6b3v

Publication Abstract from PubMed

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*Mg(2+)*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.

A therapeutic approach to pantothenate kinase associated neurodegeneration.,Sharma LK, Subramanian C, Yun MK, Frank MW, White SW, Rock CO, Lee RE, Jackowski S Nat Commun. 2018 Oct 23;9(1):4399. doi: 10.1038/s41467-018-06703-2. PMID:30352999^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.