Conversion of Squalene to the Pentacarbocyclic Hopene

Reinert, D.J.; Balliano, Gianni; Schulz, Georg E.

doi:10.1016/j.chembiol.2003.12.013

Cited by 111 publications

(57 citation statements)

References 33 publications

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“…Shc Aac is the only SHC for which a structure of a complex with the inhibitory substrate analogue 2-azasqualene has been determined (23,32). The orientation of the substrate in the active site ensures close proximity to the molecule's reactive residues and determines the stereochemical course of the cyclization.…”

Section: Resultsmentioning

confidence: 99%

Activation-Independent Cyclization of Monoterpenoids

Siedenburg

Jendrossek

Breuer

et al. 2012

Appl Environ Microbiol

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The biosynthesis of cyclic monoterpenes (C 10 ) generally requires the cyclization of an activated linear precursor (geranyldiphosphate) by specific terpene cyclases. Cyclic triterpenes (C 30 ), on the other hand, originate from the linear precursor squalene by the action of squalene-hopene cyclases (SHCs) or oxidosqualene cyclases (OSCs). Here, we report a novel terpene cyclase from Zymomonas mobilis (ZMO1548-Shc) with the unique capability to cyclize citronellal to isopulegol. To our knowledge, ZMO1548-Shc is the first biocatalyst with diphosphate-independent monoterpenoid cyclase activity. A combinatorial approach using site-directed mutagenesis and modeling of the active site with a bound substrate revealed that the cyclization of citronellal proceeds via a different mechanism than that of the cyclization of squalene.T erpenoids are widespread secondary metabolites present in nearly all organisms. They have important or even essential functions in metabolism and act, for example, as membrane stabilizers, hormones, vitamins, or photoactive compounds. Terpenes are composed of isoprene units that are synthesized either via the mevalonate pathway (13) or via the 1-deoxy-D-xylulose-5-phosphate (DXP) route (12). The common linear precursor of all monoterpenes and higher terpenoids is geranyldiphosphate (30), independent from the pathway used for the synthesis of the isoprene backbone (isopentenyldiphosphate). Terpenoids are present in nature in a large variety of both linear and cyclic forms. The formation of the ring structure of cyclic terpenoids from diphosphate-activated linear precursors is catalyzed by terpene cyclases (terpene synthases) that are specific for either geranyldiphosphate (C 10 ) (monoterpene cyclases), farnesyldiphosphate (C 15 ) (sesquiterpene cyclases), or geranyl-geranyldiphosphate (C 20 ) (diterpene cyclases). Activation by diphosphate is essential for all cyclization reactions catalyzed by class I terpene cyclases. For all currently known diphosphate-dependent cyclizations, the reaction requires the Lewis acid (Mg 2ϩ )-catalyzed ionization of the diphosphate ester of the respective precursor. After isomerization and the subsequent elimination of the diphosphate group, a primary carbocation is generated, which subsequently attacks a nearby double bond, leading to the formation of the more stable carbenium ion (R 3 C ϩ -). Finally, the reaction is terminated by deprotonation, leading to a vast variety of cyclic terpenoids (1, 5, 6).Cyclic triterpenes, such as hopanoids in bacteria or sterols in eukaryotes, arise either from the nonactivated linear precursor squalene (C 30 ) or from 2,3-oxidosqualene. The polycyclization reaction is catalyzed by squalene-hopene cyclases (SHCs), lanosterol synthases, or oxidosqualene cyclases, respectively (21, 25). The cyclization reaction of squalene involves the concerted formation of (i) five ring structures, (ii) 13 carbon-carbon bonds, and (iii) nine stereocenters, rendering it one of the most complex single-step reactions known in biochemistry. Remarka...

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Section: Resultsmentioning

confidence: 99%

Activation-Independent Cyclization of Monoterpenoids

Siedenburg

Jendrossek

Breuer

et al. 2012

Appl Environ Microbiol

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“…Reinert and coworkers published the three-dimensional structure of the A. acidocaldarius SHC with the cocrystallized substrate analogue 2-azasqualene (76). The authors suggested a barrier-free ring closure of the A to D rings followed by a pause at the 6-6-6-5 tetracyclic tertiary carbocation before concerted ring expansion of ring D and formation of the E ring.…”

Section: Vol 77 2011 Minireview 3911mentioning

confidence: 99%

“…The crystal structure of SHC with cocrystallized 2-azasqualene showed that the wall between the channel and dimer surface is rather flexible and might be appreciably enlarged by melting and displacing the mobile peptide. The produced energy may be channeled and used to release the bulky hopene into the membrane without changing the overall structure of the protein (76). Truncated analogs of the QW motif and a similar active-site motif (DDTA) occur in an ent-copalyl synthase, a kaurene synthase A, and an abietadiene synthase (51,90,96).…”

Section: Structure-function Relationships Of Shcsmentioning

confidence: 99%

Squalene-Hopene Cyclases

Siedenburg

Jendrossek

2011

Appl Environ Microbiol

124

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Hopanoids and sterols are members of a large group of cyclic triterpenoic compounds that have important functions in many prokaryotic and eukaryotic organisms. They are biochemically synthesized from linear precursors (squalene, 2,3-oxidosqualene) in only one enzymatic step that is catalyzed by squalene-hopene cyclase (SHC) or oxidosqualene cyclase (OSC). SHCs and OSCs are related in amino acid sequences and probably are derived from a common ancestor. The SHC reaction requires the formation of five ring structures, 13 covalent bonds, and nine stereo centers and therefore is one of the most complex one-step enzymatic reactions. We summarize the knowledge of the properties of triterpene cyclases and details of the reaction mechanism of Alicyclobacillus acidocaldarius SHC. Properties of other SHCs are included.

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“…The latter moiety is an isoprenic structure mimicking the squalene skeleton in azasqualene derivatives [26,33], whereas in other series of inhibitors is an electron-deficient aromatic system [4]. Crystallographic studies carried on both squalene-hopene cyclase from Alicyclobacillus acidocaldarious and human OSC provided excellent explanations of the inhibitory properties of different compounds bearing an amino function [4,7,32,33].…”

Section: Discussionmentioning

confidence: 99%

Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

Oliaro‐Bosso

Taramino

Viola

et al. 2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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Human and murine lanosterol synthases (EC 5.4.99.7) were studied as targets of a series of umbelliferone aminoalkyl derivatives previously tested as inhibitors of oxidosqualene cyclases from other eukaryotes. Tests were carried out on cell cultures of human keratinocytes and mouse 3T3 fibroblasts incubated with radiolabeled acetate, and on homogenates prepared from yeast cells expressing human lanosterol synthase, incubated with radiolabeled oxidosqualene. In cell cultures of both human keratinocytes and mouse 3T3 fibroblasts, the observed inhibition of cholesterol biosynthesis was selective for oxidosqualene cyclase. The most active compounds bear an allylmethylamino chain in position-7 of the coumarin ring. The inhibition was critically dependent on the position and length of the inhibitor side chain, as well as on the type of aminoalkyl group inserted at the end of the same chain. Molecular docking analyses, carried out to clarify details of inhibitors/enzyme interactions, proved useful to explain the observed differences in inhibitory activities.

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Conversion of Squalene to the Pentacarbocyclic Hopene

Cited by 111 publications

References 33 publications

Activation-Independent Cyclization of Monoterpenoids

Activation-Independent Cyclization of Monoterpenoids

Squalene-Hopene Cyclases

Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

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