The Enzymatic Breakdown of Pantethine to Pantothenic Acid and Cystamine

Duprè, Silvestro; Graziani, Maria Teresa; Rosei, Maria Anna; Fabi, Andrea; Grosso, Elena Del

doi:10.1111/j.1432-1033.1970.tb01119.x

Cited by 73 publications

(53 citation statements)

References 9 publications

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“…The mouse gene cluster includes Vanin-1 and Vanin-3, preferentially expressed by epithelial and myeloid cells, respectively [9,10]. The Vanin-1 gene product is a pantetheinase that catalyzes the hydrolysis of pantetheine into pantothenic acid (vitamin B5) and cysteamine [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Vanin‐1 controls granuloma formation and macrophage polarization in Coxiella burnetii infection

Meghari¹,

Berruyer-Pouyet²,

Lépidi³

et al. 2006

Eur J Immunol

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Q fever is caused by Coxiella burnetii, a bacterium that survives in MU. Vanin-1 is a membrane-anchored pantetheinase that controls tissue inflammation. Consequently, Vanin-1-deficient mice represent a unique mouse model in which stress-induced inflammation is limited by the reaction of resident tissue cells. To investigate the contribution of host tissues in the control of a bacterial infection, we infected Vanin-1-deficient mice with C. burnetii. Mortality and morbidity of mice were not affected. The lack of Vanin-1 had no effect on C. burnetii clearance but decreased the formation of granulomas in spleen and liver. Granuloma formation depends upon MU recruitment and activation in these tissues. Whereas the former was slightly impaired in mutant mice, the lack of Vanin-1 significantly affected the activation pattern of BM-derived MU stimulated by C. burnetii. While their microbicidal activity against C. burnetii was moderately impaired, they exhibited decreased inducible nitric oxide synthase (iNOS) and MCP-1 gene expression, and increased IL-10 and arginase expression. In liver from mutant mice, increased arginase expression and decreased expression of MCP-1 and iNOS were reminiscent of MU data. These results suggest a role of Vanin-1 in granuloma formation in response to C. burnetii by skewing MU activation toward an M2 program. See accompanying commentary http://dx

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Section: Introductionmentioning

confidence: 99%

Vanin‐1 controls granuloma formation and macrophage polarization in Coxiella burnetii infection

Meghari¹,

Berruyer-Pouyet²,

Lépidi³

et al. 2006

Eur J Immunol

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“…Among them, the dietary provitamin pantethine, a dimer of pantothenic acid linked by disulfide cystamine (1), has been the subject of much research. As a part of CoA, pantethine is a key regulator of lipid metabolism (2)(3)(4).…”

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confidence: 99%

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Penet

Abou-Hamdan

Coltel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

102

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We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood-brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation-coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule; however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects. Therefore, trials of pantethine treatment in adjunctive therapy for severe malaria are warranted.blood-brain barrier ͉ phosphatidylserine ͉ Plasmodium ͉ platelet activation L ow-molecular-weight thiols, widely distributed in the living world, show broad physiological activity involving multiple targets. Among them, the dietary provitamin pantethine, a dimer of pantothenic acid linked by disulfide cystamine (1), has been the subject of much research. As a part of CoA, pantethine is a key regulator of lipid metabolism (2-4). Pantethine has been shown also to inhibit in vitro platelet aggregation in a dosedependent manner (5-7), an action that was not clearly understood (5).Because platelets play a central role in the pathological process associated with cerebral malaria (CM), we examined the effects of pantethine administration to mice infected with Plasmodium berghei strain ANKA (PbA). The processes identified by using this model are relevant to the human pathology (8). Susceptible strains of mice infected with PbA develop neurological manifestations rapidly followed by death. The pathology is due not to the direct action of the parasite but to a deleterious immune response of the infected host, involving cerebral vascular inflammation with microcirculatory dysfunction (9-13). The ultimate consequence is disruption of the brain microvasculature, enhancement of blood-brain barrier (BBB) permeability, and edema formation leading to major hemodynamic dysfunction (14-16).One of the earliest steps of the inflamm...

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“…Enzyme preparations used throughout had a specific activity of not less than 3.0 units/mg, which corresponds to a purification of about 2000-fold. Activity determinations were performed as described previously [2,3]. One enzyme unit (U) is defined as the amount of protein which metabolises one micromole of pantetbeine in 1 h under the conditions described in the references just cited.…”

Section: Enzyme Preparationsmentioning

confidence: 99%

The Substrate Specificity of Pantethinase

Duprè¹,

Rosei²,

Bellussi³

et al. 1973

European Journal of Biochemistry

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The substrate specificity of pantethinase, the mammalian enzyme which has been isolated from horse kidney cortex, has been studied. The real substrate has been found to be pantetheine in the reduced form, and the involvement of one or more -SH groups of the enzyme is also considered.A number of other compounds, chemically related t o pantetheine, has also been tested as substrates. Pantethinase is able to metabolise pantetheine-4'-phosphate, with an activity about loo/, of that exhibited for pantetheine ; it is inactive on the other substances tested (pantothenoylcysteine-4'-phosphate, pantothenoylcysteine, pantetheine thiazoline, CoA).The metabolic role of pantethinase seems to be, in the light of the above results, connected with a degradative pathway of pantetheine-4'-phosphate, which is known to be one of the intermediates in the biosynthesis of CoA.A series of studies on the metabolism of cysteamine led to the identification of a new hydrolytic enzyme, which metabolises pantethine yielding pantothenic acid and cystamine, by cleavage of one of the carboamide bonds [l, 21. This enzyme, called pantethinase, is activated in the presence of cysteine (or other thiols as well), which increases enzymatic activity; nevertheless in the absence of any added thiol a little activity can be detected. To explain this behaviour two alternative hypotheses are possible : either the real substrate of the enzyme is the reduced form of pantethine or the enzyme requires the presence of reduced -SH groups in its molecule for fully catalytic activity. I n both cases the enzyme could show a little activity also in the absence of any activator, as actually observed, since the sulphidedisulphide exchange between the substrate molecule in the oxidized form and free -SH groups of the protein (or other contaminant proteins as well) could give rise to the active form(s). Of course, it can not be excluded a t all that both hypotheses are true a t the same time.

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The Enzymatic Breakdown of Pantethine to Pantothenic Acid and Cystamine

Cited by 73 publications

References 9 publications

Vanin‐1 controls granuloma formation and macrophage polarization in Coxiella burnetii infection

Vanin‐1 controls granuloma formation and macrophage polarization in Coxiella burnetii infection

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

The Substrate Specificity of Pantethinase

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