Pantetheinase is an ubiquitous enzyme which hydrolyses D-pantetheine into cysteamine and pantothenate (vitamin B5) on the dissimilative pathway of CoA. Pantetheinase isoforms are encoded by the Vnn (vanin) genes and Vnn1 is the predominant tissue isoform in mice and humans. In the present article, we review the results showing the regulation of Vnn1 expression during developmental, repair and inflammatory situations and the impact of a Vnn1 deficiency in mouse models of pathologies. We document the involvement of the Vnn1 pantetheinase in situations of increased tissue needs and propose that Vnn1 through recycling of pantothenate and release of cysteamine in tissues participates in the adaptive response of the tissue to stress.

Role of the Vnn1 pantetheinase in pantothenate metabolism

Pantothenate (vitamin B5) is absorbed in the intestine and is the precursor of CoA synthesis. This pathway is highly regulated to adapt CoA levels to cell needs in ATP production and lipid or carbohydrate metabolism. Phosphorylation of pantothenate by PanK (pantothenate kinase) is a rate-limiting enzyme step in this process [1]. PanK-deficient Drosophila show CoA deficiency, increased oxidative stress and neurodegeneration [2,3], a phenotype reversed by pantethine administration [4]. In humans, PanK mutants are responsible for neurodegenerative diseases with brain iron accumulation [5]. In mice different PanK isoforms participate in CoA homoeostasis in various subcellular compartments. CoA degradation is controlled in vivo by various enzymes (reviewed in [6]) regulating the bioavailability of the phosphopantetheine precursor which is ultimately metabolized by phosphatases and pantetheinase activity [7]. As summarized in Figure 1, pantetheinase (EC 3.5.1.92) is an ubiquitous enzyme which hydrolyses D-pantetheine into cysteamine and pantothenate (vitamin B5) [8,9]. C-terminal sequencing of purified pantetheinase revealed a homology with the previously described vanin (Vnn) genes [10]. Two Vnn genes have been identified in mouse: Vnn1 and Vnn3 [11]. Formal demonstration that Vnn1 is a pantetheinase relied on cell transfection studies [12] and later enzymatic analysis of a recombinant Vnn1 molecule [13]. There is so far no other known function for Vnn/pantetheinases. The Vnn3 gene lacks a transmembrane segment and a formal demonstration that Vnn3 is a functional pantetheinase in vivo is still lacking. Whereas Vnn1 expression is relatively ubiquitous, Vnn3 transcripts are more restricted to the haematopoietic lineage, mainly in neutrophils. Vnn1-deficient mice show reduced tissue cysteamine concentration, suggesting that Vnn1 is a predominant source of cysteamine in vivo. In humans, three isoforms, VNN1, VNN2 (also named GP80) and VNN3, have been identified [14]. Whereas VNN3 might be a pseudogene [15], VNN1 expression predominates in tissues, but transcripts have also been detected in peripheral blood mononuclear cells. VNN2 is a GPI (glycosylphosphatidylinositol)-anchored pantetheinase restricted to neutrophils [16]. In mammals, all known pantetheinases are extracellular enzymes, expressed at cell membranes via a GPI anchor (Vnn1, VNN1, VNN2) or secreted (Vnn1, Vnn3?, VNN3?) [11]. Pantetheinase homologues have been detected in mammals and insects such as Drosophila [14].

Schematic diagram of the connections between the CoA/pantetheinase pathway and cysteamine putative functions in vivo

Figure 1
Schematic diagram of the connections between the CoA/pantetheinase pathway and cysteamine putative functions in vivo

More detailed pathways are reviewed in [1,25,34] concerning the CoA, hypotaurine and ketimine pathways respectively.

Figure 1
Schematic diagram of the connections between the CoA/pantetheinase pathway and cysteamine putative functions in vivo

More detailed pathways are reviewed in [1,25,34] concerning the CoA, hypotaurine and ketimine pathways respectively.

Enzymatic activity

Pantetheinases belong to branch 4 of the nitrilase gene family and share a CN hydrolase domain and a common catalytic mechanism involving a cysteine nucleophile, a glutamate base and an active site lysine [17,18]. The branch 4 amidases encompass biotinidase (branch 4.1) and pantetheinases (branch 4.2) which recycle vitamin B8 and B5 respectively. Whereas cases of biotinidase deficiency have been identified in humans [19], there is no report of a pantetheinase deficiency, maybe due to functional redundancy among pantetheinase isoforms. Vnn pantetheinases possess an N-terminal catalytic domain and a C-terminal membrane proximal domain of unknown function. Transfection of the isolated catalytic domain confers the enzymatic activity which is abrogated by mutation of the catalytic cysteine [20]. Pantetheinase is highly specific for the pantothenate but not the cysteamine moiety [8].

Pantotheinase is heat stable and activated by thiol groups. Former studies on the native pig kidney enzyme showed the requirement for another free thiol group involved in the catalytic event [21,22]. This thiol group is not directly involved in catalysis and may be responsible for inhibition of the enzyme activity by pantethine and other disulfides. Several pantetheinase substrates have been designed on a pantetheine core. The original S-pantetheine-3-pyruvate and the more sensitive fluorescent substrate pAMC (pantothenate-7-amino-4-methylcoumarin) are hydrolysed with high specificity with an apparent Km of 28 μM at pH 8.0 and 30°C. Using the pAMC substrate and a Vnn1-specific ELISA we demonstrated the presence of Vnn1 in serum [20]. The pantothenate-p-nitroanilide derivative of pantothenate (pPNa) (Km=4 μM) is less specific for Vnn1 and can detect a residual pantetheinase activity in the serum of Vnn1-deficient mice, possibly due to Vnn3.

Impact of pantetheinase activity on pantetheine-derived metabolites

The role of pantetheinase in pantothenate/CoA homoeostasis has not been thoroughly investigated. In human serum, pantothenate concentration ranges from 1.1 to 12 μmol/l, whereas the total serum pantetheinase activity was evaluated as 11 μmol pantothenate/min per l [7]. In tissues, the highest basal expression levels of Vnn1 are detected in organs with high CoA turnover such as intestine, liver and kidney but not heart or muscle [12,20,23]. In vivo, free tissue pantetheine (approximately 13.3 nmol/g in rat kidney acetone powder) is hydrolysed into pantothenate. Oral administration of pantethine, the disulfide pantetheine dimer, provokes a transient increase in plasma pantothenate and cysteamine levels, suggesting its rapid turnover by tissue and blood pantetheinase [24]. Cysteamine concentration varies from 2.3 to 23 μmol/l in the serum of high protein fed compared with fasted rats [25]. Values reported for free cysteamine in tissues (reviewed in [26]) vary from 0.1 to 15 and 0.2 to 270 nanomol/g of tissue for rodent kidney and liver respectively. Using a more sensitive method, cysteamine concentrations of 0.35 and 0.16 μmol/g were found in kidney and liver respectively [27]. Using this assay, cysteamine could be detected in tissues from Vnn1-deficient mice (0.23 and 0.090 μmol/g in kidney and liver respectively) suggesting that another pantetheinase isoform such as Vnn3, whose expression is augmented in the liver of Vnn1-deficient mice [28], might partially compensate for Vnn1 deficiency. In vivo cysteamine can be obtained exclusively through pantetheine; a specific decarboxylase activity towards cysteine has never been described. Cysteamine, as cysteine, is a precursor for hypotaurine and taurine synthesis which are essential for brain function [25,29]. Synthesis of hypotaurine and taurine involves two independent pathways controlled by the ADO (2-aminoethanethiol) and CDO (cysteine) thiol dioxygenases respectively. The respective contribution of the two pathways remains to be investigated but ADO has the unique role of coupling CoA metabolism to taurine biosynthesis. Unexpectedly, hypotaurine levels were enhanced rather than reduced in the kidney of Vnn1-deficient mice [27]. Cysteamine also interferes with cysteine and GSH metabolism. Addition of cysteamine to cultured cells improves cysteine uptake and GSH synthesis [30] and is cytoprotective in vitro [26,31]. Unlike glutathione which must be resynthesized in cells, cysteamine can cross membranes. The tissue concentration of the cysteamine/cystamine redox couple is 10–50–fold lower than that of GSH per molar equivalent [27]. It is thus unlikely that cysteamine can compete with the redox power of glutathione within cells. However, at pharmacological doses, cysteamine is used as a cysteine chelator to bypass the defective cystinosin pathway that results in lysosomal accumulation of cysteine in cystinosis patients [32,33]. Pantetheinase activity is also associated with the production of the AECK (aminoethylcysteine ketimine) and derivatives, detectable in human tissues and bearing strong antioxidant properties [34]. Indeed, S-aminoethylcysteine, the natural precursor of the ketimine, is produced from L-serine and cysteamine by the action of the enzyme cystathionine β-synthase through a pantothenoil-S-aminoethylcysteine intermediate [35]. Therefore pantetheinase might participate in the regulation of redox homoeostasis through various mechanisms.

Vnn1 pantetheinase function: lessons from Vnn1-deficient mice

Cell proliferation

Exploration of pantetheinase function was boosted when mouse models of pantetheinase deficiency became available [12]. Results are summarized in Table 1.

Table 1
Impact of Vnn1 deficiency on mouse phenotypes
Context Phenotype Phenotype in Vnn1-knockout compared with wild-type mice Cystamine effect Interpretation Reference 
Development/repair      
 Chondrogenesis Delayed chondrogenesis and reduced expansion in vitro Increased GSH levels Enhancement of chondrogenesis in vitro Vnn1 potentiates chondrogenesis Johnson et al. [38
 Arterial ischaemia Reduced neotintima formation and myofibroblast expansion Decreased oxidative stress Enhanced ROS (reactive oxygen species) generation in vitro Vnn1 drives SMC activation and repair Dammanahalli et al. [39
Cancer      
 Collitis-associated cancer Reduction of tumour development in knockout mice Reduced cell proliferation and inflammation Not testable Vnn1 is pro-oncogenic Pouyet et al. [40
 Adrenal tumorigenesis (SF1 transgenic mouse) Decreased tumour development Reduced number of Ki67+ cells Enhanced dysplasia and tumour nodules Vnn1 is pro-oncogenic Latre de Late et al. [39a
Inflammation and infection      
 Schistosomiasis infection Increased survival; similar parasite egg level Reduced colonic lesions, increased GSH levels Not testable Vnn1 licenses inflammation Martin et al. [54
 Rickettsiosis infection Altered granuloma development and macrophage activation Similar bacterial clearance Not tested Vnn1 licenses inflammation Meghari et al. [55
Oxidative stress      
 Mouse irradiation and paraquat intoxication Increased tolerance to stress Enhanced GSH levels Not tested Vnn1 regulates redox homoeostasis Berruyer et al. [28
 Detoxication Impaired GSTA3 isoenzyme level in liver No impact on protein expression Restoration of enzymatic activity Vnn1 stabilizes GSTA3 in an active state? Di Leandro et al. [52
Autoimmune and inflammation models      
 Type 1 diabetes Increased diabetes incidence in NOD (non-obese diabetic) mice and STZ-induced model Reduced islet β-cell survival in culture In vitro cytoprotection on islet cells Vnn1 is cytoprotective Roisin-Bouffay et al. [48
 TNBS (trinitrobenzene sulfonate) colitis Reduced inflammation Enhanced PPARγ-mediated tissue protection Enhanced colitis Vnn1 licenses inflammation Berruyer et al. [23
Context Phenotype Phenotype in Vnn1-knockout compared with wild-type mice Cystamine effect Interpretation Reference 
Development/repair      
 Chondrogenesis Delayed chondrogenesis and reduced expansion in vitro Increased GSH levels Enhancement of chondrogenesis in vitro Vnn1 potentiates chondrogenesis Johnson et al. [38
 Arterial ischaemia Reduced neotintima formation and myofibroblast expansion Decreased oxidative stress Enhanced ROS (reactive oxygen species) generation in vitro Vnn1 drives SMC activation and repair Dammanahalli et al. [39
Cancer      
 Collitis-associated cancer Reduction of tumour development in knockout mice Reduced cell proliferation and inflammation Not testable Vnn1 is pro-oncogenic Pouyet et al. [40
 Adrenal tumorigenesis (SF1 transgenic mouse) Decreased tumour development Reduced number of Ki67+ cells Enhanced dysplasia and tumour nodules Vnn1 is pro-oncogenic Latre de Late et al. [39a
Inflammation and infection      
 Schistosomiasis infection Increased survival; similar parasite egg level Reduced colonic lesions, increased GSH levels Not testable Vnn1 licenses inflammation Martin et al. [54
 Rickettsiosis infection Altered granuloma development and macrophage activation Similar bacterial clearance Not tested Vnn1 licenses inflammation Meghari et al. [55
Oxidative stress      
 Mouse irradiation and paraquat intoxication Increased tolerance to stress Enhanced GSH levels Not tested Vnn1 regulates redox homoeostasis Berruyer et al. [28
 Detoxication Impaired GSTA3 isoenzyme level in liver No impact on protein expression Restoration of enzymatic activity Vnn1 stabilizes GSTA3 in an active state? Di Leandro et al. [52
Autoimmune and inflammation models      
 Type 1 diabetes Increased diabetes incidence in NOD (non-obese diabetic) mice and STZ-induced model Reduced islet β-cell survival in culture In vitro cytoprotection on islet cells Vnn1 is cytoprotective Roisin-Bouffay et al. [48
 TNBS (trinitrobenzene sulfonate) colitis Reduced inflammation Enhanced PPARγ-mediated tissue protection Enhanced colitis Vnn1 licenses inflammation Berruyer et al. [23

Vnn1 gene expression is developmentally regulated. Vnn1 expression is induced by Sox9 in Sertoli cells and chondroblasts and correlates with male gonadal differentiation [36,37] and chondrogenesis [38]. In vitro, Vnn1 expression is required for optimal chondroblast expansion and differentiation. Vnn1-deficient mice show no developmental defects under conventional housing but the life expectancy of female mice is reduced (P. Naquet and F. Galland, unpublished work).

However, several Vnn1-dependent phenotypes appeared in situations of metabolic challenge and/or tissue damage. Indeed, Vnn1 expression is induced on smooth muscle cells during arterial ischaemia [39]. In response to carotid artery ligation, Vnn1-deficient mice display decreased cell proliferation and neointima formation. Vnn1 is also expressed in the adrenal gland and this expression is boosted by the SF1 transcription factor, a prognostic marker in adrenocortical carcinomas. Interestingly, tumour-prone SF1 transgenic mice overexpress Vnn1 in the adrenal cortex and adrenocortical tumorigenesis is reduced in the absence of Vnn1, a growth-defective phenotype compensated by cystamine administration [39a]. Therefore Vnn1 expression improves cell fitness/proliferation when needs are increased during developmental, oncogenic [40] or repair processes.

Tissue damage

Tissues respond to stress through activation of inflammatory and cytoprotective pathways, processes involving nuclear receptors [41,42]. The Vnn1 promoter contains ARE (antioxidant-response element) and PPRE [PPAR(peroxisome-proliferator-activated receptor)-responsive element] sites responsible for Vnn1 up-regulation in tissues exposed to oxidative stress or PPAR stimulation respectively [20,28]. In mouse serum, the level of Vnn1 pantetheinase activity is PPARα dependent and serves as a biomarker of PPARα activation in liver. Under a high-fat diet, liver releases Vnn1-expressing microparticles in blood that mediate pro-angiogenic signals [43]. Vnn1 induction is also associated with inflammatory or cytopathic disorders such as psoriasis [44] or nephropathy [45,46]. Therefore overexpression of Vnn1 might participate in inflammatory and/or cytoprotective programmes induced in these contexts.

Cystamine administration provides protection in a model of Huntington's disease [47]. Cystamine increases the secretion of BDNF (brain-derived neurotrophic factor) possibly via neutralization of transglutaminase activity and/or an increase in HSJ1b (heat shock DnaJ-containing protein 1b) levels, both contributing to neuroprotection through control of the toxic effect of polyQ huntingtin protein aggregates on striatal neurons. Cysteamine-mediated cytoprotection was also documented in islet β-cell cultures exposed to STZ (streptozotocin)-induced toxicity and was related to a reduction in caspase 3 activation [48]. Interestingly, caspase 3 is inhibited by cystamine in vitro [49] and Vnn1-deficient mice are more susceptible to STZ-induced or Type 1 diabetes. Various other mechanisms involving cyst(e)amine-mediated protection through redox modulation have been proposed: (i) cysteamine can scavenge unsaturated aldehydes produced upon lipid peroxidation in culture [50]; (ii) cystamine protects cell cultures or animals exposed to the neurotoxic 3-nitropropionic acid compound through Nrf2 activation [51]; (iii) the detoxifying Se-independent glutathione peroxidase activity carried by GSTA3 (GST Alpha 3) is depressed in Vnn1-deficient livers and restored by cystamine administration [52]; (iv) pantetheine is an efficient cysteamine donor for the synthesis of the antioxidant S-AECK [35]. Since response to tissue stress provokes an increase in Vnn1 expression, the resulting augmentation in cyst(e)amine production may contribute to tissue tolerance to stress and the respective contributions of these mechanisms remains to be investigated.

Inflammatory or infectious diseases

Tissue tolerance reduces the negative impact of an infection on host fitness independently of pathogen burden [53]. Interestingly, in two models, schistosomiasis and rickettsiosis, the absence of tissue Vnn1 expression had little impact on pathogen burden whereas tolerance to the disease was considerably affected. In schistosomiasis, neutrophil infiltration and intestinal damage were reduced and survival increased [54]. In rickettsiosis, Vnn1-deficient mice did not develop granulomas but recruited pro-repair macrophages which limited lesions induced by inflammation [55]. Therefore in these models, tolerance is associated with altered immune cell recruitment and reduced tissue lesions.

IBDs (inflammatory bowel diseases) correspond to a dysregulated mucosal response to gut commensal microbiota in genetically susceptible hosts. We showed that VNN1 expression is significantly increased in the colonic mucosa from IBD patients [56]. Sequencing of the VNN1 gene revealed the presence of functional SNPs (single nucleotide polymorphisms) in some patients with severe colitis which correlated with high VNN1 expression levels and IBD risk. One SNP affects PPARγ recruitment. Whether deregulated VNN1 expression reflects tissue response to stress or might predispose to inflammation is still debated. In the mouse TNBS (trinitrobenzene sulfonate) colitis model, we observed that Vnn1 deficiency was, as in schistosomiasis, protective due to reduced inflammation-driven tissue lesions [23]. Vnn1 activity, inducible by PPARγ activation, antagonized PPARγ-mediated protection, suggesting the existence of a negative regulatory loop. We cannot yet exclude another mechanism based on the known ulcerogenic potential of cysteamine at high dose which in the presence of iron liberated during haemorrhages might enhance free radical production via a Fenton reaction [57]. Therefore in gut, Vn1 might play a dual role, licensing inflammation and possibly participating in mucosal protection.

Unresolved mechanistic issues

The following facts are known: (i) Vnn1 is highly expressed in tissues having high CoA turnover; (ii) Vnn1 expression is up-regulated by PPAR transcription factors which regulate CoA-consuming metabolic pathways; (iii) Vnn1 expression is up-regulated during developmental or repair processes associated with increased cell proliferation and metabolic needs; and (iv) Vnn1 expression is up-regulated by oxidative stress and tissue damage, conditions which require energy and redox control to preserve cell integrity. Although pantetheinase deficiency is not complete in the absence of Vnn1, Vnn1-deficient mice show impaired adaptation to stress. Vnn1-deficient mice have no CoA deficiency under steady-state conditions. However, under local acute demand, the ability to regenerate pantothenate in situ might be advantageous to tissues. Tissue damage may also increase the release of pantetheine metabolites which through pantetheinase recycling would refuel pantothenate levels. CoA deficiency predisposes to oxidative stress. Increased pantetheinase activity would participate in both CoA recycling and cysteamine production which might have a role in the control of cell damage. In animal models, Vnn1 deficiency is generally compensated by cystamine administration, suggesting that cyst(e)amine mediates some Vnn1-dependent functions. The low tissue concentration of cysteamine compared with that of GSH argues against a central role for cysteamine in the control of redox homoeostasis. The contribution of cysteamine-dependent metabolites is unclear and should be investigated using appropriate metabolomic approaches. Nevertheless, cyst(e)amine might form mixed disulfides with target proteins and this mechanism has been proposed to explain its modulatory activity on enzymes involved in stress response such as transglutaminases [58,59], caspase 3 [49], GSTA3 [52], γGCS (γ-glutamylcysteine synthetase) [28,54,60] and PKCε (protein kinase Cε) [61]. Inactivation of PKCε is the only example in which Cys452S-cysteaminylation was shown by MS to be a stable modification and that replacement of Cys452 by an alanine residue conferred resistance to inactivation by disulfide on PKCε [61]. More generally, most redox couples are far off any equilibrium and redox ratios cannot regulate anything unless regulation occurs between a single redox-active mediator and its specific target [62]. In this metastable condition, chemical and consequently biological processes require catalysis. Whether cysteaminylation of target enzymes is catalysed by specific sensor proteins is unknown and consequently it is difficult to extrapolate in vitro results to in vivo regulation. The development of redoxomic tools might allow us to formally identify physiological cysteamine targets in vivo. The role of Vnn/pantetheinase remains to be investigated using total pantetheinase deficiency or pan-inhibitors of enzymatic activity. Altogether, we propose that the Vnn1 pantetheinase contributes to temporal and local tissue adaptation to needs and damage and participates in tissue tolerance to stress.

Coenzyme A and Its Derivatives in Cellular Metabolism and Disease: A Biochemical Society Focused Meeting held at Charles Darwin House, London, U.K., 20–21 March 2014. Organized and Edited by Ivan Gout (University College London, U.K.), Suzanne Jackowski (St. Jude Children's Research Hospital, U.S.A.) and Ody Sibon (University of Groningen, The Netherlands).

Abbreviations

     
  • ADO

    2-aminoethanethiol

  •  
  • AECK

    aminoethylcysteine ketimine

  •  
  • GPI

    glycosylphosphatidylinositol

  •  
  • pAMC

    pantothenate-7-amino-4-methylcoumarin

  •  
  • IBD

    inflammatory bowel disease

  •  
  • GSTA3

    GST Alpha 3

  •  
  • PanK

    pantothenate kinase

  •  
  • PKC

    protein kinase C

  •  
  • PPAR

    peroxisome-proliferator-activated receptor

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • STZ

    streptozotocin

Funding

Supported by institutional grants from Inserm and Centre National de la Recherche Scientifique (CNRS) and by Institut National du Cancer (INCa) and charitable funds from the Association F. Aupetit (AFA), INCa funds AdrSF1 and Inflammation and colorectal cancer, ARC number 1103. Part of this study has been funded by the I2HD project between Centre d'Immunologie de Marseille-Luminy (CIML) and Sanofi [grant number 10756A10-106072].

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