Disease relevance of PANK1

• Unraveling the Hallervorden-Spatz syndrome: pantothenate kinase-associated neurodegeneration is the name [1].
• Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia [2].
• Mutations in the pantothenate kinase gene PANK2 are not associated with Parkinson disease [3].
• Infantile neuroaxonal dystrophy and pantothenate-kinase-associated neurodegeneration: locus heterogeneity [4].
• The human isoform 2 of pantothenate kinase (PanK2) is localized to the mitochondria, and mutations in this protein are associated with a progressive neurodegenerative disorder [5].

High impact information on PANK1

• A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome [6].
• Here we show that HSS is caused by a defect in a novel pantothenate kinase gene and propose a mechanism for oxidative stress in the pathophysiology of the disease [6].
• Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine [5].
• We conclude that the symptoms observed in pantothenate kinase-associated neurodegeneration are caused by a deficiency of the mitochondrial isoform and postulate the existence of a complete intramitochondrial pathway for de novo synthesis of coenzyme A [7].
• In the presence of missense mutations (n = 37), the age of onset correlated with residual activity of the pantothenate kinase [8].

Chemical compound and disease context of PANK1

• These results contrast with those of previous studies in which it was proposed that the avian malaria parasite Plasmodium lophurae lacks pantothenate kinase (as well as the other enzymes for the synthesis of coenzyme A) and is reliant upon the uptake of preformed coenzyme A from the host cell cytosol [9].
• METHODS: Seven children (aged 2-16 years) with dystonia of various aetiologies (dyskinetic cerebral palsy, pantothenate kinase-associated neurodegeneration and Aicardi-Goutières syndrome) underwent transcranial magnetic stimulation, H-reflex and flexor reflex studies before and after intrathecal injection of baclofen [10].

Biological context of PANK1

• Direct sequencing of the patient's genomic DNA revealed homozygous base substitutions in the pantothenate kinase gene (PANK2): the A764-->G substitution (N245S) due to consanguinity of her parents [11].
• Once the responsible gene PANK2 had been discovered on chromosome 20 it was found that this encoded for pantothenate kinase which is essential for the synthesis of coenzyme A from pantothenate; and this is integral to fatty acid synthesis and energy metabolism [12].
• A novel 3-bp deletion in the PANK2 gene of Dutch patients with pantothenate kinase-associated neurodegeneration: evidence for a founder effect [13].
• Genetic heterogeneity in patients with pantothenate kinase-associated neurodegeneration and classic magnetic resonance imaging eye-of-the-tiger pattern [14].
• Compound heterozygous mutations resulting in missense amino acid substitutions G521R and I529V were identified in the pantothenate kinase (PANK2) gene [15].

Anatomical context of PANK1

• Pantothenate kinase is essential to coenzyme A biosynthesis, and PANK2 is targeted to mitochondria, a feature that distinguishes it from the three other human pantothenate kinase homologs [1].
• Pantothenate kinase is an important rate-controlling enzyme in the synthetic pathway of all tissues studied and appears to catalyze the flux-generating reaction of the pathway in cardiac muscle [16].
• In all patients with pantothenate kinase-associated neurodegeneration, whether classic or atypical, T2-weighted magnetic resonance imaging (MRI) of the brain showed a specific pattern of hyperintensity within the hypointense medial globus pallidus [17].
• Inside the parasitized cell pantothenate undergoes phosphorylation, the first step in its conversion to coenzyme A. Parasites within saponin-permeabilized erythrocytes were shown to take up and phosphorylate pantothenate, consistent with the intracellular parasite having both a pantothenate transporter and a pantothenate kinase [9].

Associations of PANK1 with chemical compounds

• Pantothenate kinase (PanK) is thought to catalyze the first rate-limiting step in CoA biosynthesis [18].
• Recently a defect in pantothenate kinase, the key regulatory enzyme in the synthesis of coenzyme A from pantothenate, has been identified as the cause of the disease [19].
• One active peak of this enzyme was further purified on Cibacron blue 3GA to yield a preparation containing pantothenate kinase enriched to 20% of the total protein within the fraction [20].
• We report a case of pantothenate kinase-associated neurodegeneration with increased regional cerebral blood flow (rCBF) in bilateral lentiform nuclei on technetium Tc-99m ethyl cysteinate dimer single-photon emission CT (ECD-SPECT) [21].
• Further experiments demonstrated a linear increase in pantothenate kinase activity during spinach seed germination, consistent with a role for this enzyme in the developmental utilization of seed triacylglycerol [20].

Other interactions of PANK1

• Long-term benefit to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration [22].
• Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria [23].
• RECENT FINDINGS: Recent developments in genetics, including the finding of mutations in the pantothenate kinase gene and ferritin light chain gene, have demonstrated a direct relationship between the presence of a mutation in the iron-regulatory pathways and iron deposition in the brain resulting in neurodegeneration [24].
• The term "neuroacanthocytosis" is normally used to refer to autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome, but there are other movement disorders in which erythrocyte acanthocytosis may also be seen, such as Huntington disease-like 2 and pantothenate kinase-associated neurodegeneration [25].

Analytical, diagnostic and therapeutic context of PANK1

• The newly described defect of the pantothenate kinase enzyme enables a novel therapeutic approach to be considered, based on the mutation analyses of the PANK2 gene, as well as the prenatal diagnosis of this disorder [19].

References