PANK2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic (IBA) nuclear localization. Human PanK2 does have a functional NLS (residues 82-94) and a dynamic nuclear pool that shuttles to mitochondria in a cell-cycle-dependent manner (PMID:23152917), so a nuclear annotation is defensible, but it is a minor, dynamic pool and not the site of the enzyme's core catalytic contribution to CoA biosynthesis. Reason: Nuclear localization is experimentally observed but represents a minor, shuttling pool; the predominant and functionally relevant location is mitochondrial. Supporting Evidence: PMID:23152917 Human PanK2 was also detected in the nucleus, and functional nuclear localization and export signals were identified and experimentally confirmed.
GO:0005829 cytosol	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic (IBA) cytosol annotation propagated across the PanK family. Cytosolic activity is the norm for PANK1 and PANK3 and for rodent PanK2, but the primate PANK2 mitochondrial isoform acquired a mitochondrial targeting signal and acts predominantly in the mitochondrial intermembrane space (PMID:17825826, PMID:23152917). Cytosolic presence in humans is best attributed to the shorter non-mitochondrial isoforms / the shuttling pool. Reason: Cytosol is a plausible location for some PANK2 isoforms but not the core compartment of the mitochondrial enzyme; retain as non-core. Supporting Evidence: file:human/PANK2/PANK2-uniprot.txt [Isoform 4]: Cytoplasmic isoform that catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
GO:0015937 coenzyme A biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of the core biological process. PANK2 catalyzes step 1 of 5 in CoA biosynthesis from pantothenate; this is the defining role of the pantothenate-kinase family and is strongly supported experimentally (PMID:15659606, PMID:16272150, PMID:17242360). Supporting Evidence: PMID:12554685 The kinase catalyses the first and rate-limiting step in the biosynthesis of coenzyme A, a key molecule in energy metabolism.
GO:0004594 pantothenate kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of the core molecular function, consistent with direct biochemical assays of the human enzyme (PMID:15659606, PMID:16272150, PMID:17242360, PMID:17825826). Supporting Evidence: file:human/PANK2/PANK2-uniprot.txt [Isoform 1]: Mitochondrial isoform that catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis
GO:0004594 pantothenate kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment (ARBA/EC/RHEA) of the core molecular function, consistent with the experimentally established EC 2.7.1.33 activity. Supporting Evidence: file:human/PANK2/PANK2-uniprot.txt [Isoform 1]: Mitochondrial isoform that catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis
GO:0005524 ATP binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: ATP is the phosphoryl donor of the pantothenate kinase reaction and its site is also where acetyl-CoA inhibits; ATP binding is real but part of the kinase activity. Reason: Cosubstrate binding is subsidiary to GO:0004594 and is treated as non-core consistently with the other kinases of the pathway. Supporting Evidence: file:human/PANK2/PANK2-uniprot.txt Reaction=(R)-pantothenate + ATP = (R)-4'-phosphopantothenate + ADP +
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic (UniProt SubCell mapping) nucleus annotation, mirroring the experimental IDA nucleus call (PMID:23152917). Retain as non-core minor pool, same rationale as the IBA nucleus annotation. Supporting Evidence: PMID:23152917 Human PanK2 was also detected in the nucleus, and functional nuclear localization and export signals were identified and experimentally confirmed.
GO:0005737 cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic (UniProt SubCell) cytoplasm annotation, reflecting the cytoplasmic localization assigned to the shorter isoforms (isoforms 2, 3, 4). Broad and not the core compartment of the mitochondrial enzyme. Supporting Evidence: file:human/PANK2/PANK2-uniprot.txt SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm {ECO:0000269\|PubMed:12554685, ECO:0000305}.
GO:0005739 mitochondrion	IEA GO_REF:0000044	ACCEPT	Summary: Electronic (UniProt SubCell) mitochondrion annotation, consistent with the well-established experimental mitochondrial localization of the human enzyme (PMID:12554685, PMID:15659606, PMID:23152917). Core location. Supporting Evidence: PMID:12554685 An in vitro import assay and in vivo immunolocalization experiments demonstrate a mitochondrial localization of this isoform.
GO:0005758 mitochondrial intermembrane space	IEA GO_REF:0000044	ACCEPT	Summary: Electronic (UniProt SubCell) IMS annotation, matching the experimental submitochondrial localization determined by digitonin/protease-protection (PMID:23152917). This is the specific, functionally relevant compartment. Supporting Evidence: PMID:23152917 Human PanK2, known to associate with mitochondria, was specifically localized to the intermembrane space.
GO:0005829 cytosol	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Electronic (ARBA) cytosol annotation, redundant with the IBA and IDA cytosol calls. Not the core compartment; retain as non-core. Supporting Evidence: file:human/PANK2/PANK2-uniprot.txt [Isoform 4]: Cytoplasmic isoform that catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
GO:0015937 coenzyme A biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (InterPro/UniPathway) assignment of the core CoA biosynthetic process, consistent with experimental IMP and IBA support. Supporting Evidence: PMID:12554685 The kinase catalyses the first and rate-limiting step in the biosynthesis of coenzyme A, a key molecule in energy metabolism.
GO:0005515 protein binding	IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1...	REMOVE	Summary: IPI to bare "protein binding" from a 14-3-3 (YWHAZ) affinity proteomics screen. The interaction is plausible given the phosphoserine sites (Ser168/169/189) in the PANK2 N-terminal disordered region, but "protein binding" is uninformative about function. Removed under the GO:0005515 protein-binding policy as uninformative; the interaction itself is not disputed. Reason: Bare protein binding from a high-throughput interaction screen is uninformative under the project protein-binding policy and identifies no PANK2 function; removal does not mean the interaction is false.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	REMOVE	Summary: IPI to bare "protein binding" from the OpenCell endogenous-tagging IP-MS interactome. High-throughput interaction evidence; uninformative as a molecular-function statement. Removed under the GO:0005515 protein-binding policy as uninformative; the interaction itself is not disputed. Reason: Bare protein binding from a high-throughput interaction screen is uninformative under the project protein-binding policy and identifies no PANK2 function; removal does not mean the interaction is false.
GO:0005515 protein binding	IPI Q9BZ23-2 PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: IPI to bare "protein binding" from a neurodegenerative-disease yeast two-hybrid interactome screen (isoform Q9BZ23-2). Many partners recorded (ACRV1, ABLIM2, PMF1, etc.); no established functional role. Removed under the GO:0005515 protein-binding policy as uninformative; the interaction itself is not disputed. Reason: Bare protein binding from a high-throughput interaction screen is uninformative under the project protein-binding policy and identifies no PANK2 function; removal does not mean the interaction is false.
GO:0015937 coenzyme A biosynthetic process	TAS Reactome:R-HSA-196783	ACCEPT	Summary: Reactome-traceable assignment of the core CoA biosynthetic process. PANK2 catalyzes the first of five reactions in CoA biosynthesis from pantothenate. Supporting Evidence: Reactome:R-HSA-196783 It is synthesized from the vitamin pantothenate in a sequence of five reactions
GO:0004594 pantothenate kinase activity	TAS Reactome:R-HSA-196857	ACCEPT	Summary: Reactome-traceable assignment of the core pantothenate kinase activity ("PANK2 phosphorylates PanK"). Consistent with all experimental evidence. Supporting Evidence: Reactome:R-HSA-196857 Pantothenate kinase 2 (PANK2) catalyzes the reaction of ATP and pantothenate to form ADP and phosphopantothenate.
GO:0005829 cytosol	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence (IDA) cytosol localization. Likely reflects the shorter non-mitochondrial isoforms and/or the nucleocytoplasmic shuttling pool. Experimental but not the core mitochondrial compartment. Supporting Evidence: file:human/PANK2/PANK2-uniprot.txt [Isoform 4]: Cytoplasmic isoform that catalyzes the phosphorylation of pantothenate to generate 4'-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
GO:0004594 pantothenate kinase activity	EXP PMID:17825826 Localization and regulation of mouse pantothenate kinase 2.	ACCEPT	Summary: Experimental demonstration of pantothenate kinase activity of the human mitochondrial enzyme, with characterization of feedback inhibition by acetyl-CoA and activation by palmitoylcarnitine. Core molecular function. Supporting Evidence: PMID:17825826 Human and mouse PanK2 possessed similar biochemical properties, with inhibition by acetyl-CoA and activation by palmitoylcarnitine.
GO:0005737 cytoplasm	EXP PMID:12554685 An isoform of hPANK2, deficient in pantothenate kinase-assoc...	KEEP AS NON CORE	Summary: This study identified two PANK2 first-exon isoforms; the isoform lacking the N-terminal mitochondrial extension is cytoplasmic, whereas the mitochondrial-targeted isoform localizes to mitochondria. The cytoplasm call applies to the non-mitochondrial isoform and is not the core compartment of the disease-relevant mitochondrial enzyme. Supporting Evidence: PMID:12554685 The resulting transcripts encode distinct isoforms of hPANK2, one of which carries an N-terminal extension with a predicted mitochondrial targeting signal.
GO:0005739 mitochondrion	EXP PMID:12554685 An isoform of hPANK2, deficient in pantothenate kinase-assoc...	ACCEPT	Summary: In vitro import assay and in vivo immunolocalization demonstrated mitochondrial localization of the PANK2 isoform carrying the N-terminal mitochondrial targeting signal. Core location. Supporting Evidence: PMID:12554685 An in vitro import assay and in vivo immunolocalization experiments demonstrate a mitochondrial localization of this isoform.
GO:0005739 mitochondrion	EXP PMID:17825826 Localization and regulation of mouse pantothenate kinase 2.	ACCEPT	Summary: Human PanK2 is a mitochondrial protein (in contrast to the cytosolic mouse ortholog). Core mitochondrial location. Supporting Evidence: PMID:17825826 PanK2 is a mitochondrial protein in humans
GO:0005758 mitochondrial intermembrane space	TAS Reactome:R-HSA-196857	ACCEPT	Summary: Reactome-traceable IMS localization, consistent with the experimental submitochondrial mapping in PMID:23152917. This is the specific, functionally meaningful location. Supporting Evidence: Reactome:R-HSA-196857 supports a model in which the enzyme is located in the intermembrane space, hence freely accessible to small molecules from the cytosol
GO:0004594 pantothenate kinase activity	IMP PMID:22221393 Metabolic consequences of mitochondrial coenzyme A deficienc...	ACCEPT	Summary: Metabolic phenotyping of PKAN patients with PANK2 mutations supports the pantothenate kinase function (elevated pantothenate in premature-stop patients confirms loss of the phosphorylating activity). Core molecular function. Supporting Evidence: PMID:22221393 pantothenate levels are higher in patients with premature stop mutations in PANK2
GO:0005739 mitochondrion	IMP PMID:22221393 Metabolic consequences of mitochondrial coenzyme A deficienc...	ACCEPT	Summary: Consistent with the established mitochondrial localization of the human enzyme; PANK2 is described as the rate-limiting enzyme in mitochondrial CoA biosynthesis. Core location. Supporting Evidence: PMID:22221393 pantothenate kinase 2 (PANK2), the rate-limiting enzyme in mitochondrial coenzyme A biosynthesis
GO:0015937 coenzyme A biosynthetic process	IMP PMID:22221393 Metabolic consequences of mitochondrial coenzyme A deficienc...	ACCEPT	Summary: PANK2 mutations cause mitochondrial CoA deficiency in patients; this directly implicates PANK2 in the CoA biosynthetic process. Core biological process. Supporting Evidence: PMID:22221393 Mutations in pantothenate kinase 2 (PANK2), the rate-limiting enzyme in mitochondrial coenzyme A biosynthesis, represent the most common genetic cause of this disorder.
GO:0015939 pantothenate metabolic process	IMP PMID:22221393 Metabolic consequences of mitochondrial coenzyme A deficienc...	ACCEPT	Summary: PANK2 is the entry enzyme of pantothenate (vitamin B5) metabolism, and PKAN is an inborn error of vitamin B5 metabolism; patient pantothenate levels change with PANK2 genotype. Correct: phosphorylation of pantothenate is a step of pantothenate metabolism, complementary to the CoA biosynthetic term. Supporting Evidence: PMID:22221393 PKAN is an inborn error of Vitamin B5 metabolism
GO:0019217 regulation of fatty acid metabolic process	IMP PMID:22221393 Metabolic consequences of mitochondrial coenzyme A deficienc...	MARK AS OVER ANNOTATED	Summary: This annotation derives from metabolic-profiling observations that PKAN patient fibroblasts/plasma show lipid-metabolism defects. These are secondary, downstream consequences of reduced CoA availability (CoA is an obligate cofactor for fatty-acid metabolism), not a distinct regulatory function of PANK2. Over-annotation of a phenotypic readout as a regulatory role. Reason: Lipid-metabolism perturbations in PANK2-deficient cells are downstream effects of CoA depletion; annotating PANK2 as a regulator of fatty acid metabolism over-interprets a metabolic consequence. Supporting Evidence: PMID:22221393 Global metabolic profiling and follow-up studies in patient-derived fibroblasts also reveal defects in bile acid conjugation and lipid metabolism, pathways that require coenzyme A.
GO:0090207 regulation of triglyceride metabolic process	IMP PMID:22221393 Metabolic consequences of mitochondrial coenzyme A deficienc...	MARK AS OVER ANNOTATED	Summary: Same rationale as the fatty-acid regulation annotation: altered triglyceride/lipid metabolism in PKAN patient material is a downstream consequence of CoA deficiency rather than a dedicated regulatory function of PANK2. Reason: Downstream metabolic consequence of CoA depletion; over-interprets a profiling observation as a regulatory role. Supporting Evidence: PMID:22221393 Global metabolic profiling and follow-up studies in patient-derived fibroblasts also reveal defects in bile acid conjugation and lipid metabolism, pathways that require coenzyme A.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput high-confidence mitochondrial proteome places PANK2 in mitochondria, corroborating the extensive experimental localization data. Core location. Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). PMID:12554685 An in vitro import assay and in vivo immunolocalization experiments demonstrate a mitochondrial localization of this isoform.
GO:0001525 angiogenesis	IMP PMID:30221726 Silencing of pantothenate kinase 2 reduces endothelial cell ...	MARK AS OVER ANNOTATED	Summary: Silencing PANK2 reduces the angiogenic properties of HUVECs, and pank2 knockdown perturbs zebrafish vasculature in a CoA-rescuable way; the phenotype is a downstream consequence of CoA supply. Reason: PANK2 performs no step of angiogenesis; the vascular phenotype follows from reduced CoA synthesis and is rescued by CoA, so the process annotation over-interprets an indirect effect (treated like the PPCS cardiac phenotype). Supporting Evidence: PMID:30221726 PANK2 expression was required for normal angiogenetic properties of human umbilical vein endothelial cells.
GO:0004594 pantothenate kinase activity	IMP PMID:15659606 Altered neuronal mitochondrial coenzyme A synthesis in neuro...	ACCEPT	Summary: Mature PanK2 catalyzes the initial step of CoA synthesis; disease mutations reduce catalytic activity. Direct experimental support for the core molecular function. Supporting Evidence: PMID:15659606 The mature protein catalyzes the initial step in coenzyme A (CoA)
GO:0004594 pantothenate kinase activity	IMP PMID:16272150 Biochemical properties of human pantothenate kinase 2 isofor...	ACCEPT	Summary: Biochemical characterization of human PanK2 isoforms and 14 disease mutants for pantothenate kinase activity, including feedback inhibition by CoA thioesters. Core molecular function. Supporting Evidence: PMID:16272150 PanK2 was extremely sensitive to feedback inhibition by CoA thioesters (IC50 values between 250 and 500 nM)
GO:0004594 pantothenate kinase activity	IMP PMID:17242360 Activation of human mitochondrial pantothenate kinase 2 by p...	ACCEPT	Summary: Purified human PanK2 pantothenate kinase activity assayed for regulation: competitive inhibition by acetyl-CoA with respect to ATP and activation by palmitoylcarnitine. Core molecular function. Supporting Evidence: PMID:17242360 Acetyl-CoA was a competitive inhibitor of purified PanK2 with
GO:0005739 mitochondrion	IDA PMID:15659606 Altered neuronal mitochondrial coenzyme A synthesis in neuro...	ACCEPT	Summary: Direct immunolocalization: PanK2 protein is localized to mitochondria of neurons in human brain. Core location. Supporting Evidence: PMID:15659606 PanK2 protein is localized to mitochondria of neurons in human brain
GO:0005634 nucleus	IDA PMID:23152917 Compartmentalization of mammalian pantothenate kinases.	KEEP AS NON CORE	Summary: Human PanK2 was detected in the nucleus by live-cell imaging, with a functional NLS (residues 82-94) and NES; the protein traffics nucleus->mitochondria and is absent from the nucleus during G2. A genuine but dynamic, minor pool; not the core compartment. Reason: Nuclear localization is a dynamic, cell-cycle-regulated minor pool that migrates to mitochondria; the enzyme's core catalytic role is mitochondrial. Supporting Evidence: PMID:23152917 The hPanK2 protein was detected in both mitochondrial and nuclear compartments
GO:0005739 mitochondrion	IDA PMID:23152917 Compartmentalization of mammalian pantothenate kinases.	ACCEPT	Summary: Direct imaging confirmed hPanK2 in the mitochondrial compartment (predominant steady-state location). Core location. Supporting Evidence: PMID:23152917 The hPanK2 protein was detected in both mitochondrial and nuclear compartments
GO:0005758 mitochondrial intermembrane space	IDA PMID:23152917 Compartmentalization of mammalian pantothenate kinases.	ACCEPT	Summary: Submitochondrial localization determined experimentally (digitonin permeabilization + protease protection): mature hPanK2 co-fractionates with the IMS marker SMAC, placing it in the mitochondrial intermembrane space. This is the specific, functionally relevant compartment (freely accessible to cytosol-derived acylcarnitines and allowing phosphopantothenate export). Supporting Evidence: PMID:23152917 the mature hPanK2 protein was located in the IMS of mitochondria

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Notes

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