Defining the Product Chemical Space of Monoterpenoid Synthases.

Boxue Tian,Matthew P Jacobson,C Dale Poulter,Jacquelyn S Fetrow

doi:10.1371/journal.pcbi.1005053

Boxue Tian, Matthew P Jacobson + Show 2 more

Open Access

https://doi.org/10.1371/journal.pcbi.1005053

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Abstract

Terpenoid synthases create diverse carbon skeletons by catalyzing complex carbocation rearrangements, making them particularly challenging for enzyme function prediction. To begin to address this challenge, we have developed a computational approach for the systematic enumeration of terpenoid carbocations. Application of this approach allows us to systematically define a nearly complete chemical space for the potential carbon skeletons of products from monoterpenoid synthases. Specifically, 18758 carbocations were generated, which we cluster into 74 cyclic skeletons. Five of the 74 skeletons are found in known natural products; some of the others are plausible for new functions, either in nature or engineered. This work systematizes the description of function for this class of enzymes, and provides a basis for predicting functions of uncharacterized enzymes. To our knowledge, this is the first computational study to explore the complete product chemical space of this important class of enzymes.

Highlights

Terpenoids, which have diverse carbon skeletons, are an important class of natural products [1,2,3]
Terpenoid synthases create diverse carbon skeletons by catalyzing complex carbocation rearrangements, making them challenging for enzyme function prediction
The diverse carbocycle structures arise from complex carbocation rearrangements catalyzed by terpenoid synthases

Summary

Introduction

Terpenoids, which have diverse carbon skeletons, are an important class of natural products [1,2,3]. Cyclic terpenoids are created by terpenoid synthases (sometimes called terpenoid cyclases [5]), which catalyze the cyclizations of linear terpenes such as geranyl diphosphate through carbocation rearrangements [6]. The cyclized carbocationic intermediates are quenched by phosphorylation, deprotonation, or hydration to yield products (Fig 1). The intrinsic reactivity of carbocations plays an important role in the outcome of cyclization [7,8,9]. Terpenoids are classified as monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), sesterterpenes (C25), triterpenes (C30) and sesquarterpenes (C35) according to the number of C5 isoprenoid units incorporated into their carbon skeletons

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