[PMID]: | 28570807 |
[Au] Autor: | Pan LL; Song LF; Miao Y; Yang Y; Merz KM |
[Ad] Endereço: | Department of Chemistry and Department of Biochemistry and Molecular Biology, Michigan State University , 578 South Shaw Lane, East Lansing, Michigan 48824, United States. |
[Ti] Título: | Mechanism of Formation of the Nonstandard Product in the Prenyltransferase Reaction of the G115T Mutant of FtmPT1: A Case of Reaction Dynamics Calling the Shots? |
[So] Source: | Biochemistry;56(24):2995-3007, 2017 Jun 20. |
[Is] ISSN: | 1520-4995 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | FtmPT1 is a fungal indole prenyltransferase that affords Tryprostatin B from Brevianamide F and dimethylallyl pyrophosphate; however, when a single residue in the active site is mutated (Gly115Thr), a novel five-membered ring compound is obtained as the major product with Tryprostatin B as the minor product. Herein, we describe detailed studies of the catalysis of the Gly115Thr mutant of FtmPT1 with a focus on the observed regioselectivity of the reaction. We employ one- and two-dimensional potential of mean force simulations to explore the catalytic mechanism, along with molecular dynamics simulations exploring the reaction dynamics of the prenyl transfer reaction. Single-point electronic structure calculations were also used to explore the performance of the self-consistent charge density functional tight-binding method to model specific reaction steps. Importantly, we observe that the two reaction pathways have comparable activation parameters and propose that the origin of the novel product is predicated, at least in part, on the topology of the potential energy surface as revealed by reaction dynamics studies. |
[Mh] Termos MeSH primário: |
Dimetilaliltranstransferase/genética Dimetilaliltranstransferase/metabolismo Glicina/genética Proteínas Mutantes/metabolismo Mutação Treonina/genética
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[Mh] Termos MeSH secundário: |
Dimetilaliltranstransferase/química Conformação Molecular Simulação de Dinâmica Molecular Proteínas Mutantes/química Proteínas Mutantes/genética Teoria Quântica
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Mutant Proteins); 2ZD004190S (Threonine); EC 2.5.1.1 (Dimethylallyltranstransferase); EC 2.5.1.1 (FtmPT1 protein, Aspergillus fumigatus); TE7660XO1C (Glycine) |
[Em] Mês de entrada: | 1709 |
[Cu] Atualização por classe: | 170926 |
[Lr] Data última revisão:
| 170926 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170602 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1021/acs.biochem.7b00248 |
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