Does nature click? Theoretical prediction of an enzyme-catalyzed transannular 1,3-dipolar cycloaddition in the biosynthesis of lycojaponicumins A and B

Krenske, Elizabeth H., Patel, Ashay and Houk, K. N. (2013) Does nature click? Theoretical prediction of an enzyme-catalyzed transannular 1,3-dipolar cycloaddition in the biosynthesis of lycojaponicumins A and B. Journal of the American Chemical Society, Articles ASAP 46: A-E. doi:10.1021/ja409928z

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Author Krenske, Elizabeth H.
Patel, Ashay
Houk, K. N.
Title Does nature click? Theoretical prediction of an enzyme-catalyzed transannular 1,3-dipolar cycloaddition in the biosynthesis of lycojaponicumins A and B
Journal name Journal of the American Chemical Society   Check publisher's open access policy
ISSN 0002-7863
1520-5126
1943-2984
Publication date 2013-11-06
Year available 2013
Sub-type Article (original research)
DOI 10.1021/ja409928z
Open Access Status
Volume Articles ASAP
Issue 46
Start page A
End page E
Total pages 5
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
Biosynthetic 1,3-dipolar cycloadditions are rare. No enzymes have yet been identified whose function is to catalyze this class of reactions. Recently, however, a 1,3-dipolar cycloaddition was proposed as a key step in the biosynthesis of two Lycopodium alkaloids, lycojaponicumins A and B. The lycojaponicumins’ fused bicyclic tetrahydroisoxazole ring system was proposed to originate from a transannular 1,3-dipolar cycloaddition between a nitrone and an enone in a nine-membered macrocycle. We have used quantum mechanical calculations to predict whether this cycloaddition could constitute a feasible step in a biosynthetic pathway. Our calculations define a general computational approach for analyzing whether a putative biosynthetic reaction is likely to be enzyme-catalyzed. The quantum mechanically predicted rate of the uncatalyzed reaction in water is compared with the rate enhancement theoretically achievable when the reaction is catalyzed by a theozyme (theoretical enzyme). Density functional theory calculations (M06-2X) predict that the uncatalyzed transannular 1,3-dipolar cycloaddition of the putative lycojaponicumin precursor in water is moderately facile (ΔG = 21.5 kcal/mol, k = 10–3 s–1) and that an enzyme could accelerate the cycloaddition by placing hydrogen bond donors around the enone while maintaining an otherwise nonpolar active site. The theoretical enzyme-catalyzed process has ΔG ≈ 17 kcal/mol, corresponding to a 2000-fold rate enhancement, and the predicted kcat (2 s–1) is similar to those of known enzymes involved in secondary metabolic pathways. Thus, theory predicts that the proposed transannular 1,3-dipolar cycloaddition is a plausible step in a biosynthetic pathway leading to the lycojaponicumins and suggests that dipolar cycloadditions can be accelerated by enzyme catalysis.
Keyword Chemistry, Multidisciplinary
Chemistry
CHEMISTRY, MULTIDISCIPLINARY
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID FT120100632
CHE-1059084
T32 GM 008496
Institutional Status UQ
Additional Notes Publication Date (Web): November 6, 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
 
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Citation counts: TR Web of Science Citation Count  Cited 16 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 15 Nov 2013, 23:35:49 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences