During its intra-erythrocytic growth phase, the malaria parasite Plasmodium falciparum relies heavily on glycolysis for its energy requirements. Pyruvate kinase (PYK) is essential for regulating glycolytic flux and for ATP production, yet the allosteric mechanism of P. falciparum PYK (PfPYK) remains poorly understood. Here we report the first crystal structure of PfPYK in complex with substrate analogues oxalate and the ATP product. Comparisons of PfPYK structures in the active R-state and inactive T-state reveal a 'rock-and-lock' allosteric mechanism regulated by rigid-body rotations of each subunit in the tetramer. Kinetic data and structural analysis indicate glucose 6-phosphate is an activator by increasing the apparent maximal velocity of the enzyme. Intriguingly, the trypanosome drug suramin inhibits PfPYK, which points to glycolysis as a set of potential therapeutic targets against malaria.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbrc.2020.08.048 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The big potassium (BK) channels remain open with a small limiting probability of ∼ 10 at minimal Ca and negative voltages < -100 mV. The molecular origin and functional significance of such "intrinsic opening" are not understood. Here we combine atomistic simulations and electrophysiological experiments to show that the intrinsic opening of BK channels is an inherent property of the vapor barrier, generated by hydrophobic dewetting of the BK inner pore in the deactivated state.
View Article and Find Full Text PDFComputational Study of the Activation Mechanism of Wild-Type Parkin and Its Clinically Relevant Mutant.
ACS Chem Neurosci
January 2025
Graduate School of Engineering and Natural Sciences, Istanbul Medipol University, Istanbul 34810, Turkey.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It impairs the control of movement and balance. Parkin mutations worsen the symptoms in sporadic cases and cause the early onset of the disease.
View Article and Find Full Text PDFInduction of IMPDH-Based Cytoophidia by a Probable IMP-Dependent ARL13B-IMPDH Interaction.
Biochemistry (Mosc)
December 2024
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, 13145-1384, Iran.
Inosine Monophosphate Dehydrogenase (IMPDH) catalyzes rate-limiting step of the reaction converting inosine monophosphate (IMP) to guanine nucleotides. IMPDH is up-regulated in the healthy proliferating cells and also in tumor cells to meet their elevated demand for guanine nucleotides. An exclusive regulatory mechanism for this enzyme is filamentation, through which IMPDH can resist allosteric inhibition by the end product, GTP.
View Article and Find Full Text PDFAttributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors.
Pharmacol Ther
January 2025
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects.
View Article and Find Full Text PDFΤhiazolidine-4-One Derivatives with Variable Modes of Inhibitory Action Against DPP4, a Drug Target with Multiple Activities and Established Role in Diabetes Mellitus Type II.
Pharmaceuticals (Basel)
January 2025
School of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
DPP4 is an enzyme with multiple natural substrates and probable involvement in various mechanisms. It constitutes a drug target for the treatment of diabetes II, although, also related to other disorders. While a number of drugs with competitive inhibitory action and covalent binding capacity are available, undesired side effects exist partly attributed to drug kinetics, and research for finding novel, potent, and safer compounds continues.
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!