kimia bahanalam

Abstract

Saponins are bioactive compounds generally considered to be produced by plants to counteract pathogens and herbivores. Besides their role in plant defense, saponins are of growing interest for drug research as they are active constituents of several folk medicines and provide valuable pharmacological properties. Accordingly, much effort has been put into unraveling the modes of action of saponins, as well as in exploration of their potential for industrial processes and pharmacology. However, the exploitation of saponins for bioengineering crop plants with improved resistances against pests as well as circumvention of laborious and uneconomical extraction procedures for industrial production from plants is hampered by the lack of knowledge and availability of genes in saponin biosynthesis. Although the ability to produce saponins is rather widespread among plants, a complete synthetic pathway has not been elucidated in any single species. Current conceptions consider saponins to be derived from intermediates of the phytosterol pathway, and predominantly enzymes belonging to the multigene families of oxidosqualene cyclases (OSCs), cytochromes P450 (P450s) and family 1 UDP-glycosyltransferases (UGTs) are thought to be involved in their biosynthesis. Formation of unique structural features involves additional biosynthetical enzymes of diverse phylogenetic background. As an example of this, a serine carboxypeptidase-like acyltransferase (SCPL) was recently found to be involved in synthesis of triterpenoid saponins in oats. However, the total number of identified genes in saponin biosynthesis remains low as the complexity and diversity of these multigene families impede gene discovery based on sequence analysis and phylogeny.

This review summarizes current knowledge of triterpenoid saponin biosynthesis in plants, molecular activities, evolutionary aspects and perspectives for further gene discovery.


Graphical abstract

Biosynthesis of triterpenoid saponins branches off phytosterol anabolism by alternative cyclization of 2,3-oxidosqualene. Mainly P450s and UGTs are involved in further biosynthetic steps.

Research highlights

► Saponins are bioactive compounds participating in plant defense. ► Saponins derive from phytosterol biosynthesis. ► OSCs mediate oxidosqualene cyclization. ► P450s catalyze sapogenin modification. ► UGTs are involved in conferring biological activity of saponins.

Keywords

  • Saponins;
  • Hemolytic activity;
  • Triterpenes;
  • Oxidosqualene cyclases;
  • Cytochromes P450;
  • UDP-gylcosyltransferases;
  • Phylogeny;
  • Gene discovery

Figures and tables from this article:

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Fig. 1. Examples for saponins from Saponaria officinalis (soapwort) and Quilllaja saponaria (soapbark). Both plants produce complex mixtures of triterpenoid saponins, with at least 13 compounds in S. officinalis (Koike et al., 1999) and up to around 70 structurally discrete saponins in Q. saponaria (Bankefors et al., 2008).
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Fig. 2. Two representative triterpenoid (oleanolic acid) and steroidal (diosgenin) sapogenin skeletons.
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Fig. 3. Example of a steroidal glycoalkaloid aglycone skeleton (solasodine).
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Fig. 4. Monodesmosidic (3-O-β-d-glucopyranosyl-(1,4)-β-d-glucopyranosyl-oleanolic acid; A) and bidesmosidic (3-O-β-d-glucopyranosyl-(1,4)-β-d-glucopyranosyl-olean-12-en-28-O-β-d-glucopyranosyl ester; B) saponins.
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Fig. 5. Schematic models of the molecular mechanisms of saponin activities towards membranes. Saponins integrate with their hydrophobic part (sapogenin) into the membrane. Within the membrane they form complexes with sterols, which subsequently, driven by interaction of their extra-membranous orientated saccharide residues, accumulate into plaques. Sterical interference of these saccharide moieties causes membrane curvature subsequently leading to (A) pore formation in the membrane (Armah et al., 1999) or (B) hemitubular protuberances resulting in sterol extraction via vesiculation (Keukens et al., 1995). Alternatively, after membrane integration saponins may migrate towards sphingolipid/sterol enriched membrane domains (C) prior to complex formation with the incorporated sterols, thereby interfering with specific domain functionalities (Lin and Wang, 2010). Similarly to (B), accumulation of saponins in confined membrane domains has further been suggested to cause deconstructive membrane curvature in a dose-dependent manner.
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Fig. 6. Early steps in biosynthesis of phytosterols and triterpenoid saponins leading to the common precursor 2,3-oxidosqualene. IPP – Isopentenyl pyrophosphate, DMPP – dimethylallyl pyrophosphate, GPP – geranyl pyrophosphate, FPP – farnesyl pyrophosphate.
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Fig. 7. Oxidosqualene cyclase (OSC) catalyzed cyclization cascades of 2,3-oxidosqualene into different triterpenoid sapogenin skeletons.
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Fig. 8. Bootstrapped neighbor joining tree of known OSCs. CLUSTAL W alignment and bootstrap analysis were performed with MEGA4 (version: 4.0.2) using default parameters (Tamura et al., 2007) and with the putative Chlamydomonas reinhardtii cycloartenol synthase as outgroup (GenBank ID: XP_001689874). The given scale represents 0.05 amino acid substitutions per site. Bootstrap values below 50 are not shown. The name of individual enzymes is followed by the plant order (color coded according to their taxonomic subclass [taxonomy according to http://www.uniprot.org/taxonomy/]) as well as the plant species they originate from. 2,3-Oxidosqualene cyclization products identified to emerge from the activity of the corresponding OSC are indicated in squared brackets: aa – α-amyrin, ara – arabidiol, ba – β-amyrin, bac – baccharis oxide, bar – baruol, bau – baurenol, ca – cycloartenol, cam – camelliol C, cur – cucurbitadienol, da – δ-amyrin, dam – dammarenediol, fri – friedelin, ge – germanicol, glu – glutinol, ism – isomultiflorenol, isotir – isotirucallol, ls – lanosterol, lu – lupeol, lud – lupane-3β,20-diol, mar – marneral, tal – thalianol, tar – taraxasterol, tax – taraxerol, tir – tirucalla-7,24-dien-3β-ol, n.d. – no activity observed, unchar. – not biochemically characterized, minor – additional byproducts either reported to be of minor appearance or to represent <10% of the observed products. *Although CsOSC2 groups with chair–boat–chair directing OSCs, its products derive from direction of 2,3-oxidosqualene into chair–chair–chair formation. The underlying sequences in FASTA format as well as the alignment and the phylogentic tree are also available at http://www.p450.kvl.dk/OSC-sequences.fasta, http://www.p450.kvl.dk/OSC-alignment.pdf and http://www.p450.kvl.dk/OSC-phyltree.pdf, respectively.
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Fig. 9. Catalytic activities of P450s involved in saponin biosynthesis. The function of CYP93E3 has only been assayed with β-amyrin, and the specific reaction catalyzed by CYP51H10 in avenacin biosynthesis has not been elucidated. Accumulation of mainly β-amyrin and low amounts of 23-hydroxy-β-amyrin in CYP51H10 mutant lines indicates involvement in an early biosynthetical step (biochemical activities are according to ,  and ).
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Fig. 10. Glycosylation of oleanane type sapogenins by UGTs in triterpenoid saponin biosynthesis. The position specificity of UGT71G1 and UGT73K1 has not been elucidated. Putative glycosylation positions suggested by the authors are indicated by numbering (biochemical activities are according to ,  and ).
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Fig. 11. Saccharide chain elongation during soyasaponin I biosynthesis in Glycine max catalyzed by UGT73P2 and UGT91H4 (Shibuya et al., 2010).
Table 1. Overview of OSCs reported in the literature. 2,3-Oxidosqualene cyclization products identified to emerge from the activity of the corresponding OSC are indicated in squared brackets: aa – α-amyrin, ara – arabidiol, ba – β-amyrin, bac – baccharis oxide, bar – baruol, bau – baurenol, ca – cycloartenol, cam – camelliol C, cur – cucurbitadienol, da – δ-amyrin, dam – dammarenediol, fri – friedelin, ge – germanicol, glu – glutinol, ism – isomultiflorenol, isotir – isotirucallol, ls – lanosterol, lu – lupeol, lud – lupane-3β,20-diol, mar – marneral, tal – thalianol, tar – taraxasterol, tax – taraxerol, tir – tirucalla-7,24-dien-3β-ol, n.d. – no activity observed, unchar. – not biochemically characterized, minor – additional byproducts either reported to be of minor appearance or to represent <10% of the observed products.
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