Speaker
Description
Carnitine O-acetyltransferase (CRAT) is a mitochondrial enzyme central to acetyl-CoA/carnitine homeostasis and metabolic flexibility. Mutations in the CRAT gene, such as the p.Tyr110Cys variant associated with early-onset Leigh syndrome, impair mitochondrial function and energy metabolism [1]. Here we present a structure-based virtual screening and docking workflow that enabled the identification of candidate small-molecule modulators targeting CRAT's carnitine-binding site [2]. Using homology modeling, molecular dynamics, and docking simulations (AutoDock4.2), we screened a curated chemical library against both wild-type and p.Tyr110Cys CRAT variants [2]. Prioritized ligands were validated through in vitro enzymatic assays on recombinant proteins and patient-derived fibroblast lysates [2]. Compounds such as artemisinin showed variant-selective activation, highlighting therapeutic potential. Beyond their relevance for treating inborn mitochondrial disorders, several ligands identified through this workflow [2] may hold promise for modulating host immune and metabolic responses during infection. Remarkably, CRAT shares a conserved catalytic core, acyl-carnitine binding architecture, and overall structural similarity with structurally related carnitine acyltransferases, including CROT, CPT1/2, and CRAT, underscoring the potential to extrapolate ligand scaffolds or selectivity principles across this enzyme family [3]. Given CRAT’s role in regulating acetyl-CoA flux, mitochondrial homeostasis, and energy distribution, its pharmacological activation could support immune cell function and tissue resilience under stress conditions such as bacterial, fungal, or viral infection. In this context, CRAT-targeting compounds may serve as host-directed therapeutic agents, capable of reinforcing metabolic defenses without directly targeting the pathogen, an attractive strategy in the era of rising antimicrobial resistance. This work highlights the broader translational potential of CRAT modulators across both metabolic and infectious disease domains.
