A therapeutic approach to pantothenate kinase associated neurodegeneration

Lalit Kumar Sharma,Matthew W. Frank,Richard E. Lee,Chitra Subramanian,Mi-Kyung Yun,Stephen W. White,Charles O. Rock,Suzanne Jackowski

doi:10.1038/s41467-018-06703-2

Lalit Kumar Sharma, Matthew W. Frank + Show 6 more

Open Access

https://doi.org/10.1038/s41467-018-06703-2

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Abstract

Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.

Highlights

Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels
PANK activation in cells requires a high-affinity pantazine, and a PANK inhibition assay without acetyl-CoA was used to rank the pantazines
PANK2 is a major PANK isoform expressed in the brain, and pantothenate kinase associated neurodegeneration (PKAN) symptoms are thought to arise from a CoA deficiency that compromises important neuronal processes including iron metabolism, synaptic transmission, synaptic vesicle cycling, neuron projection development, and protein quality control[40]

Summary

Introduction

Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. The PANK2 gene is abundant in human neuronal tissues and the majority of the mutations associated with PKAN result in the expression of truncated or mutant PANK2 proteins with little or no catalytic activity[16]. Phosphopantetheine, CoA, or S-acetylphosphopantetheine have been suggested as PKAN modulators based on their ability to reverse hopantenate inhibition of CoA synthesis[24,25,26,27,28,29,30] All these approaches use compounds with physicochemical properties that suggest they will not penetrate the blood brain barrier[31,32], and protected phosphopantothenates have no effect on mouse brain CoA levels[23]. PZ-2891-treated knockout mice gain weight, and have improved locomotor activity and life span These data suggest pantazines as a novel approach to treating PKAN

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