molecules Review Biotransformation of Oleanane and Ursane Triterpenic Acids Natalia A. Luchnikova 1,2 , Victoria V. Grishko 3 and Irina B. Ivshina 1,2,* 1 Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Ural Branch of the Russian Academy of Sciences, 614081 Perm, Russia; [email protected] 2 Department of Microbiology and Immunology, Perm State National Research University, 614990 Perm, Russia 3 Institute of Technical Chemistry, Perm Federal Research Center, Ural Branch of the Russian Academy of Sciences, 614013 Perm, Russia; [email protected] * Correspondence: [email protected]; Tel.: +7-342-2808114 Academic Editor: Derek J. McPhee Received: 9 October 2020; Accepted: 23 November 2020; Published: 25 November 2020 Abstract: Oleanane and ursane pentacyclic triterpenoids are secondary metabolites of plants found in various climatic zones and regions. This group of compounds is highly attractive due to their diverse biological properties and possible use as intermediates in the synthesis of new pharmacologically promising substances. By now, their antiviral, anti-inflammatory, antimicrobial, antitumor, and other activities have been confirmed. In the last decade, methods of microbial synthesis of these compounds and their further biotransformation using microorganisms are gaining much popularity. The present review provides clear evidence that industrial microbiology can be a promising way to obtain valuable pharmacologically active compounds in environmentally friendly conditions without processing huge amounts of plant biomass and using hazardous and expensive chemicals. This review summarizes data on distribution, microbial synthesis, and biological activities of native oleanane and ursane triterpenoids. Much emphasis is put on the processes of microbial transformation of selected oleanane and ursane pentacyclic triterpenoids and on the bioactivity assessment of the obtained derivatives. Keywords: biological activity; biotransformation; glycyrrhetinic acid; oleanolic acid; ursolic acid 1. Introduction Drugs derived from secondary plant metabolites make up about 25% of the global pharmaceutical market [1]. Secondary metabolites of plants are several groups of compounds; the most numerous (about 25,000 representatives) and diverse group is terpenic hydrocarbons and their oxygen-containing derivatives (terpenoids). Depending on the number of isoprene units (C5H8) in their structure, they contain a certain number of carbon atoms and are classified into mono-(C10), sesqui-(C15), di-(C20), triterpenoids (C30), etc. Naturally occurring triterpenoids are represented by more than 100 various types of skeletons [2]. Native triterpenoids, in particular, oleanane and ursane representatives, are of interest for researchers due to their availability and multiple biological activities, including antimicrobial, anti-inflammatory, antitumor, cytotoxic, hepatoprotective, and other activities [3–7]. Triterpenic molecules, however, are highly hydrophobic which significantly limits their use as effective pharmacological agents. At present, one of the most common ways to increase the effectiveness and bioavailability of triterpenoids is by chemical modification. This usually requires high temperature and pH, use of expensive reagents, and introduction of protective groups of molecule reactive centers [8–11]. An alternative way to obtain valuable derivatives is by biotransformation under normal and environmentally friendly conditions employing the catalytic activity of microorganisms with high regio- and stereoselectivity in one Molecules 2020, 25, 5526; doi:10.3390/molecules25235526 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 34 Molecules 2020, 25, 5526 2 of 31 [8–11]. An alternative way to obtain valuable derivatives is by biotransformation under normal and environmentally friendly conditions employing the catalytic activity of microorganisms with high technologicalregio- and stereoselectivity stage. Furthermore, in one microbial technological conversion stage. Furthermore, ensures specific microbial modifications conversion of triterpenic ensures moleculespecific modifications sites that are ofeither triterpenic not modified molecule orsites poorly that are modified either not by modified synthetic or transformations poorly modified [12 by]. Notesynthetic that, transformations among the known [12]. microbialNote that, biocatalysts,among the known members microbial of mycelial biocatalysts, fungi are members the most of studiedmycelial[ 13fungi–15] arewhereas the most bacterial studied catalysts [13–15] are whereas only represented bacterial catalysts by a few are gram-positive only represented species by [16 a– few20]. Thegram-positive first papers species on microbial [16–20]. The transformation first papers ofon triterpenoids microbial transformation were published of triterpenoids in the 1960s were [21]. Thepublished earliest in informationthe 1960s [21]. related The earliest to bioconversion information processes related to of bioconversion oleanane derivatives processes catalyzed of oleanane by fungi,derivatives such catalyzed as Curvularia by fungi, lunata suchATCC as 13432,CurvulariaTrichotecium lunata ATCC roseum 13432,ATCC Trichotecium 8685, Cunninghamella roseum ATCCsp. ATCC8685, Cunninghamella 3229, Mucor griseo-cyanus sp. ATCC 3229,ATCC Mucor 1207-a, griseo-cyanusHelicostylum ATCC piriforme 1207-a, HelicostylumATCC 8992, piriformeFusarium ATCC lini, and8992,Cunninghamella Fusarium lini, and blakesleana Cunninghamelladates back blakesleana to about dates the sameback to time about [22– the25]. same The time data [22–25]. on bacterial The transformationdata on bacterial of oleananetransformation triterpenoids of oleanane by Streptomyces triterpenoidssp. G-20by Streptomyces and Chainia sp. antibiotica G-20 andIFO Chainia 12,246 wereantibiotica reported IFO in12,246 the second were reported half of the in1980s the second [26,27]. half As forof microbialthe 1980s transformations[26,27]. As for ofmicrobial ursane pentacyclictransformations triterpenoids of ursane bypentacyclic both fungal triterpenoids (Mucor plumbeus by both ATCCfungal 4740(Mucor [28 plumbeus]) and bacterial ATCC 4740 (Nocardia [28]) sp.and NRRLbacterial 5646 (Nocardia [29]) strains, sp. NRRL those 5646 studies [29]) were strains, initiated those only studies in the were 2000s. initiated Henceforth, only in the the interest 2000s. inHenceforth, the topic discussedthe interest has in beenthe topic increasing discussed and thehas Activebeen increasing Triterpenoid and Biocatalysts the Active ListTriterpenoid has been expandedBiocatalysts every List has year, been as isexpanded the number every of year, various as is bioactive the number triterpenic of various derivatives bioactive formed triterpenic via biotransformationsderivatives formed [via30– biot32].ransformations [30–32]. Now, preparationpreparation of biologicallybiologically active compounds based on pentacyclic triterpenoids is an actual research discussed in plenty of experimental and review publications [8,12,32–34]. [8,12,32–34]. However, However, the reviews are are overwhelmingly overwhelmingly focused focused on on chemical chemical transformations transformations or or describe describe specific specific types types of ofbiological biological activities activities of triterpenoids. of triterpenoids. Less Less frequently, frequently, they they deal dealwith with biological biological transformations. transformations. The Thelatest latest of the of thefew few reviews reviews on onmicrobial microbial transformati transformationsons of of pentacyclic pentacyclic triterpenoids triterpenoids include include literature data upup to to 2016 2016 [12 ,[12,32,33,35].32,33,35]. Our Our review review summarizes summarizes the data the from data 2013 from to the 2013 present to the on distribution,present on microbialdistribution, biosynthesis, microbial biosynthesis, biological activity, biological and ac mainlytivity, biotransformationand mainly biotransformation of oleanane of and oleanane ursane pentacyclicand ursane triterpenoidspentacyclic totriterpenoids obtain promising to obtain biologically promising active biologically compounds active or intermediatescompounds or of theirintermediates synthesis. of their synthesis. 2. Distribution in Nature Plant pentacyclic triterpenoids are represented by more than two dozen structural types; the most common are oleanane and ursane ones (Figure1 1).). InIn freefree forms,forms, triterpenoidstriterpenoids areare nonvolatilenonvolatile lipophilic substances that are soluble in organic solventssolvents andand insolubleinsoluble inin water.water. The mostmost availableavailable oleanane triterpenoids are oleanolic acid 1 (OA, 3β-hydroxy-olean-12-en-28-oic acid, C H O , CAS oleanane triterpenoids are oleanolic acid 1 (OA, 3β-hydroxy-olean-12-en-28-oic acid, C3030H4848O33, CAS 508-02-1) and glycyrrhetinic acid 2 (GA, 3β-hydroxy-11-oxo-18β-olean-12-en-30-oic acid, C H O , 508-02-1) and glycyrrhetinic acid 2 (GA, 3β-hydroxy-11-oxo-18β-olean-12-en-30-oic acid, C3030H4646O4, CAS 471-53-4), and ursolic acid 3 (UA, 3β-hydroxy-urs-12-en-28-oic acid, C H O , CAS 77-52-1) is CAS 471-53-4), and ursolic acid 3 (UA, 3β-hydroxy-urs-12-en-28-oic acid, C3030H4848O3, CAS 77-52-1) is the most available ursane triterpenoid. Biosynthesis of oleanane and ursane pentacyclic triterpenoids in plants occurs occurs by by conversion conversion of of the the acyclic acyclic triterpene triterpene squalene squalene (4) ( 4to) to2,3-oxidosqualene