Expression of the Vanin Gene Family in Normal and Inflamed Human Skin: Induction by Proinflammatory Cytokines

Jansen, Patrick A.; Kamsteeg, Marijke; Rodijk-Olthuis, Diana; Vlijmen-Willems, Ivonne M.J.J. van; Jongh, Gys J. de; Bergers, Mieke; Tjabringa, Geuranne S.; Zeeuwen, Patrick L.J.M.; Schalkwijk, Joost

doi:10.1038/jid.2009.67

Cited by 70 publications

(67 citation statements)

References 52 publications

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“…Although their specific functional differences remain to be elucidated, products derived from these alternative splice variants may have some biological activities other than pantetheinase enzyme. Human VNN3 mRNA is reported to be expressed in the lung, liver, and peripheral blood cells (10,15). Jansen et al (15) also demonstrated that the human VNN3 mRNA is detected in inflamed skin keratinocytes that are induced by inflammatory cytokines, and VNN3 is elevated in psoriatic skin lesions.…”

Section: Vanin-3/vnn3mentioning

confidence: 90%

The Linkage Between Coenzyme A Metabolism and Inflammation: Roles of Pantetheinase

Nitto

Onodera

2013

J Pharmacol Sci

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Abstract.Pantetheinase is an enzyme hydrolyzing pantetheine, an intermediate of the coenzyme A degradation pathway. Pantetheinase has long been considered as the enzyme that recycles pantothenic acid (vitamin B 5 ) generated during coenzyme A breakdown. Genetic analyses showed that mammals have multiple genes known as vanin family genes. Recent studies using mice lacking the vanin-1 gene (pantetheinase gene) suggest that pantetheinase is actively involved in the progression of inflammatory reactions by generating cysteamine. Additional studies using human leukocytes demonstrate that human neutrophils have abundant pantetheinase proteins on the surface and inside the cells. The second pantetheinase protein, GPI-80/VNN2, is suggested to work as a modulator of the function of Mac-1 (CD11b/CD18), an adhesion molecule important to neutrophil functions. This review delineates the characteristics of the pantetheinase/vanin gene family and how they affect inflammation.

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Section: Vanin-3/vnn3mentioning

confidence: 90%

The Linkage Between Coenzyme A Metabolism and Inflammation: Roles of Pantetheinase

Nitto

Onodera

2013

J Pharmacol Sci

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“…For example, VNN1-deficient mice are resistant to intestinal inflammation, oxidative stress, and experimental colitis (15,16). VNN1 also plays a critical role in malaria susceptibility, psoriasis, carcinogenesis, and cardiovascular disease (29)(30)(31)(32). Importantly, the vnn1 gene is one of the major targets of PPARa in the mouse liver, which strongly implies that VNN1 is involved in the regulation of energy metabolism (18).…”

Section: Discussionmentioning

confidence: 99%

Vanin-1 Is a Key Activator for Hepatic Gluconeogenesis

et al. 2014

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Vanin-1 (VNN1) is a liver-enriched oxidative stress sensor that has been implicated in the regulation of multiple metabolic pathways. Clinical investigations indicated that the levels of VNN1 were increased in the urine and blood of diabetic patients, but the physiological significance of this phenomenon remains unknown.In this study, we demonstrated that the hepatic expression of VNN1 was induced in fasted mice or mice with insulin resistance. Gain-and loss-of-function studies indicated that VNN1 increased the expression of gluconeogenic genes and hepatic glucose output, which led to hyperglycemia. These effects of VNN1 on gluconeogenesis were mediated by the regulation of the Akt signaling pathway. Mechanistically, vnn1 transcription was activated by the synergistic interaction of peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a) and hepatocyte nuclear factor-4a (HNF-4a). A chromatin immunoprecipitation analysis indicated that PGC-1a was present near the HNF-4a binding site on the proximal vnn1 promoter and activated the chromatin structure. Taken together, our results suggest an important role for VNN1 in regulating hepatic gluconeogenesis. Therefore, VNN1 may serve as a potential therapeutic target for the treatment of metabolic diseases caused by overactivated gluconeogenesis.

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“…Based on structural homology of pantothenamides with pantetheine and the knowledge that pantetheine is hydrolyzed by pantetheinases of the vanin family into pantothenic acid and cysteamine, we hypothesized that this class of enzymes could also hydrolyze pantothenamides. In a previous study, we showed that vanins are ubiquitously expressed (16). Using an aminomethylcoumarine derivative of pantothenic acid, which is a pantothenamide with a fluorescent leaving group as a substrate (19), pantetheinase activity in serum is readily detected.…”

Section: Resultsmentioning

confidence: 99%

“…The encoded proteins were shown to possess pantetheinase activity by the hydrolysis of pantetheine into pantothenic acid (vitamin B5) and the low-molecular-weight thiol cysteamine (15). We found vanin family members to be broadly expressed in nearly all human tissues (16). On the basis of sequence similarities, vanins were classified as members of the biotinidase branch of the nitrilase superfamily (17).…”

mentioning

confidence: 98%

Combination of Pantothenamides with Vanin Inhibitors as a Novel Antibiotic Strategy against Gram-Positive Bacteria

Jansen

Hermkens

Zeeuwen

et al. 2013

Antimicrob Agents Chemother

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eThe emergence of resistance against current antibiotics calls for the development of new compounds to treat infectious diseases. Synthetic pantothenamides are pantothenate analogs that possess broad-spectrum antibacterial activity in vitro in minimal media. Pantothenamides were shown to be substrates of the bacterial coenzyme A (CoA) biosynthetic pathway, causing cellular CoA depletion and interference with fatty acid synthesis. In spite of their potential use and selectivity for bacterial metabolic routes, these compounds have never made it to the clinic. In the present study, we show that pantothenamides are not active as antibiotics in the presence of serum, and we found that they were hydrolyzed by ubiquitous pantetheinases of the vanin family. To address this further, we synthesized a series of pantetheinase inhibitors based on a pantothenate scaffold that inhibited serum pantetheinase activity in the nanomolar range. Mass spectrometric analysis showed that addition of these pantetheinase inhibitors prevented hydrolysis of pantothenamides by serum. We found that combinations of these novel pantetheinase inhibitors and prototypic pantothenamides like N5-Pan and N7-Pan exerted antimicrobial activity in vitro, particularly against Grampositive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes) even in the presence of serum. These results indicate that pantothenamides, when protected against degradation by host pantetheinases, are potentially useful antimicrobial agents. There is a continuous battle between humans and microorganisms, and the development of resistance against current antibiotics creates a need to develop new drug scaffolds and targets (1). There are several classes of antibiotic-resistant pathogens that are emerging as major threats. Methicillin-resistant and vancomycin-resistant Staphylococcus aureus strains (MRSA and VRSA) and multidrug-resistant Streptococcus pneumoniae are serious health problems in both hospital settings and the community. Multidrug-resistant Gram-negative bacteria (e.g., Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) are a second group of organisms that pose a threat of untreatable infections. Finally, poverty-related conditions such as tuberculosis and parasitic diseases, which are particularly important in developing countries, are a cause of great concern, as the already-limited number of treatment modalities is decreasing because of resistance. The development of new antibiotics has been slow, and most compounds to date have been derived from a limited number of molecular scaffolds targeting a few microbial molecular pathways. Discovery of new scaffolds and new targets should clearly be a priority, although the commercial prospects of antibiotic development are unfavorable (1).In 1970, amides derived from pantothenic acid (vitamin B5), were reported to possess antibiotic activity in vitro (2). During the last few decades, many of these pantothenamides have been synthesized and the pu...

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Expression of the Vanin Gene Family in Normal and Inflamed Human Skin: Induction by Proinflammatory Cytokines

Cited by 70 publications

References 52 publications

The Linkage Between Coenzyme A Metabolism and Inflammation: Roles of Pantetheinase

The Linkage Between Coenzyme A Metabolism and Inflammation: Roles of Pantetheinase

Vanin-1 Is a Key Activator for Hepatic Gluconeogenesis

Combination of Pantothenamides with Vanin Inhibitors as a Novel Antibiotic Strategy against Gram-Positive Bacteria

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