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Review
. 2012 Mar 14;112(3):1681-709.
doi: 10.1021/cr200073d. Epub 2011 Oct 21.

Enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis

Christopher J Thibodeaux  1 , Wei-chen Chang, Hung-wen Liu
Affiliations
Review

Enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis

Christopher J Thibodeaux et al. Chem Rev. .
No abstract available

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Figures

Figure 1
Figure 1
Representative three membered ring-containing natural products.
Figure 2
Figure 2
Representative epoxide-containing natural products whose biosynthetic gene clusters contain genes encoding putative P450 epoxidases.
Figure 3
Figure 3
Representative natural products whose epoxide moieties are likely installed by flavindependent epoxidases. See also hedamycin (118) in Figure 2.
Figure 4
Figure 4
Chemical structures of several polyether natural products whose biosynthetic gene clusters have been sequenced.
Scheme 1
Scheme 1
Mechanism of action of (A) duocarmycin, (B) dynemicin, and (C) mitomycin.
Scheme 2
Scheme 2
Representative examples of prenyltransferase- and terpene synthase-catalyzed reactions.
Scheme 3
Scheme 3
Mechanistic link between prenyltransferases and terpene synthases. Both families of enzymes catalyze C-C bond formation via reactive carbocation intermediates (such as 23, 24 and 25).
Scheme 4
Scheme 4
Chemical mechanism of squalene synthase, which proceeds through the stable cyclopropyl intermediate, presqualene pyrophosphate (30).
Scheme 5
Scheme 5
Proposed chemical mechanism for chrysanthemyl pyrophosphate (CPP) synthase, which catalyzes the first step in the biosynthesis of the pyrethrin class of insecticides.
Scheme 6
Scheme 6
Rearrangement of the tertiary heptyl cation (45) likely involves a protonated cyclopropane transition state (46).
Scheme 7
Scheme 7
Monoterpene synthase-catalyzed formation of cyclopropane rings in the carene (22), sabinene (51), and thujene (52) families of monoterpenoids.
Scheme 8
Scheme 8
Casbene (55), a diterpene produced from geranylgeranyl pyrophosphate (53) by casbene synthase, is the likely intermediate for the ingenane (56), tigliane (57), and lathyrane (58) families of diterpenoid natural products.
Scheme 9
Scheme 9
Proposed chemical mechanisms for cycloartenol (64) and lanosterol (65) synthases.
Scheme 10
Scheme 10
SAM-dependent cyclopropane biosynthesis catalyzed by CFA and CMA synthases.
Scheme 11
Scheme 11
The cyclopropane-containing natural products FR-900848 (74) and U-106305 (75) are likely biosynthesized by a series of insertion of a SAM-derived methylene group into each of the reacting alkene moiety.
Scheme 12
Scheme 12
ACC synthase-catalyzed cyclopropane formation, which proceeds from the resonance-stabilized carbanion (81) via an intramolecular SN2 reaction.
Scheme 13
Scheme 13
Halogenated carrier protein-linked intermediates serve as the substrates for SN2-like cyclopropane ring formation in the biosynthesis of coronatine (88), kutzneride 2 (92), and curacin A (97). The triggering mechanism for cyclopropane formation in each case is believed to involve a carbanionic intermediate (or transition state).
Scheme 13
Scheme 13
Halogenated carrier protein-linked intermediates serve as the substrates for SN2-like cyclopropane ring formation in the biosynthesis of coronatine (88), kutzneride 2 (92), and curacin A (97). The triggering mechanism for cyclopropane formation in each case is believed to involve a carbanionic intermediate (or transition state).
Scheme 14
Scheme 14
Generalized chemical mechanism for acyl-CoA dehydrogenases.
Scheme 15
Scheme 15
Putative mechanism for cyclopropane formation in hormaomycin (101).
Scheme 16
Scheme 16
Typical catalytic cycle for a P450-dependent epoxidase.
Scheme 17
Scheme 17
Two-state reactivity model for P450 enzymes.
Scheme 18
Scheme 18
Alternative mechanism of epoxidation by P450 enzymes involving a Cpd 0 species (110).
Scheme 19
Scheme 19
Radical and ionic pathways to allene oxide (125) catalyzed by a catalase-related allene oxide synthase from the cyanobacterium Acaryochloris marina.
Scheme 20
Scheme 20
Generalized chemical mechanism for flavin dependent epoxidases.
Scheme 21
Scheme 21
Involvement of epoxide intermediate in the biosynthesis of polyether natural products.
Scheme 22
Scheme 22
Cofactor-independent epoxidation catalyzed by DHAE I.
Scheme 23
Scheme 23
The epoxidation reaction catalyzed by HppE involves the two-electron oxidation of a secondary alcohol.
Scheme 24
Scheme 24
Proposed chemical mechanism for HppE.
Scheme 25
Scheme 25
HppE-catalyzed conversion of substrate analogues to the corresponding ketones likely proceeds via hydrogen atom abstraction and ketyl radical intermediates.
Scheme 26
Scheme 26
The epoxidation reaction catalyzed by H6H is α-KG-dependent and involves the two-electron oxidation of a secondary alcohol.
Scheme 27
Scheme 27
Oxygen activation catalyzed by Fe(II)/α-KG-dependent enzymes and the proposed mechanism of H6H catalyzed two-electron oxidation of a secondary alcohol to generate scopolamine (162).
Scheme 28
Scheme 28
Epoxidation reactions catalyzed by the Fe(II)/α-KG dependent enzymes DdaC and PenD/PntD during Nβ-epoxysuccinamoyl-DAP-Val (168) and pentalenolactone (169) biosynthesis, respectively.
Scheme 29
Scheme 29
Structure-based mechanism proposed for the haloalcohol dehydrogenase, HheC, which likely catalyzes formation of an epoxide from a 1,2-haloalcohol via an SN2-type reaction.
Scheme 30
Scheme 30
The major compound (175) isolated from the alcohol extract of the tightly bound maduropeptin (119) from MdpA.
Scheme 31
Scheme 31
(A) Proposed biosynthetic pathway of mitomycin C starting from glucosamine (176) and AHBA (177). (B) Proposed mechanism of reductive activation of FR66979 (181) via 183 to crosslink DNA.
Scheme 32
Scheme 32
Incorporation of various precursors into the azabicyclic fragment (circled in red) of azinomycin.
Scheme 33
Scheme 33
Proposed biosynthetic pathway for the azabicyclic moiety of azinomycin.
Scheme 34
Scheme 34
Proposed biosynthetic pathway for aziridine ring formation in the azicemicins.
Scheme 35
Scheme 35
A potential biosynthetic route to the aziridine moiety.
See this image and copyright information in PMC

References

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