Pyridoxal Phosphatase (PDXP) is a Druggable Target for the Flavone 7,8-Dihydroxyflavone

מושגי ליבה

7,8-dihydroxyflavone is a direct and potent inhibitor of the enzyme pyridoxal phosphatase (PDXP), which controls the levels of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, in the brain.

תקציר

The content discusses the role of pyridoxal phosphatase (PDXP) in regulating pyridoxal 5'-phosphate (PLP) levels in the brain and the discovery of 7,8-dihydroxyflavone (7,8-DHF) as a direct PDXP inhibitor.
Key highlights:

PDXP expression and activity increase with age in the murine hippocampus, leading to a decline in non-protein-bound PLP levels.
A high-throughput screening campaign identified 7,8-DHF as a preferential and direct PDXP inhibitor, with submicromolar potency.
Structural analysis of the 7,8-DHF-PDXP complex revealed the binding mode and key interactions stabilizing the inhibitor in the active site.
In primary hippocampal neurons, 7,8-DHF increased the PLP/pyridoxal ratio in a PDXP-dependent manner, validating PDXP as a cellular target.
The discovery of 7,8-DHF as a PDXP inhibitor provides a potential mechanistic explanation for its effects in brain disorder models, which have been previously attributed to BDNF-mimetic activity.
More potent and selective PDXP inhibitors may be useful tools to explore the potential benefits of elevated PLP levels in the brain.

סטטיסטיקה

Hippocampal PDXP and PDXK expression levels are markedly higher in middle-aged compared to juvenile mice.
Total hippocampal PLP levels decrease with age in both PDXP-WT and PDXP-KO mice, but remain consistently higher in PDXP-KO mice.
The age-dependent decline in non-protein-bound PLP levels is PDXP-dependent.
7,8-DHF inhibits murine and human PDXP with submicromolar potency (IC50 ~1 μM).
7,8-DHF increases the PLP/pyridoxal ratio in PDXP-WT, but not in PDXP-KO hippocampal neurons.

ציטוטים

"Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades."
"We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors."
"Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain."

תובנות מפתח מזוקקות מ:

7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase

by Zink,C., Wit... ב- www.biorxiv.org 10-05-2023

https://www.biorxiv.org/content/10.1101/2023.10.04.560852v2

שאלות מעמיקות

How might more potent and selective PDXP inhibitors be developed based on the structural insights provided by the 7,8-DHF-PDXP co-crystal structures?

The structural insights gained from the 7,8-DHF-PDXP co-crystal structures offer valuable information for the development of more potent and selective PDXP inhibitors. Here are some strategies that could be employed:

Structure-Based Drug Design: The detailed interactions between 7,8-DHF and PDXP in the crystal structures can guide the design of new compounds with improved binding affinity and specificity. By modifying the chemical structure of 7,8-DHF and optimizing key interactions with PDXP residues, more potent inhibitors can be developed.

Virtual Screening: Using computational methods such as molecular docking and virtual screening, a library of small molecules can be screened against the PDXP structure to identify potential inhibitors. The 7,8-DHF-PDXP co-crystal structures can serve as a reference for evaluating the binding modes of new compounds.

Fragment-Based Drug Design: Fragment-based approaches can be utilized to design inhibitors that target specific regions of the PDXP active site. By fragment linking or growing, smaller molecules can be optimized to enhance their potency and selectivity.

Allosteric Modulation: The co-crystal structures may reveal allosteric sites on PDXP that can be targeted to modulate its activity. Allosteric inhibitors can offer advantages in terms of selectivity and reduced off-target effects.

Kinetic Studies: Understanding the kinetic mechanisms of PDXP inhibition by 7,8-DHF can aid in the design of inhibitors with different modes of action. By targeting specific steps in the catalytic cycle, inhibitors can be tailored to disrupt PDXP function effectively.

By leveraging the structural insights provided by the 7,8-DHF-PDXP co-crystal structures, researchers can rationally design novel PDXP inhibitors with enhanced potency, selectivity, and therapeutic potential.