Mevalonate diphosphate decarboxylases (MDDs) catalyze the ATP-dependent-Mg-decarboxylation of mevalonate-5-diphosphate (MVAPP) to produce isopentenyl diphosphate (IPP), which is essential in both eukaryotes and prokaryotes for polyisoprenoid synthesis. The substrates, MVAPP and ATP, have been shown to bind sequentially to MDD. Here we report crystals in which the enzyme remains active, allowing the visualization of conformational changes in Enterococcus faecalis MDD that describe sequential steps in an induced fit enzymatic reaction. Initial binding of MVAPP modulates the ATP binding pocket with a large loop movement. Upon ATP binding, a phosphate binding loop bends over the active site to recognize ATP and bring the molecules to their catalytically favored configuration. Positioned substrates then can chelate two Mg ions for the two steps of the reaction. Closure of the active site entrance brings a conserved lysine to trigger dissociative phosphoryl transfer of γ-phosphate from ATP to MVAPP, followed by the production of IPP.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414129 | PMC |
| http://dx.doi.org/10.1038/s41467-020-17733-0 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Genome-Wide Identification and Expression Profile of () Gene Family in L.
Int J Mol Sci
January 2025
State Key Laboratory of Tropical Crop Breeding, Sanya Institute, Rubber Research Institute, Chinese Academy of Tropical Agricultural Sciences, Sanya 572025, China.
The biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are essential for sesquiterpenes and triterpenes, respectively, is primarily governed by the mevalonate pathway, wherein () plays a pivotal role. This study identified eight members of the FPS gene family in , designated -, through bioinformatics analysis, revealing their distribution across several chromosomes and a notable tandem gene cluster. The genes exhibited strong hydrophilic properties and key functional motifs crucial for enzyme activity.
View Article and Find Full Text PDFCharacteristics and Functions of , a Terpenoid Synthesis-Related Gene in Lamb.
Int J Mol Sci
January 2025
State Key Laboratory of Tree Genetics and Breeding, Nanjing Forestry University, Nanjing 210037, China.
Terpenoids, abundant and structurally diverse secondary metabolites in plants, especially in conifer species, play crucial roles in the plant defense mechanism and plant growth and development. In , terpenoids' biosynthesis relies on both the mevalonate (MVA) pathway and the 2-methyl-D-erythritol-4-phosphate (MEP) pathway, with 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase (HDS) catalyzing the sixth step of the MEP pathway. In this study, we cloned and conducted bioinformatics analysis of the gene from .
View Article and Find Full Text PDFApo structure of Mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate synthase DXPS: Dynamics and implications for inhibitor design.
Biochem Biophys Res Commun
February 2025
Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. Electronic address:
The enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) catalyses the first step of the MEP pathway, a key process for isoprenoid biosynthesis in bacteria that is absent in humans, making it a promising drug target. We present the structure of Mycobacterium tuberculosis DXPS in its apo form, obtained through a soaking method that removes thiamine diphosphate (ThDP) and metals from pre-formed crystals. The apo structure had three regions with absence of electron density near the active site that are unique to the apo form of the enzyme.
View Article and Find Full Text PDFSynthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization.
Mol Metab
December 2024
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. Electronic address:
Article Synopsis
- The study aimed to explore the effects of targeting the mevalonate pathway (MVP) in rhabdomyosarcoma (RMS), a common soft tissue tumor in young individuals.
- In silico analyses showed that higher levels of MVP-related genes correlated with poorer patient survival, while in vitro tests revealed that MVP inhibitors significantly reduced RMS cell growth, migration, and survival.
- In vivo experiments demonstrated the effectiveness of MVP inhibition in RMS xenografts, highlighting the potential of these inhibitors as a therapeutic strategy against RMS.
Development of Komagataella phaffii as a cell factory for efficient de novo production of β-caryophyllene.
N Biotechnol
December 2024
Xianghu Laboratory, Hangzhou 310027, China; State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Laboratory (Hangzhou) for Risk Assessment of Agricultural Products of Ministry of Agriculture, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, Zhejiang, China. Electronic address:
β-Caryophyllene is a natural bicyclic sesquiterpene found in a large number of plants around the world. It has anti-inflammatory, anticancer and analgesic biological activities associated with its important medicinal value, and has also attracted attention in the field of bioenergy with high energy density. Due to the low amount of β-caryophyllene in plants and complex purification process, microbial biosynthesis is considered as a promising alternative for the industrial development of β-caryophyllene.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!