Category:TP6

Triterpene (C30)

Ring configuration

Steroid

The basic structure is 4 carbon rings, cyclopenta[a]phenanthrene, gonane, or sterane. The rings B/C are always trans in all natural steroids. If the rings C/D are trans, it is called gonane. If its stereochemistry is unspecified, it is called sterane. Most steroids take gonane form, but in cardenolides and bufanolides, the rings C/D are cis.


Cyclopenta[a]phenanthrene	Gonane

The majority of steroids have methyl groups sticking out from the bridgehead positions C-10 and C-13. When these methyl groups (or hydrogens) stand above the plane, they are called β-configuration. Those below the plane are called α-configuration. If the configuration at any site is unknown, it is indicated as ξ (Greek Xi). By default, hydrogen atoms or substituents at the positions C-8, 9, 10, 13, and 14 are assumed to be 8β, 9α, 10β, 13β, and 14α configurations. C-5 is a special position, because there are as many 5α steroids as 5β are.


cholestane backbone	5α-configuration	5β-configuration

Triterpenes

In almost all pentacyclic triterpenes in angiosperms, the methyl group at the DE-ring fusion is β-configuration. Some triterpenes in ferns, mosses, gymnosperms have α-methyl group at the DE-ring fusion.

Biosynthesis

Overview

The starting point is squalene, which is formed by joining two FPPs tail-to-tail. Bacterial cyclases use squalene directly^[1], but those of the other species use 2,3-oxidosqualene for cyclization.


squalene	2,3-oxidosqualene

In bacteria, squalene is cyclized via the 17α-deoxydammarenyl cation to hopene and other triterpenes.
In eukaryotes, 2,3-oxidosqualene is cyclized via the protosteryl cation to lanosterol (animals and fungi), cycloartenol (plants) or parkeol (sea cucumbers) by a series of 1,2-hydride and methyl shifts (Wagner-Meerwein shifts).
In plants, a trace amount of phytosterols comes from lanosterol ^[2] At3g45130 is lanosterol synthase in Arabidopsis and its orthologs exist in asterids Taraxacum officinale and Panax ginseng and eurosid Luffa cylindrica. Lanosterol synthase exists broadly among eudicots ^[3]. Parkeol is also widespread in plants.
In plants, various triterpenes arise from the 17β-dammarenyl cation.

References

↑ Bacterial squalene cyclases can accept oxidosqualene as their substrates, but oxidosqualene usually does not exist in bacteria
↑ Ohyama K, Suzuki M, Kikuchi J, Saito K, Muranaka T (2009) Dual biosynthetic pathways to phytosterol via cycloartenol and lanosterol in Arabidopsis Proc Natl Acad Sci USA 106(3):725-730
↑ Kolesnikova MD, Xiong Q, Lodeiro S, Hua L, Matsuda SPT (2006) Lanosterol biosynthesis in plants Arch Biochem Biophys 447:87-95

Oxidosqualene Cyclase in Eukaryotes

Any path of reactions from the root (2,3-oxidosqualene) to any triterpene backbone with a colored background is catalyzed by a single enzyme called oxidosqualene cyclase (OSC) or terpene synthase h (tpsh).^[1]

Backbone Color Code:	Animals, fungi, and yeast	Plants only
Six-membered rings:	chair (C), or boat (B)

2,3-oxidosqualene

lanosterol/
cycloartenol
syntase^[2]

stepwise
cyclization^[3]

lupeol/
β-amyrin
synthase^[4]

stepwise
cyclization

17β-protosteryl cation (C-B-C)^[5]

1,2-shift

lanosteryl cation (C-C-C)

17β-dammarenyl cation (C-C-C)^[6]

D-ring
expansion

	fungus only^[7]
	protostane

1,2-shifts

all eukaryotes

D-ring
expansion

dammarane
euphane
tirucalane etc.^[8]

cation with the chain at C18 or C17 position

or

all steroids
lanostane
cycloartane
cucurbitane
ergostane etc.


baccharane shionane

baccarenyl cation (C-C-C-C)

E-ring
cyclization
(from 17β)

No 17α known
in nature ^[9]

E-ring
cyclization
(from 18α)

E-ring cyclization
(from 17α/β)

E-ring cyclization
(from 18α/β)

arborinyl cation (C-B-C-C)

unnamed cation (C-B-C-C)

21α-hopyl cation (C-C-C-C)
21β-moretyl cation (C-C-C-C)^[10]

H18α-lupyl cation (C-C-C-C)
H18β-lupyl cation (C-C-C-B)

1,2-shifts

E-ring expansion

1,2-shifts

E-ring expansion

1,2-shifts

E-ring expansion

1,2-shifts

E-ring expansion

arborinane (C-B-C-C)
stictane (C-B-C-C-C)^[11]

hancokinane (C-B-C-C)

hopane (C-C-C-C)
gammacerane (C-C-C-C-C)
fernane (C-C-C-C)
swertane (C-C-C-C-C)

oleanane^[12] (C-C-C-C-C)
lupane (C-C-C-C)
germanicane
taraxastane (C-C-C-C-C)
ursane (C-C-C-C-C/B)
friedomadeirane (C-C-C-C)^[13]

References
↑ Terpene synthases a-f are responsible for mono-, sesquie- and diterpenes. Tps g is the squalene cyclase. ↑ Lanosterol synthase is the most accessible enzyme among oxidosqualene cyclases, e.g. from mammalian liver or yeast. Cycloartenol synthase is the basic OSC in plants, although lanosterol synthase is also found. For the grouping of cyclases, check the review by Xiong Q et al. (2005) in this page. References. Corey EJ, Russey WE, Ortiz-de-Montellano PR (1966) 2,3-Oxidosqualene, an intermediate in the biological synthesis of sterols from squalene J Am Chem Soc 88:4750-1 Kolesnikova MD, Xiong Q, Lodeiro S, Hua L, Matsuda SPT (2006) Lanosterol biosynthesis in plants Arch Biochem Biophys 447:87-95 In Arabidopsis, cycloartenol synthase can be converted to lanosterol synthase with only two amino acid substitutions: His477 to Asn and Ile481 to Val. Tyr410 is also important for specificity. Lodeiro S, Schulz-Gasch T, Matsuda SPT (2005) Enzyme redesign: two mutations cooperate to convert cycloartenol synthase into an accurate lanosterol synthase J Am Chem Soc 127:14132-14133 ↑ The cyclization process is stepwise, not concerted as previously thought. As one clue, squalene is not fully folded in the cyclase active site. Ref. Reinert DJ, Balliano G, Schulz GE (2004) Conversion of squalene to the pentacarbocyclic hopene. Chem Biol 11:121-6 ↑ Lupeol synthases are found in Glycyrrhiza glabra, Betula platyphylla, Taraxacum officinale, and Olea europea. They form a clade (74-81% identical) that is distinct from other OSCs. Lupeol synthase evolved before the divergence of asterids and eurosids. On the other hand, β-amyrin synthases are considerably more distant (48-50% identical) than are the CAS enzymes (70-79% identical). β-amyrin synthases in eudicotsa nd monocots may have independent origins. Haralampidis K, Bryan G, Qi X, Papadopoulou K, Bakht S, Melton R, Osbourn A (2001) A new class of oxidosqualene cyclases directs synthesis of antimicrobial phytoprotectants in monocots Proc Natl Acad Sci U S A 98(23):13431-6 Qi X, Bakht S, Leggett M, Maxwell C, Melton R, Osbourn A (2004) A gene cluster for secondary metabolism in oat: implications for the evolution of metabolic diversity in plants Proc Natl Acad Sci U S A 101(21):8233-8 ↑ The C-17 chain of rotosteryl cation is β-configuration, not α. Ref. Corey EJ, Virgil SC (1991) An experimental demonstration of the stereochemistry of enzymic cyclization of 2,3-oxidosqualene to the protosterol system, forerunner of lanosterol and cholesterol. J Am Chem Soc 113:4025-6 ↑ The C-17 chain of dammarenyl cation is β-configuration. Ref. Xiong Q, Rocco F, Wilson WK, Xu R, Ceruti M, Matsuda SPT (2005) Structure and reactivity of the dammarenyl cation: configuration transmission in triterpene synthesis. J Org. Chem. 70:5362-75 ↑ Oxygenated protostane are known in Cephalosporium caerulens, Fusidium coccineum, and Aspergillus fumigatus (Ascomycota). Ref. Hattori H, Igarashi H, Iwasaki S, Okuda S, (1969) Isolation of 3bhydroxy- 4b-methylfusida-17(20)[16,21-cis],24 diene (3b-hydroxyprotosta- 17(20)[16,21-cis],24 diene) and a related triterpene alcohol Tetrahedron Lett 13, 1023–1026 Tiwari KP, Choudhary RN (1981) Chemical examination of Wisteria sinensis Proc Natl Acad Sci India A 51, 263–271 ↑ Dammarane derivatives are unusually prevalent in the genus Euphorbia. ↑ No 17α cyclization for the ring-B boat form. Also no squalene cyclase is known for the ring-B boat form. Ref. Xiong Q, Rocco F, Wilson WK, Xu R, Ceruti M, Matsuda SPT (2005) Structure and reactivity of the dammarenyl cation: configurational transmission in triterpene synthesis. J Org Chem 70:5362-75 ↑ The 21R stereocenter is usually lost in hydride shift. ↑ C-B-C-C-C rings are very rare and stictanediol from Ascomycota Sticta genus is the sole example. Ref. Chin WJ, Corbett RE, Heng CK, Wilkins AL (1973) Lichens and fungi. XI. Isolation and structural elucidation of a new group of triterpenes from Sticta coronata, S. colensoi, and S. flavicans. J Chem Soc Perkin Trans 1:1437–46 ↑ β-amyrin has the oleanane skeleton ↑ E-ring cyclization precedes D-ring expansion.
Reviews
Xu R, Fazio GC, Matsuda SPT (2004) On the origins of triterpenoid skeletal diversity. Phytochemstry 65:261-291 PMID 14751299 Philips DR, Rasbery JM, Bartel B, Matuda SPT (2006) Biosynthetic diversity in plant triterpene cyclization Curr Opin Plant Biol 9:305-314

Squalene Cyclase in Bacteria and Ferns

Squalene cyclase (SC) or terpene synthase g (tpsg) are found in prokaryotes, ciliates, and lower plants (mosses and ferns) and can convert squalene, which is symmetric, as well as 2,3-oxidosqualene. Main products are hopanol and tetrahymanol, and only generate all-chair cations.

squalene

squalene-hopene cyclase^[1]

17α-deoxydammarenyl cation^[2]

D-ring
expansion

E-ring cyclization
from 17α

hopene

hopyl cation

Hopanoids are widespread: they are found in alpha-proteobacteria, cyanobacteria, ferns, and geological sediments.

Almost all mono-, di-, tri- and tetracyclic terpenes from squalene are found in ferns: Polypodium, Lemmaphyllum, and Pyrrosia. Notable exception is Z-Dammara-17(20),24-diene from moss Floribundaria^[3]. Pentacyclic terpenes from squalene, on the other hand, are found also in angiosperms such as Achillea, Erysimum, Castanopsis and in Ascomycota.

↑ SH cyclase is the most investigated enzyme among squalene cyclases.
Ref. Kannenberg EL, Poralla K (1999) Hopanoid biosyntehsis and function in bacteria. Naturwissenschaften 86:168-76.
↑ The C-17 chain of deoxydammarenyl cation is α-configuration, not β as in eukaryotes.
Ref. Wendt KU, Schulz GE, Corey EJ, Liu DR (2000) Enzyme mechanisms for polycyclic triterpene formation. Angew Chem, Int Ed 39:2812-33
↑ Toyota M, Masuda K, Asakawa Y (1998) Triterpenoid constituents of the moss Floribundaria aurea subsp. nipponica. Phytochemistry 48:297–299

Bis-oxidosqualene Cyclase

Squalene is oxidized by squalene oxidase to become 2,3-oxidosqualene. Further epoxidation of this symmetric molecule produces 2,3-(S)-22,23-(S)-bis-oxidosqualene, which is converted to 24,25-epoxylanostan-3-ol or 24,25-epoxycycloartan-3-ol. Epoxylanosterol is known to negatively regulate sterol biosynthesis^[1].


2,3-oxidosqualene	2,3-22,23-bis-oxidosqualene

↑ Gardner RG, Shan H, Matsuda SPT, Hampton RY (2001) A positive oxysterol-derived signal for 3-hydroxy-3-methylglutaryl CoA reductase degradation in yeast. J Biol Chem 276:8681–869

Design of Tri-terpene ID numbers

12-DIGIT

T

P

3

x

y

r

h

g

n

c

x ... species information

Symbol at x	Kingdom	Phyla	Examples
I	Animalia	Arthropoda (Insects, crabs)	ecdysteroids
V		Chordate (Vertebrates)	sex steroids, corticosteroids, anabolic steroids
O		Others	marine steroids
P	Plantae	Phytosterols	lanosterols, cholesterols, brassinolides
S	Plantae	Saponins	saponins
F	Fungi	ergosterols	ergosterols
B	Bacteria	bacterial sterols	hopanoids

y ... backbone structure (母核構造)

Symbol at y	Carbons	Steroids
GN	C17	gonane
ES	C18	estrane
AD	C19	androstane
PG	C21	pregnane
CA	C24	cholane
CL	C27	cholestane
CM	C28	campestane
EG	C28	ergostane
SG	C29 (4 rings)	stigmastane
PR	C29 (4 rings)	poriferastane

Symbol at y	Carbons	Triterpenoids
PS	C30	protostane
EU	C30	euphane
LN	C30	lanostane
CY	C30	cycloartane
FS	C29	fusidane
HP	C30 (5 rings)	hopane
FN	C30 (5 rings)	fernane
CC	C30	cucurbitane
DM	C30	dammarane
BC	C30	baccharane
HL	C30	holostane
PF	C29 (5 rings)	pfaffane
LP	C30 (5 rings)	lupane
OL	C30 (5 rings)	oleanane
FD	C30 (5 rings)	friedelane
TR	C30 (5 rings)	taraxastane
UR	C30 (5 rings)	ursane
SR	C30 (5 rings)	serratane