Crystal structure of archaeal <scp>HMG</scp>‐CoA reductase: insights into structural changes of the C‐terminal helix of the class‐I enzyme

Vögeli, Bastian; Shima, Seigo; Erb, Tobias J.; Wagner, T.

doi:10.1002/1873-3468.13331

Cited by 11 publications

(11 citation statements)

References 40 publications

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“…2f ). This altered conformation of the Lβ2-Lα1 loop is not seen in any of the previous class I and II HMGR crystal structures 24, 26, 30, 40–50 and allows alternative conformations of the Cys 267 residue ( Fig. 2e,g,h ).…”

Section: Resultsmentioning

confidence: 53%

“…Conserved active site residues ( e - g ) are shown with yellow surface. h , Overlay of apo AtHMG1 (blue cartoon and sticks) with all published structures of HMGR (grey cartoon and sticks) 24, 26, 30, 40–50 . This conformation has not been seen in any published HMGR crystal structure to date.…”

Section: Resultsmentioning

confidence: 99%

“…Atorvastatin superimposed on apo AtHMG1 (e, g) illustrates the equivalent residue, E265, likely too far away to H-bond to statins. h, Overlay of apo AtHMG1 (blue cartoon and sticks) with all published structures of HMGR (grey cartoon and sticks) 24,26,30,[40][41][42][43][44][45][46][47][48][49][50] . This conformation has not been seen in any published HMGR crystal structure to date.…”

Section: Crystal Structure Determination Refinement and Model Buildingmentioning

confidence: 99%

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A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action

Haywood

Breese

Zhang

et al. 2022

Preprint

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HMGR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is the rate limiting enzyme of the eukaryotic mevalonate pathway successfully targeted by statins to treat hypercholesterolemia in humans. The first statins to market have also been shown to be herbicidal yet their development as herbicides has been hindered by the risk of off-target effects. Here we present the crystal structure of a HMGR from Arabidopsis thaliana (AtHMG1) that exhibits a wider active site than all know structures from non-plant species. This enabled the rational design of statin derivatives with plant-specificity. By sequence analysis of natural statin fungal gene clusters, we could also engineer statin-resistant transgenic plants. These results suggest HMGR is a viable herbicide target, modifiable to provide a tolerance trait.

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Section: Resultsmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Crystal Structure Determination Refinement and Model Buildingmentioning

confidence: 99%

See 1 more Smart Citation

A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action

Haywood

Breese

Zhang

et al. 2022

Preprint

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“…S3A). All the three mutations were located far away from its catalytic site K239 (Vogeli et al ., 2019). Two residues – S287C and M322V – are located between two subunits of the protein, while V379A is exposed on the protein surface (Fig.…”

Section: Discussionmentioning

confidence: 99%

High‐efficiency transformation of archaea by direct PCR products with its application to directed evolution of a thermostable enzyme

Song

Zhu

Zhou

et al. 2020

Microbial Biotechnology

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Summary Hyperthermophilic archaea with unique biochemical and physiological characteristics are important organisms for fundamental research of life science and have great potential for biotechnological applications. However, low transformation efficiency of foreign DNA molecules impedes developments in genetic modification tools and industrial applications. In this study, we applied prolonged overlap extension PCR (POE‐PCR) to generate multimeric DNA molecules and then transformed them into two hyperthermophilic archaea, Thermococcus kodakarensis KOD1 and Pyrococcus yayanosii A1. This study was the first example to demonstrate the enhanced transformation efficiencies of POE‐PCR products by a factor of approximately 100 for T. kodakarensis KOD1 and 8 for P. yayanosii A1, respectively, relative to circular shuttle plasmids. Furthermore, directed evolution of a modestly thermophilic enzyme, Methanothermococcus okinawensis 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGR), was conducted to obtain more stable ones due to high transformation efficiency of T. kodakarensis (i.e. ~3 × 104 CFU per μg DNA). T. kodakarensis harbouring the most thermostable MoHMGR mutant can grow in the presence of a thermostable antibiotic simvastatin at 85°C and even higher temperatures. This high transformation efficiency technique could not only help develop more hyperthermophilic enzyme mutants via directed evolution but also simplify genetical modification of archaea, which could be novel hosts for industrial biotechnology.

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“…They are competitive inhibitors of the HMG-CoA reductase (HMGR) that catalyzes the conversion of HMG-CoA to mevalonate ( Endo, 1992 ; Istvan, 2003 ). HMGR is the rate-controlling enzyme of the mevalonate (MVA) pathway in human cell and is the target of statin inhibitors that regulate cholesterol concentration in human blood ( Tabernero et al, 1999 ; Vögeli et al, 2019 ); hence, once HMGR is inhibited by statins, the cholesterol synthesis is impeded ( Figure 1A ). In addition to the usage as cholesterol-lowering medicines, recent studies also proposed the potential application of statins as anti-cancer drugs ( Iannelli et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Construction of Escherichia coli Whole-Cell Biosensors for Statin Efficacy and Production Test

Wang

Zhao

et al. 2020

Front. Cell Dev. Biol.

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Statins are widely used cholesterol-lowering drugs. Their potential application in anticancer treatment is also under investigation. The individual variance in statin response has been observed, which may be caused by the variation in human HMG-CoA reductase (hHMGR)-the inhibition target of statin drugs. Herein, we reported the design and construction of two Escherichia coli whole-cell biosensors. The first one is statin-efficacy testing sensor, which is composed of two separate modules: a hybrid mevalonate (MVA) pathway and a HMG-CoA sensing system. A truncated hHMGR was used as the key enzyme of the MVA pathway and a promiscuous transcription factor (TF) BsFapR was used as the HMG-CoA sensor. When hHMGR was inhibited by statins, HMG-CoA accumulated intracellularly and was sensed by BsFapR, which subsequently turned on its cognate promoter. This biosensor has the potential to be used as a "precision medicine" tool-selecting potent statin drugs for individual patients. The second one is a statin-production testing sensor, which is based on another promiscuous TF AraCM that can sense statins. This biosensor can be used in optimization of statin-producing strains. The prototypes of these two biosensors were successfully constructed and their further optimization is highly expected.

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Crystal structure of archaeal HMG‐CoA reductase: insights into structural changes of the C‐terminal helix of the class‐I enzyme

Cited by 11 publications

References 40 publications

A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action

A resistance-gene-directed tolerance trait and selective inhibitors proffer HMG-CoA reductase as a new herbicide mode of action

High‐efficiency transformation of archaea by direct PCR products with its application to directed evolution of a thermostable enzyme

Construction of Escherichia coli Whole-Cell Biosensors for Statin Efficacy and Production Test

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