure 12.

Biotransformation products of sclareolide (128).

2.6 Flavonoids

As most important phytochemicals in food, the dietary flavonoids exert a wide range of benefits for human health. Recent researches have explored diverse biological and pharmacological activities of natural flavonoids—antioxidant activity, anti-inflammatory activity, anti-Alzheimer’s disease, antibacterial activity, antifungal activity, anti-HIV activity, anticoagulant activity, antileishmanial activity, and anti-obesity activity [87, 88, 89, 90, 91]. Microbial biotransformation strategies for production of flavonoids have attracted considerable interest because they allow yielding novel flavonoids, which do not exist in nature.

The main reactions during microbial biotransformation are hydroxylation, dehydroxylation, O-methylation, O-demethylation, glycosylation, deglycosylation, dehydrogenation, hydrogenation, C ring cleavage of the benzo-γ-pyrone system, cyclization, and carbonyl reduction. Cunninghamella, Penicillium, and Aspergillus strains are very popular to biotransform flavonoids, and they can perform almost all the reactions with excellent yields (Figure 13). Isoflavones are usually hydroxylated at the C-3′ position of the B ring by microorganisms. Chalcones 147-152 were regioselectively cyclized to flavanones (Figure 14). Hydrogenation of flavonoids was only reported on transformation of chalcones to dihydrochalcones (Figure 14) [92, 93].

Figure 13.

The main reactions during biotransformation of chalcone whit microorganisms.

Figure 14.

Biotransformation products obtained from biotransformation of chalcones 147-152 with A. niger.

Aspergillus niger is one of the most applied microorganisms in the flavonoids’ biotransformation; for example, A. niger can transfer flavanone to flavan-4-ol, 2′-hydroxydihydrochalcone, flavone, 3-hydroxyflavone, 6-hydroxyflavanone, and 4′-hydroxyflavanone. The hydroxylation of flavones by microbes usually happens on the ortho position of the hydroxyl group on the A ring and C-4′ position of the B ring, and microbes commonly hydroxylate flavonols at the C-8 position. Natural flavonoids, such as naringenin (166), hesperetin (167), chrysin (168), apigenin (169), and luteolin (170) were subjected to microbiological transformations by Rhodotorula glutinis (KCh 735). Yeast was able to regioselectively C-8 hydroxylate 167, 168, 169, and 170 to generate 171 (17%), 172 (31%), 173 (12.9%), and 174 (25%), respectively. Naringenin (166) was transformed to carthamidin (175) and isocarthamidin (176) in a ratio of 1:19, respectively (Figure 15) [94].

Figure 15.

Biotransformation products of flavanone (166, 167) and flavone (168170).

The microorganisms tend to hydroxylate flavanones at the C-5, 6, and 4′ positions; however, for prenylated flavanones, dihydroxylation often takes place on the Δ4(5) double bond on the prenyl group (the side chain of A ring), although cyclization of the prenyl group to dihydrofurane derivatives is rather common biotransformation pathway of prenylated flavonoids. Prenylated flavanones are a unique class of naturally occurring flavonoids characterized by the presence of a prenylated side chain (prenyl, geranyl) in the flavonoid skeleton [95]. The prenyl chain generally refers to the 3,3-dimethylallyl substituent (3,3-DMA), geranyl and lavandulyl. It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal, as well as estrogenic activities. Figure 16 demonstrated the microbial biotransformation of kurarinone (177) using C. echinulata and C. militaris [96, 97].

Figure 16.

Microbial biotransformation of kurarinone (177) using C. echinulate and C. militaris.

Incubation of Absidia coerulea (AM93) with prenylnaringenin (178) led to metabolite 179 (8-prenylnaringenin 7-O-β-d-glucopyranoside, 49.3%), while B. bassiana transformed 178 into 180 (8-prenylnaringenin 7-O-β-d-4″-O-methyl-glucopyranoside, 32.9%); the metabolites 179 and 180 originated in Sabouraud medium. In the absence of glucose in the culture of A. coerulea, the sulfation of substrate 178 (8-prenylnaringenin-7-sulfate, 181, 31.1%) occurs, while B. bassiana into the same product (180). The capacity of some fungi—Cunninghamella elegans, Streptomyces fulvissimus, Mucor ramannianus, and B. bassiana—in the sulfation of certain phenolic compounds has been reported (Figure 17) [98].

Figure 17.

Biotransformation products of prenylnaringenin (178).

Regioselective glycosylation of biologically active flavonoid aglycones catalyzed by microorganisms is an interesting and desired reaction, which significantly increases the water solubility of the compound and, therefore, may improve bioavailability of flavonoids. Absidia glauca AM177, A. coerulea AM93, Rhizopus nigricans UPF701, Beauveria bassiana AM278, and B. bassiana AM446 are able to conjugate sugar moiety to chalcones, flavanones, and isoflavanones with high regioselectivity. Therefore, it is possible to use Beauveria and Absidia for the microbial transformation of simple or prenylated flavonoids by glycosidation reactions [97, 99].

Bavachinin (182) is one kind compound of flavanones and isolated from the aerial parts and dried fruits of Psoralea corylifolia, and bavachinin displays a broad range of biological activities, such as antioxidant, antibacterial, antifungal, anti-inflammatory, antitumor, anti-pyretic, and analgesic properties [100, 101]. Bavachinin (182) was subject to biotransformation by cultured cells of A. flavus (ATCC 30899); C. elegans (CICC 40250) afforded the same product 183 [(S)-6-((R)-2,3-dihydroxy-3-methylbutyl)-2-(4-hydroxyphenyl)-7-methoxychromen-4-one]. On the other hand, one major product 184 [(2S,4R)-2-(4-hydroxyphenyl)-7-methoxy-6-(3-methylbut-2-en-1-yl)-chromen-4-ol] was obtained by P. raistrickii (ATCC 10490) by the reduction at the position of ketone group of the C-ring (Figure 18) [102].

Figure 18.

Biotransformation products of bavachinina (182).

The biotransformation of xanthohumol (185), a prenylated chalcone isolated from hops by selected fungi, Absidia coerulea (AM93), Rhizopus nigricans (UPF701), Mortierella mutabilis (AM404), and Beauveria bassiana (AM446), was investigated. The incubation of A. coerulea with 185 resulted in the isolation of xanthohumol 4′-O-β-d-glucopyranoside (186, 29%). This metabolite was also produced by R. nigricans (186, 14.2%). Biotransformation of 185 with B. bassiana and M. mutabilis yielded xanthohumol 7-O-β-D(4‴-O-methyl)-glucopyranoside (187, 23%) and isoxanthohumol 7-O-β-glucopyranoside (188, 49%), respectively (Figure 19) [103]. The compounds 188 (9.3%) and 186 (12%) were also observed as products of 185 transformation by Cunninghamella elegans [104]. Another way to obtain 188 is by the transformation of isoxanthohumol (189, 61.6%) with Absidia glauca; although the efficiency of this process was high (61.6% yield), it required the chemical isomerization of 185 to 189, prior to biotransformation [105].

Figure 19.

Biotransformation products of xanthohumol (185).

2″-(2″-hydroxyisopropyl)-dihydrofurano-[4″,5″:3′,4′]-4,2′-dihydroxy-6′-methoxychalcone (190), mixture of diastereoisomers of (2S, 2″S) and (2S, 2″R) 2″-(2″-hydroxyisopropyl)-dihydrofurano-[4″,5″:7,8]-4′-hydroxy-5-methoxyflavanone (191), and (Z)-2″-(2″-hydroxyisopropyl)-dihydrofurano-[4″,5″-6,7]-3′,4′-dihydroxy-4-methoxyaurone (192) were obtained by transformation of 185 in Aspergillus ochraceus (AM 465) culture (Figure 19) [106].

Figure 20.

Biotransformation products of isoxanthohumol (189).

Incubation of xanthohumol (185) both with Fusarium avenaceum (AM11) and F. oxysporum (AM727) gave a single metabolite 2″-(2″-hydroxyisopropyl)-dihydrofurano-[4″,5″:3′,4′]-4′,2-dihydroxy-6′-methoxy-α,β-dihydrochalcone (193), which turned out to be the product of the prenyl group cyclization and α,β-double bond reduction. F. tricinctum reduced α,β-double bond of 185 to give 4,2′,4′-trihydroxy-6′-methoxy-3-prenyl-α,β-dihydrochalcone (194). Penicillium albidum (AM79) oxidized 185 at the double bond of prenyl group to xanthohumol H (195) [107]. The culture of the yeast, Rhodotorula marina (AM 77), converted 185 and 4-methoxychalcone (196) to α,β-dihydroxanthohumol (197) and 4-methoxydihydrochalcone (198) with the yields of 18% and 20%, respectively [108]. Penicillium albidum (AM79) dihydroxylated the Δ2″(3″) double bond of xanthohumol to produce 3′-[3″-hydroxy-3″-methylbutyl]-4,2′,4′-trihydroxy-6′-methoxychalcone (199, 22.84%) (Figure 19).

Figure 21.

Biotransformation products of sylbin (204).

B. bassiana AM278 and Absidia glauca AM177 converted isoxanthohumol (189) into glucoside derivatives (200, 201), whereas Fusarium equiseti AM15 transformed it into (2R)-2-(2-hydroxyisopropyl)-dihydrofurano-[2,3:7,8]-4-hydroxy5-methoxyflavanone (202) (Figure 20) [95, 106].

C. echinulata (ATCC 9244) sulfated silybin (203) to silybin-7-sulfate (204) and 2,3-dehydrosylibin-7-sulfate (205). Sulfonation at the C-7 position of silybin significantly decreased the DPPH free radical scavenging potential; however, further dehydrogenation Δ2(3) to 2,3-dehydrosilbyn-7-sulfate (206) drastically enhanced the DPPH free radical scavenging potential activity [109] (Figure 21).

2.7 Enzymes isolated from microorganisms and their application

Enzymes are the most proficient catalysts, offering much more competitive processes than chemical catalysts. A number of enzyme-based processes have been commercialized for producing several valuable products. During the 1980s and 1990s, engineering of enzymes based on structural information allowed extension of their substrate ranges, enabling the synthesis of unusual intermediates. Accordingly, the use of enzymes has been expanded to the manufacture of pharmaceutical intermediates and fine chemicals [110]. Microorganisms and enzymes (biocatalysts) are highly enantio-, chemo-, and regioselective in a wide range of reaction conditions. Selectivity is extremely desirable in the synthesis of different synthesis products, since it offers advantages such as minimizing the side reactions that do not require protection and deprotection steps, which allows for shorter synthesis. Biocatalysis provides a technology that is environmentally safer, and it effectively reduces the level of waste and even eliminates the waste generation rather than remediation and disposal of wastes at the end of the process. In addition to, biocatalysts have many attractive features in the context of green chemistry and sustainable development. Various enzymes used in different industrial processes have been described in the literature. Table 6 indicates some enzymes, their source, and some applications [111, 112, 113].

Microbial enzymesMicroorganismApplication
α-AmylaseBacillus amyloliquefaciens
B. stearothermophilus
B. licheniformis
Baking, brewing, starch liquefaction
Clarification of fruit juice
Textile industry
Paper industry
GlucoamylaseAspergillus niger
A. awamori
Rhizopus oryzae
Beer production
High glucose and high fructose syrups
ProteasesA. usami
Lactase (β-galactosidase)Kluyveromyces lactis
K. fragilis
Lactose intolerance reduction in people
Prebiotic food ingredients
LipaseCandida antarctica
C. cylindraceae Ay30
Helvina lanuginosa
Pseudomonas sp.
Geotrichum candidum
Cheese flavor development
Textile indutry
Medicinal applications
Use in cosmetics
Use as biosensors
Use in biodegradation
PhospholipasesFusarium oxysporumCheese flavor development
EsterasesBacillus licheniformisEnhancement of flavor and fragrance in fruit juice
XylanasesStreptomyces sp.
Bacillus sp.
Pseudomonas sp.
Clarification of fruit juice
Beer quality improvement
Glucose oxidaseA. niger
Penicillium glaucum
P. adametzzi
Food shelf life important
Food flavor improvement
LaccaseFunalia trogii
Bacillus licheniformis
Bacillus vallismortis
Polyphenol removal from wine
baking
PectinasesA. niger
A. wentii
Rhizopus sp.
Clarification of fruit juice
CatalaseA. niger
Metarhizium anisopliae
Psychrobacter piscatorri
Food preservation
Removal of H2O2 from milk prior to cheese production
PeroxidaseStreptomyces viridosporusDevelopment of flavor, color and nutritional quality of food

Table 6.

Enzymes, source, and some applications.

2.8 Extremophiles

A very interesting research area in biology and biotechnology is the of extremophile microorganisms. Extremophiles can be divided into group according to (i) temperature tolerance, (ii) salt concentration, (iii) pH range, or (iv) pressure conditions. Enzymes from extremophilic microorganisms offer versatile tools for sustainable developments in a variety of industrial applications as they show important environmental benefits due to their biodegradability, specific stability under extreme conditions, improved use of raw materials, and decreased amount of waste products. Although major advances have been made in the last decade, our knowledge of the physiology, metabolism, enzymology, and genetics of this fascinating group of extremophilic microorganisms and their related enzymes is still limited [114, 115, 116].

The outstanding properties of thermozymes are suited to industries that employ elevated temperatures, such as the pulp and paper, food, brewing, and feed processing industries. Thermophiles are often highly resistant to harsh conditions such as chemical denaturing agents, wide pH ranges, and/or nonaqueous solvents. Examples of such enzymes are cellulases, xylanases, pectinases, chitinases, amylases, pullulanases, proteases, lipases, glucose isomerases, alcohol dehydrogenases, and esterases. Thermophilic enzymes have played important roles not only at the industrial level but also in pharmaceutical applications requiring use of specific aldolases for the synthesis of enantiopure compounds (Table 7) [118].

SourceEnzymeActivityBioprocess/industryReference
Sulfolobus solfataricus
S. acidocaldarius
Thermoproteus texas Hyperthermus butylicus
AldolaseStereoselective C-C bond formationPharmaceutical industry[117]
Pyrococcus furiosusHydrogenaseFinal stage of glucose oxidation by oxidative pentose phosphate cycleEnhanced production of biohydrogen[119]
Geobacillus thermoleovoransCarboxylesteraseCarboxyl ester hydrolysisAgriculture, food, and pharmaceutical industries[120]
Bacillus pumilusAcidic thermostable lipaseDegradation of palm oilTreatment of palm oil-containing wastewater[121]
Geobacillus sp.LipaseHydrolysis of diver’s lipid substratesBiofuel, cosmetics, or perfume production, leather and pulp industries[122]
Microbial community from solid-state
fermentation reactor
ProteaseDegradation of hair waste from tanneryLeather industry[123]
Sulfolobus tokodaiiChitinaseHydrolysis of β-(1, 4)-glycosidic bonds in chitinBiomedical, pharmaceutical, food, and environmental[124]
Acidothermus cellulolyticusEndoxylanaseβ-(1,4)-xylan cleavageBiofuel production from lignocellulose[125]
Thermotoga neapolitanaPullulanaseHydrolysis of α-(1, 6)-glucosidic linkagesBiofuel production[126]

Table 7.

Extremophile microorganisms and some applications of their enzymes.

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3. Conclusion

Due to microorganisms’ abundant multienzyme systems, microbial transformation possesses advantages against chemosynthesis of environmental friendliness, mild reaction conditions, and high stereo-, regio, and chemo-selectivities as well as in improving conversion rates and reducing cost. Thus, microbial transformation technique is being increasingly used to structurally modify natural and synthetic compounds.

The hydrolytic and reductive capabilities of microorganisms have been known and are currently used in preparative and industrial reactions. Various classes of bioactive organic compounds have been subjected to enzymatic transformation to obtain more active and less toxic substances or to elucidate their metabolic pathways.

For example, biotransformation-derived steroids are used for a wide range of pharmacotherapeutic purposes, such as anti-inflammatory, immunosuppressive, progestational, diuretic, anabolic, as neurosteroids, and as contraceptive. Researchers continue to discover more useful steroid compounds and to isolate microorganisms that can perform the structural transformations desired. New technologies such as genomics, metanogenomics, gene shuffling, and DNA evolution provide valuable tools for improving or adapting enzyme properties to the desired requirements.

An alternative may be extremophilic microorganisms such as biocatalysts for countless future industrial applications that are more environmentally friendly.

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Acknowledgments

The authors thank Carrera de Biología, FES-Zaragoza, UNAM, Al Departamento de Química Orgánica, FES-Cuautitlán, UNAM.

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Conflict of interest

The authors report no conflicts of interest.

References

  1. 1. Lehman LR, Stewart JD. Filamentous fungi: Potentially useful for the biohydroxilation of non-actived carbón centres. Current Organic Chemistry. 2001;5:439-470. DOI: 10.2174/1385272013375490
  2. 2. Pollard DJ, Woodley JM. Biocatalysis for pharmaceutical intermediates: The future is now. Trends in Biotechnology. 2006;25:66-72. DOI: 10.1016/j.tibtech.2006.12.005
  3. 3. Straathof AJJ. The production of fine chemicals by biotransformation. Current Opinion in Biotechnology. 2002;13:548-556. DOI: 10.1016/S0958-1669(02)00360-9
  4. 4. Parra A, Rivas F, Garcia-Granados A, Martínez A. Microbial transformation of triterpenoids. Mini-Reviews in Organic Chemistry. 2009;6:307-320. DOI: 10.2174/157019309789371569
  5. 5. Schrewe M, Julsing MK, Buhler B, Schmid A. Whole-cell biocatalysis for selective and productive C-O functional group introduction and modification. Chemical Society Reviews. 2013;42:6346. DOI: 10.1039/c3cs60011d
  6. 6. Brenna E, Fugati C, Gatti FG, Serra S. Biocatalytic methods for the synthesis of enantioenriched odor active compounds. Chemical Reviews. 2011;111:4036-4072. DOI: 10.1021/cr100289r
  7. 7. Sultana N, Saeed SZ. Enzymatic biotransformation of terpenes as bioactive agents. Journal of Enzyme Inhibition and Medicinal Chemistry. 2013;28:113-1128. DOI: 0.3109/14756366.2012.727411
  8. 8. Silva EO, Gonçalves NS, Santos RA, Furtado NAJC. Microbial metabolism of atovaquone and cytotoxicity of the produced phase I metabolite. European Journal of Drug Metabolism and Pharmacokinetics. 2016;41:645-650
  9. 9. Pervaiz I, Ahmad S, Madni MA, Ahmad H, Khaliq FH. Microbial biotransformation: A tool for drug designing. Applied Biochemistry and Microbiology. 2013;49:437-450. DOI: 10.1134/S0003683813050098
  10. 10. Zhan Y, Liu H, Wu Y, Wei P, Chen Z, William JS. Biotransformation of artemisinin by Aspergillus niger. Applied Microbiology and Biotechnology. 2015;99:3443-3446. DOI: 10.1007/s00253-015-6464-x
  11. 11. Ponnapalli MG, Sura MB, Sudhakar R, Govindarajalu G, Sijwali PS. Biotransformation of Artemisinin to 14-hydroxydeoxyartemisinin: C-14 hydroxylation by Aspergillus flavus. Journal of Agricultural and Food Chemistry. 2018;66:10490-10495. DOI: 10.1021/acs.jafc.8b03573
  12. 12. Srivastava S, Luqman S, Fatima A, Dorokar MP, Negi AS, Kumar JK, et al. Biotransformation of artemisinin mediated through fungal strains for obtaining derivatives with novel activities. Scientia Pharmaceutica. 2009;77:87-95. DOI: 10.3797/scipharm.0803-15
  13. 13. Parhikov IA, Muraludharan KM, Avery MA, Williamson JS. Transformation of artemisinin by Cunninghamella elegans. Applied Microbiology and Biotechnology. 2004;64:782-786. DOI: 10.1007/s00253-003-1524-z
  14. 14. Zhan Y, Wu Y, Xu F, Bai Y, Guan Y, Williamson JS, et al. A novel dihydroxylated derivative of artemisinin from microbial transformation. Fitoterapia. 2017;120:93-97. DOI: 10.1016/j.fitote.2017.05.015
  15. 15. Goswami A, Saikia PP, Barua NC, Bordoloi M, Yadav A, Bora TC, et al. Bio-transformation of artemisinin using soil microbe: Direct C-acetoxylation of artemisinin at C-9 by Penicillium simplissimum. Bioorganic & Medicinal Chemistry Letters. 2010;20:359-361. DOI: 10.1016/j.bmcl.2009.10.097
  16. 16. Gaur R, Darokar MP, Ajayakumar PV, Shukla RS, Bhakuni RS. In vitro antimalarial studies of novel artemisinin biotransformed products and its derivatives. Phytochemistry. 2014;107:135-140. DOI: 10.1016/j.phytochem.2014.08.004
  17. 17. Liu J-H, Chen Y-G, Yu B-Y, Chen Y-J. A novel ketone derivative of artemisinin biotransformed by Streptomyces griseus ATCC 13273. Bioorganic & Medicinal Chemistry Letters. 2006;16:1909-1912. DOI: 10.1016/j.bmcl.2005.12.076
  18. 18. Saraswati S, Agrawal S-S, Alhaider A-A. Ursolic acid inhibits tumor angiogenesis and induces apoptosis through mitochondrial-dependent pathway in Ehrlich ascites carcinoma tumor. Chemico-Biological Interactions. 2013;206:153-165. DOI: 10.1016/j.phytol.2019.04.019
  19. 19. Zhang C, Xu S-H, Ma B-L, Wang W, Yu B-Y, Zhang J. New derivatives of ursolic acid through the biotransformation by Bacillus megaterium CGMCC 1.1741 as inhibitors on nitric oxide production. Bioorganic & Medicinal Chemistry Letters. 2017;27:2575-2578. DOI: 10.1016/j.bmcl.2017.03.076
  20. 20. Zhang C-X, Ma W-J, Liu D-L, Jia X-J, Zhao Y-M. Biotransformation of ursolic acid by Alternaria longipes AS3.2875. Natural Product Research. 2018;32:536-543. DOI: 10.1080/14786419.2017.1327860
  21. 21. Wang Y, Xiang L, Chen M, Zhang Z-X, He X. Substrate specify for the 2β-hydroxylation of ursolic acid by Alternaria alternate and the antitumor activities of those metabolites. Journal of Molecular Catalysis B: Enzymatic. 2012;83:51-56. DOI: 10.1016/j.molcatb.2012.07.005
  22. 22. S-b F, Yang J-S, J-l C, Sun D-A. Biotransformation of ursolic acid by Syncephalastrum racemosum CGMCC 3.2500 and anti-HCV activity. Fitoterapia. 2013;86:123-128. DOI: 10.1016/j.fitote.2013.02.007
  23. 23. Huang F-X, Yang W-Z, Ye F, Tian J-Y, Hu H-B, Feng L-M, et al. Microbial transformation of ursolic acid by Syncephalastrum racemosum (Cohn). Phytochemistry. 2012;82:56-60. DOI: 10.1016/j.phytochem.2012.06.020
  24. 24. Fu S-B, Yang J-S, Cui J-L, Meng Q-F, Feng X, Sun D-A. Multihydroxylation of ursolic acid by Pestalotiopsis microspora isolated from the medicinal plant Huperzia serrate. Fitoterapia. 2011;82:1057-1061. DOI: 10.1016/j.fitote.2011.06.09
  25. 25. Zhanga S-S, Hea L-S, Zhaoa Y-M, Fub S, Liua D-L, Yua Z-H, et al. Three new triterpenoids transformed from ursolic acid by Mucor spinosus (AS 3.3450) and their cytotoxicity. Phytochemistry Letters. 2019;32:33-37. DOI: 10.1016/j.phytol.2019.04.019
  26. 26. Wang Y, Sun Y, Wang C, Huo X, Liu P, Wang C, et al. Biotransformation of 11-keto-b-boswellic acid by Cunninghamella blakesleeana. Phytochemistry. 2013;96:330-336. DOI: 10.1016/j.phytochem.2013.07.018
  27. 27. Yu-Juan Q, Bing F, Xin-Bo S, Wen-Bin Z, He-Shui Y, Li-Li Z, et al. Biotransformation of glycyrrhetinic acid by Cunninghamella blakesleeana. Chinese Journal of Natural Medicines. 2010;8:373-381. DOI: 10.3724/SP.J.1009.2010.00373
  28. 28. Maatooq GT, Marzouk AM, Gray AI, Rosazza JP. Bioactive microbial metabolites from glycyrrhetinic acid. Phytochemistry. 2010;71:262-270. DOI: 10.1016/j.phytochem.2009.09.014
  29. 29. Mufler K, Leipold D, Scheller M-C, Haas C, Steingroewer J, Bley T, et al. Biotransformation of triterpenes. Process Biochemistry. 2011;46:1-15. DOI: 10.1016/j.procbio.2010.07.015
  30. 30. Chi H, Ji G. Transformation of Ginsenosides Rb1 and Re from Panaxginseng by food microorganisms. Biotechnology Letters. 2005;27:765-771. DOI: 10.1007/s10529-005-5632-y
  31. 31. Han Y, Sun B, Jiang B, Hu X, Spranger MI, Zhang Y, et al. Microbial transformation of ginsenosides Rb1, Rb3 and Rc by Fusarium sacchari. Journal of Applied Microbiology. 2010;109:792-798. DOI: 10.1111/j.1365-2672.2010.04707.x
  32. 32. Gao J, Xu W, Fang Q, Liang F, Jin R, Wu D, et al. Efficient biotransformation for preparation of pharmaceutically active ginsenoside compound K by Penicillium oxalicum sp. Annales de Microbiologie. 2013;63:139-149. DOI: 10.1007/s13213-012-0454-3
  33. 33. Dong A, Ye M, Guo H, Zhen J, Guo D. Microbial transformation of ginsenoside Rb1 by Rhizopus stolonifer and Curvularia lunata. Biotechnology Letters. 2003;25:339-344
  34. 34. Shirane N, Hashimoto Y, Ueda K, Takbnaka H, Katoh K. Ring a cleavage 3-oxo-olean-12-en-28-oic acid by the fungus Chaetomium longirostre. Phytochemistry. 1996;43:99-104
  35. 35. Martinez A, Perojil A, Rivas F, Parra A, Garcia-Granados A, Fernandez-Vivas A. Biotransformation of oleanolic and maslinic methyl esters by Rhizomucor miehei CECT 2749. Phytochemistry. 2015;117:500-508. DOI: 10.1016/j.phytochem.2015.07.020
  36. 36. Kouzi SA, Chatterjee P, Pezzuto JM, Hamann MT. Microbial transformations of the antimelanoma agent betulinic acid. Journal of Natural Products. 2000;63:1653-1657
  37. 37. Chatterjee P, Kouzi SA, Pezzuto JM, Hamann MT. Biotransformation of the antimelanoma agent betulinic acid by Bacillus megaterium ATCC 13368. Applied and Environmental Microbiology. 2000;66:3850-3855
  38. 38. Chatterjee P, Pezzuto JM, Kouzi SA. Glucosidation of betulinic acid by Cunninghamella species. Journal of Natural Products. 1999;62:761-763
  39. 39. Akihisa T, Takamine Y, Yoshizumi K, Tokuda H, Kimura Y, Ukiya M, et al. Microbial transformations of two lupane-type triterpenes and anti-tumor promoting effects of the transformation products. Journal of Natural Products. 2002;65:278-282
  40. 40. Goswami A, Guo Z, Tullya TP, Rinaldia FA, Huangb XS, Swidorskib JJ, et al. Microbial transformations of betulinic and betulonic acids. Journal of Molecular Catalysis B: Enzymatic. 2015;117:45-53. DOI: 10.1016/j.molcatb.2015.04.012
  41. 41. Wang W-W, Xu S-H, Zhao Y-Z, Zhang C, Zhang Y-Y, Yu B-Y, et al. Microbial hydroxylation and glycosylation of pentacyclic triterpenes as inhibitors on tissue factor procoagulant activity. Bioorganic & Medicinal Chemistry Letters. 2017;27:1026-1030. DOI: 10.1016/j.bmcl.2016.12.066
  42. 42. Yana S, Lina H, Huang H, Yanga M, Xua B, Chena G. Microbial hydroxylation and glycosidation of oleanolic acid by Circinella muscae and their anti-inflammatory activities. Natural Product Research. 2019;33:1849-1855. DOI: 10.1080/14786419.2018.1477150
  43. 43. Akihisa T, Watanabe K, Yoneima R, Suzuki T, Kimura Y. Biotransformation of cycloartane-type triterpenes by the fungus Glomerella fusarioides. Journal of Natural Products. 2006;69:604-607
  44. 44. Wang F-Q, Li B, Wang W, Zhang C-G, Wei D-Z. Biotransformation of diosgenin to nuatigenin-type steroid by a newly isolated strain, Streptomyces virginiae IBL-14. Applied Microbiology and Biotechnology. 2007;77:771-777. DOI: 10.1007/s00253-007-1216-1
  45. 45. Adham NZ, Zaki RA, NAim N. Microbial transformation of disogenin and its precursor furestanol glycosides. World Journal of Microbiology and Biotechnology. 2009;25:481-487. DOI: 10.1007/s11274-008-9913-1
  46. 46. Wu G-W, Gao J-M, Shi X-W, Hang Q, Wei S-P, Ding K. Microbial transformations of diosgenin by the white-rot Basidiomycete Coriolus versicolor. Journal of Natural Products. 2011;14:2095-2101. DOI: 10.1021/np2003484
  47. 47. Xu M, Huo X-K, Tian X-G, Dong P-P, Wang C, Huang S-S, et al. Microbial transformation of diosgenin by Cunninghamella blakesleana AS 3.970 and potential inhibitory effects on P-glycoprotein of its metabolites. RSC Advances. 2015;78(78):081-78089. DOI: 10.1039/c5ra122553h
  48. 48. Zhao Y, Sun LM, Wang XN, Shen T, Ji M, Li X, et al. Microbial transformation of diosgenin by Syncephalastrum racemosum (Cohn) Schroeter. Chinese Chemical Letters. 2010;21:76-80. DOI: 10.1016/j.cclet.2009.08.015
  49. 49. Dong T, Wua G-W, Wang X-N, Gao J-M, Chen J-G, Lee S-S. Microbiological transformation of diosgenin by resting cells of filamentous fungus, Cunninghamella echinulata CGMCC3.2716. Journal of Molecular Catalysis B: Enzymatic. 2010;67:251-266. DOI: 10.1016/j.molcatb.2010.09.001
  50. 50. Peterson DH, Murray HC. Microbiological oxygenation of steroids at carbon-11. Journal of the American Chemical Society. 1952;74:1871-1872
  51. 51. Habibi Z, Yousefi M, Ghanian S, Mohammadi M, Ghasemi S. Biotransformation of progesterone by Absidia griseolla var. igachii and Rhizomucor pusillus. Steroids. 2012;77:1446-1449. DOI: 10.1016/j.steroids2012.08.010
  52. 52. Shan L, Jiao K, Yin M, Huang J, Chen Y, Qin S, et al. Biotransformation of 5-en-3β-ol steroids by Mucor circinelloides lusitanicus. Biocatalysis and Biotransformation. 2016;34:83-88. DOI: 10.3109/10242422.2015.1089865
  53. 53. Choudhary MI, Erum S, Atif M, Malik R, Tameen K, Atta-ur-Rhaman. Biotransformation of (20S)-20-hydroxymethylpregna-1,4-dien-3-one by four filamentous fungi. Steroids. 2011;76:1288-1296. DOI: 10.1016/j.steroids.2011.06.007
  54. 54. Cano-Flores A, Gómez X, Ramos R. Biotransformation of steroids using different microorganisms. In: JAR S, editor. Chemistry and Biological Activity of Steroids. Rijeka: IntechOpen; 2018. DOI: 10.5772/intechopen.85849
  55. 55. Peart PC, McCook KP, Rusell FA, Reynolds WF, Reese PB. Hydroxylation of steroids by Fusarium oxysporum, Exophiala jeanselmei and Ceratocystis paradoxa. Steroids. 2011;76:1317-1330. DOI: 10.1016/j.steroids.2011.06.010
  56. 56. Kristan K, Lanisnik Rizner T. Steroid-transforming in fungi. The Journal of Steroid Biochemistry and Molecular Biology. 2012;129:79-91. DOI: 10.1016/j.jsbmb.2011.08.012
  57. 57. Fernandes P, Cruz A, Angelova B, Pinheiro HM, Cabral JMS. Microbial conversion of steroid compounds: Recent developments. Enzyme and Microbial Technology. 2003;32:688-705. DOI: 10.1016/S0141-0229(03)00029-2
  58. 58. Suzuki K, Sanga K, Chikaoka Y, Itagaki E. Purification and properties of cytochrome P-450 (P-450lun) catalyzing steroid 11β-hydroxylation in Curvularia lunata. Biochimica et Biophysica Acta. 1993;1203:215-223. DOI: 10.1016/0167-4838(93)90086-7
  59. 59. Lu W, Du L, Wang M, Jia X, Wen J, Huang Y, et al. Optimisation of hydrocortisone production by Curvularia lunata. Applied Biochemistry and Biotechnology. 2007;142:17-28. DOI: 10.1007/s12010-007-0005-8
  60. 60. Bhosale S, Saratale G, Govindwar S. Biotransformation enzymes in Cunninghamella blakesleeana (NCIM-687). Journal of Basic Microbiology. 2006;46:444-448. DOI: 10.1002/jobm.200510117
  61. 61. Petrica S, Hakkib T, Bernhardtb R, Zigonc D, Cresna B. Discovery of a steroid 11-hydroxylase from Rhizopus oryzae and its biotechnological application. Journal of Biotechnology. 2010;150:428-437. DOI: 10.1016/j.jbiotec.2010.09.928
  62. 62. Schmitz D, Janocha S, Kiss FM, Berhardt R. CYP106A2—A versatile biocatalyst with high potential for biotechnological production of selectively hydroxylated steroid and terpenoid compounds. BBA Proteins and Proteomics. 2018;1866:11-22. DOI: 10.1016/j.bbapap.2017.07.011
  63. 63. Berrie JR, Williams RAD, Smith KE. Microbial transformation of steroids—XI. Progesterone transformation by Streptomyces roseochromogenes—Purification and characterisation of the cytochrome P450 progesterone 16α-hydroxylase system. The Journal of Steroid Biochemistry and Molecular Biology. 1999;71:153-165
  64. 64. Berrie JR, Williams RAD, Smith KE. Microbial transformation of steroids—XII. Progesterone hydroxylation profiles are modulated by post-translational modification of an electron transfer protein in Streptomyces roseochromogenes. The Journal of Steroid Biochemistry and Molecular Biology. 2001;77:87-96
  65. 65. Tang R, Shen Y, Wang M, Zhou H, Zhao Y. Highly efficient synthesis of boldenone from androst-4-ene-3,17-dione by Arthrobacter simplex and Pichia pastoris. Process Biochemistry. 2019;42:933-940. DOI: 10.1007/s00449-019-02092-y
  66. 66. Hunter AC, Khuenl-B RH, Barret P, Dodd HT, Dedi C. Transformation of some 3-substituted steroids by Aspergillus tamarii KITA reveals stereochemical restriction of steroid binding orientation in the minor hydroxylation pathway A. Journal of Steroid Biochemistry and Molecular Biology. 2010;118:171-176. DOI: 10.1016/j.jsbmb.2009.12.003
  67. 67. Donova MV, Ergova OV. Microbial steroid transformations: Current state and prospect. Applied Microbiology and Biotechnology. 2012;94:1423-1447. DOI: 10.1007/978-1-4939-7183-1
  68. 68. Sultana N. Microbial biotransformation of bioactive and clinically useful steroids and some salient features of steroids and biotransformation. Steroids. 2018;136:76-92. DOI: 10.1016/j.steroids.2018.01.007
  69. 69. Tong W-Y, Dong X. Microbial biotransformation: Recent developments on steroid drugs. Recent Patents on Biotechnology. 2009;3:141-153
  70. 70. Lin Y, Song X, Fu J, Lin J, Qu Y. Microbial transformation of androst-4-ene-3,17-dione by Bordetella sp B4 CGMC2229. Journal of Chemical Technology & Biotechnology. 2009;84:789-793. DOI: 10.1002/jctb.2113
  71. 71. Lobastova TG, Gulevskaya SA, Sukhodolskaya GV, Donova MV. Dihydroxylation of dehydroepiandrosterone in positions 7α and 15α by mycelial fungi. Applied Biochemistry and Microbiology. 2009;45:617-622
  72. 72. Li H, Liu H-M, Ge W, Huang L, Shan L. Synthesis of 7α-hydroxy-dehydroepiandrosterone and 7α-hydroxy-dehydroepiandrosterone. Steroids. 2005;70:970-973
  73. 73. Lobastova TG, Khomutov SM, Vasiljeva LL, Lapitskaya MA, Pivnitsky KK, Donova MV. Synthesis of 3β-hydroxy-androsta-5,7-dien-17-one from 3β-hydroxyandrost-5-en-17-one via microbial 7α-hydroxylation. Steroid. 2009;74:233-237. DOI: 10.1016/j.steroids.2008.10.019
  74. 74. Al-Awadi S, Afzal M, Oommen S. Studies of Bacillus stearothermophilus. Part III. Transformation of testosterone. Applied Microbiology and Biotechnology. 2003;62:48-52. DOI: 10.1007/s00253-003-1269-8
  75. 75. Al-Awadi S, Afzal M, Oommen S. Studies on Bacillus stearothermophilus. Part IV. Influence of enhancers on biotransformation of testosterone. Steroids. 2005;70:323-327
  76. 76. Janeczkoa T, Dmochowska-Gladysz J, Kostrezewa-Suslowa E, Bialonskab A, Ciunikb Z. Biotransformations of steroid compounds by Chaetomium sp. KCH 6651. Steroids. 2009;74:657-660. DOI: 10.1016/j.steroids.2009.02.006
  77. 77. Romanoa A, Romanoa D, Ragg E, Costantinoc F, Lennac R, Gandolfid R, et al. Steroid hydroxylations with Botryodiplodia malorum and Colletotrichum lini. Steroid. 2006;71:429-434. DOI: 10.1016/j.steroids.2006.01.014
  78. 78. Lisowska K, Dlugonski J. Concurrent corticosteroid and phenanthrene transformation by filamentous fungus Cunninghamella elegans. The Journal of Steroid Biochemistry and Molecular Biology. 2003;85:63-69
  79. 79. Manosroi J, Chisti Y, Manosroi A. Biotransformation of cortexolone to hydrocortisone by molds using a rapid color-development assay. Applied Biochemistry and Microbiology. 2006;42:479-483
  80. 80. Wu Y, Li H, Zhang X-M, Gong JS, Rao Z-M, Shi J-S, et al. Efficient hydroxylation of functionalized steroids by Colletotrichum lini ST-1. Journal of Molecular Catalysis B: Enzymatic. 2015;120:111-118. DOI: 10.1016/j.molcatb.2015.07.003
  81. 81. Agnieszka Bartmanska A, Dmochowska-Gładysz J. Transformation of steroids by Trichoderma hamatum. Enzyme and Microbial Technology. 2007;40:1615-1621. DOI: 10.1016/j.enzmictec.2006.11.011
  82. 82. Choudhary MI, Siddiqui ZA, Musharraf SG, Nawaz SA, Atta-ur-Rahman. Microbial transformation of prednisone. Natural Product Research. 2005;19:311-317. DOI: 10.1080/14786410410001729168
  83. 83. Cano A, Ramírez-Apan MT, Delgado G. Biotransformation of sclareolide by filamentous fungi: Cytotoxic evaluations of the derivates. Journal of the Brazilian Chemical Society. 2011;22:1177-1182. DOI: 10.1590/S0103-50532011000600025
  84. 84. Atta-ur-Rahman, Farooq A, Choudhary MI. Microbial transformation of sclareolide. Journal of Natural Products. 1997;60:1038-1040. DOI: 10.1021/np970076h
  85. 85. Choudhary MI, Musharraf SG, Sami A, Atta-ur-Rahman. Microbial transformation of sesquiterpenes, (−)-ambrox and (+)-sclareolide. Helvetica Chimica Acta. 2004;87:2685-2694
  86. 86. Ata A, Conci LJ, Betteridge J, Orhan I, Sener B. Novel microbial transformations of sclareolide. Chemical and Pharmaceutical Bulletin. 2007;55:118-123. DOI: 10.1248/cpb.55.118
  87. 87. Cao H, Chen X, Jassbi AR, Xiao J. Microbial biotransformation of bioactive flavonoids. Biotechnology Advances. 2015;33:214-233. DOI: 10.1016/j.biotechadv.2014.10.012
  88. 88. Andrae-Marobela K, Ghislain FW, Okatch H, Majinda R. Polyphenols: A diverse class of multi-target anti-HIV-1 agents. Current Drug Metabolism. 2013;7:392-413. DOI: 10.2174/1389200211314990095
  89. 89. Liao XL, Luo JG, Kong LY. Flavonoids from Millettia nitida var. Hirsutissima with their anticoagulative activities and inhibitory effects on NO production. Journal of Natural Medicines. 2013;67:856-861. DOI: 10.1007/s11418-013-0745-4
  90. 90. Ogungbe IV, Erwin WR, Setzer WN. Antileishmanial phytochemical phenolics: Molecular docking to potential protein targets. Journal of Molecular Graphics & Modelling. 2014;48:105-117. DOI: 10.1016/j.jmgm.2013.12.010
  91. 91. Kim H, Bartley GE, Arvik T, Lipson R, Nah SY, Seo K, et al. Dietary supplementation of chardonnay grape seed flour reduces plasma cholesterol concentration, hepatic steatosis, and abdominal fat content in high-fat diet-induced obese hamsters. Journal of Agricultural and Food Chemistry. 2014;62:1919-1925. DOI: 10.1021/jf404832s
  92. 92. Asha S, Vidyavathi M. Cunninghamella—A microbial model for drug metabolism studies—A review. Biotechnology Advances. 2009;27:16-29. DOI: 10.1016/j.biotechadv.2008.07.005
  93. 93. Alarcón J, Alderete J, Escobar C, Araya R, Cespedes CL. Aspergillus niger catalyzes the synthesis of flavonoids from chalcones. Biocatalysis and Biotransformation. 2013;31:160-167. DOI: 10.3109/10242422.2013.813489
  94. 94. Sordon S, Madej A, Poplonski J, Bartmanska A, Tronina T, Brzezowska E, et al. Regioselective ortho-hydroxylations of flavonoids by yeast. Journal of Agricultural and Food Chemistry. 2016;64:5525-5530. DOI: 10.1021/acs.jafc.6b02210
  95. 95. Bartmanska A, Huszcza E, Tronina T. Transformation of isoxanthohumol by fungfi. Journal of Molecular Catalysis B: Enzymatic. 2009;61:221-224. DOI: 10.1016/j.molcatb.2009.07.008
  96. 96. Chen X, Mukwaya E, Wong MS, Zhang Y. A systematic review on biological activities of prenylated flavonoids. Pharmaceutical Biology. 2014;52:655-660. DOI: 10.3109/13880209.2013.853809
  97. 97. Cao H, Chen X, Jassbi AR, Xiao J. Microbial transformation of bioactive flavonoids. Biotechnology Advances. 2015;33:214-223. DOI: 10.1016/j.biotechadv.2014.10.012
  98. 98. Bartmanska A, Tronina T, Huszcza E. Transformation of 8-prenylnaringenin by Absidia coerula and Beauveria bassiana. Bioorganic & Medicinal Chemistry Letters. 2012;22:6451-6453. DOI: 10.1016/j.bmcl.2012.08.060
  99. 99. Tronina T, Strugala P, Poplonski J, Wloch SS, Bartmanska A, Huszcza E. The influence of glycosylation of natural and synthetic prenylated flavonoids on binding to human serum albumin and inhibition of cyclooxygenases COX-1 and COX-2. Molecules. 2017;22:1230-1250. DOI: 10.3390/molecules22071230
  100. 100. Haraguchi H, Inoue J, Tamura Y, Mizutani K. Antioxidative components of Psoralea corylifolia (Leguminosae). Phytotherapy Research. 2002;16:539e544. DOI: 10.1002/ptr.972
  101. 101. Lim SH, Ha TY, Ahn J, Kim S. Estrogenic activities of Psoralea corylifolia L, seed extracts and main constituents. Phytomedicine. 2011;18:425-430. DOI: 10.1016/j.phymed.2011.02.002
  102. 102. Luo J, Liang Q, Shen Y, Chen X, Yin Z, Wang M. Biotransformation of bavachinin by three fungal cell cultures. Journal of Bioscience and Bioengineering. 2014;117:191-196. DOI: 10.1016/j.jbiosc.2013.08.001
  103. 103. Tronina T, Bartmanska A, Milczarek M, Wietrzyk J, Poplonski J, Roj E, et al. Antioxidant and antiproliferative activity of glycosides obtained by biotransformation of xanthohumol. Bioorganic & Medicinal Chemistry Letters. 2013;23:1957-1960. DOI: 10.1016/j.bmcl.2013.02.031
  104. 104. Kim HJ, Lee I-S. Microbial metabolism of the prenylated chalcone xanthohumol. Journal of Natural Products. 2006;69:1522-1524. DOI: 10.1021/np060310g
  105. 105. Bartmanska A, Huszcza E, Tronina T. Transformation of isoxanthohumol by fungi. Journal of Molecular Catalysis B: Enzymatic. 2009;61:221-224. DOI: 10.1016/j.molcatb.2009.07.008
  106. 106. Tronina T, Bartmanska A, Poplonski J, Huszcza E. Transformation of xanthohumol by Aspergillus ochraceus. Journal of Basic Microbiology. 2014;54:66-71. DOI: 10.1002/jobm201200320
  107. 107. Tronina T, Bartmanska A, Filip-Psurska B, Wietrzyk J, Poplonski J, Huszcza EA. Fungal metabolites of xanthohumol with potent antiproliferative activity on human cancer cell lines in vitro. Bioorganic & Medicinal Chemistry. 2013;21:2001-2006. DOI: 10.1016/j.bmc.2013.01.026
  108. 108. Stompor M, Potaniec B, Szumny A, Zieliński P, Żołnierczyk AK, Anioł M. Microbial synthesis of dihydrochalcones using Rhodococcus and Gordonia species. Journal of Molecular Catalysis B: Enzymatic. 2013a;97:283-288
  109. 109. Abourashed EA, Mikell JR, Khan IA. Bioconversion of silybin to phase I and II microbial metabolites with retained antioxidant activity. Bioorganic & Medicinal Chemistry. 2012;20:2784-2788. DOI: 10.1016/j.bmc.2012.03.046
  110. 110. Choi J-M, Han S-S, Kim H-S. Industrial applications of enzyme biocatalysis: Current status and future aspects. Biotechnology Advances. 2015;33:1443-1454. DOI: 10.1016/j.biotechadv.2015.02.014
  111. 111. De Carvalho CCCR. Enzymatic and whole cell catalysis: Finding new strategies for old processes. Biotechnology Advances. 2011;29:75-83
  112. 112. Muñoz SD, Hoyos P, Hernáiz MJ, Alcántara AR, Sánchez-Moreno JM. Industrial biotransformations in the synthesis of building blocks leading to enantiopure drugs. Bioresource Technology. 2012;115:196-207. DOI: 10.1016/j.biortech.2011.11.131
  113. 113. Patel RN. Biocatalysis for synthesis of pharmaceuticals. Bioorganic & Medicinal Chemistry. 2018;26:1252-1274. DOI: 10.1016/j.bmc.2017.05.023
  114. 114. Van Den Burg B. Extremophiles as a source for novel enzymes. Current Opinion in Microbiology. 2003;6:213-218. DOI: 10.1016/S1369-5274(03)00060-2
  115. 115. Antranikian G, Vorgias CE, Bertoldo C. Extreme environments as a resource for microorganisms and novel biocatalysts. Advances in Biochemical Engineering/Biotechnology. 2005;96:219-262. DOI: 10.1007/b135786
  116. 116. Elleuche S, Schroder C, Sahm K, Antranikian G. Extremozymes-biocatalysts with unique properties from extremophilic microorganisms. Current Opinion in Biotechnology. 2014;29:116-123. DOI: 10.1016/j.copbio.2014.04.003
  117. 117. Falcicchio P, Wolterink-Van Loo S, Franssen MC, van der Oost J. DHAP-dependent aldolases from (hyper) thermophiles: Biochemistry and applications. Extremophiles. 2014;18:1-13. DOI: 10.1007/s00792-013-0593-x
  118. 118. Urbieta MS, Donati ER, Chan KG, Shahar S, Li Sin L, Goh KM. Thermophiles in the genomic era: Biodiversity, science, and applications. Biotechnology Advances. 2015;33:633-647. DOI: 10.1016/j.biotechadv.2015.04.007
  119. 119. Woodward J, Orr M, Cordray K, Greenbaum E. Biotechnology: Enzymatic production of biohydrogen. Nature. 2000;405:1014-1015
  120. 120. Soliman N, Abdel-Fattah Y, Mostafa HE, Gaballa A. Heterologous expression of thermostable esterase gene from Geobacillus thermoleovorans YN under different expression promoters. International journal of Environmental Science and Technology. 2014;11:119-126. DOI: 10.1007/s13762-013-0360-7
  121. 121. Saranya P, Kumari HS, Rao BP, Sekaran G. Lipase production froma novel thermo-tolerant and extreme acidophile Bacillus pumilus using palmoil as the substrate and treatment of palm oil-containing wastewater. Environmental Science and Pollution Research International. 2014;21:3907-3919. DOI: 10.1007/s11356-013-2354-x
  122. 122. Gudiukaitė R, Gegeckas A, Kazlauskas D, Citavicius D. Influence of N-and/or C-terminal regions on activity, expression, characteristics and structure of lipase from Geobacillus sp. 95. Extremophiles. 2014;18:131-145. DOI: 10.1007/s00792-013-0605-x
  123. 123. Abraham J, Gea T, Sánchez A. Substitution of chemical dehairing by proteases from solid state fermentation of hair wastes. Journal of Cleaner Production. 2014;74:191-198
  124. 124. Staufenberger T, Imhoff JF, Labes A. First crenarchaeal chitinase found in Sulfolobus tokodaii. Microbiological Research. 2012;167:262-269
  125. 125. Barabote RD, Parales JV, Guo Y-Y, Labavitch JM, Parales RE, Berry AM. Xyn10A, a thermostable endoxylanase from Acidothermus cellulolyticus 11B. Applied and Environmental Microbiology. 2010;76:7363-7366
  126. 126. Kang J, Park K-M, Choi K-H, Park C-S, Kim G-E, Kim D, et al. Molecular cloning and biochemical characterization of a heat-stable type I pullulanase from Thermotoga neapolitana. Enzyme and Microbial Technology. 2011;48:260-266

Written By

Arturo Cano-Flores, Javier Gómez, Iker S. Escalona-Torres and Benjamín Velasco-Bejarano

Submitted: 08 October 2019 Reviewed: 31 October 2019 Published: 16 January 2020