Our group studies the enzymes involved in the fatty acid transport into the mitochondria such as carnitine palmitoyltransferases (CPT-I and -II) as well as those involved in the ketogenesis pathway (HMG-CoA synthase and lyase).

A molecular approach is applied to study the regulation of these genes, including expression assays in vivo and in vitro in heterologous systems of both wild type and mutated forms. 3D models for these proteins are obtained by direct homology and threading.

Moreover, we study the function of CPT-I in the regulation of fatty acids and its possible application in the treatment of diabetes type II. We analyse the effect of CPT-I over insulin secretion in beta-cells and the different uptake of glucose in myocites. In addition, we study the mechanisms of insulin-resistance in muscle and CPT-I involvement.

Another research line is focused on trans-splicing process in mammals, more exactly, the ability of the carnitine octanoil transferase gene (COT) to produce transcripts with repeated exons.

RESEARCH INTERESTS

1. Molecular study of fatty-acid transport genes in mitochondria: Carnitine palmitoyl transferase I, Carnitine octanoyl transferase and Carnitine Acetyl transferase. 3D structural models and functionality.

2. Molecular mechanisms of carnitine palmitoil transferases I function in insulin secretion in pancreatic beta cells and depletion of insulin resistance in muscle cells.

3. Screening of mutations in metabolic diseases of ketogenesis (deficiency in HMG-CoA synthase and HMG-CoA lyase).

4. Molecular aspects of trans-splicing in mammals.

Dolors Cucurull

Professor

dserra@ub.edu

PUBLICATIONS

1. Molecular study of fatty-acid transport genes in mitochondria: Carnitine palmitoyl transferase I, Carnitine octanoyl transferase and Carnitine Acetyl transferase. 3D structural models and functionality.

• Asins, G., Serra, D., Arias, G. & Hegardt, F.G.
  Developmental changes in Carnitine Palmitoyl Transferases I and II gene expression in intestine and liver of suckling rats
  Biochemical Journal (1995) 306, 379-38. Abstract
• Arias, G., Matas, R., Asins, G., Hegardt, F.G. & Serra, D.
  The effect of fasting and insulin treatment on carnitine palmitoyltransferase I and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase mRNA levels in liver from suckling rats
  Biochemical Society Transactions (1997) 23, S493. Abstract
• Mascaró, C., Acosta, E., Ortiz, JA., Marrero, PF., Hegardt, F.G. y Haro, D.
  Control of human type Carnitine Palmitoyl Transferase I gene transcription by peroxisome proliferator-activated receptor
  Journal of Biological Chemistry (1998) 273, 8560-8563. Abstract
• Berge, R.K.; Garras, A.; Asins, G.; Serra, D.; Hegardt, F.G.; Madsen, L.
  Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase and carnitine palmitoyltransferase II are potential control sites of hepatic ketogenesis under conditions of peroxisome proliferation
  Lipids (1999) 34, S163-163.
• Mascaró, C., Acosta, E., Ortiz, J.A., Rodriguez, J.C., Marrero, P.F., Hegardt, F.G. and Haro, D.
  Characterization of a response element for peroxisomal proliferator activated receptor (PPRE) in human muscle-type carnitine palmitoyltransferase I
  Advances in Experimental Medicine and Biology (1999) 466, 79-85.
• Morillas, M., Clotet, J., Rubí, B., Serra, D., Asins, G., Ariño, J. y Hegardt, F.G.
  Identification of the two histidine residues responsible for the inhibition by malonyl-CoA in peroxisomal carnitine octanoyltransferase from rat liver
  Febs Letters (2000) 466, 183-186.Abstract
• Morillas, M., Clotet, J. Rubí, B., Serra, D., Ariño, J., Hegardt, F.G. y Asins, G.
  Inhibition by etomoxir of rat liver carnitine octanoyltransferase is produced through the coordinate interaction with two histidine residues
  Biochemical Journal. (2000) 351, 495-502 Abstract
• Miliar, A., Serra, D., Casaroli, R., Vilaró, S., Asins, G. y Hegardt, F.G.
  Developmental changes in carnitine octanoyltransferase gene expression in intestine and liver of suckling rats
  Archives of Biochemistry and Biophysics (2001) 385, 283-289. Abstract
• Madsen, L., Garras, A., Asins, G., Serra, D., Hegardt, F.G. y Berge, R.
  Mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase and carnitine palmitoyltransferase II are potential control sites of hepatic ketogenesis under conditions of peroxisome proliferation
  Biochemical Pharmacology (1999) 57, 1011-1019.
• Nicot, C., Hegardt, F.G. Woldegiorgis, G., Haro, D., Marrero, P.
  Pig liver carnitine palmitoyltransferase I, with low Km for carnitine and high sensitivity to malonyl-CoA inhibition, is a natural chimera of rat liver and muscle enzymes
  Biochemistry (2001) 40, 1351-1357. Abstract
• Morillas, M., Gómez-Puertas, P., Roca, R., Serra, D., Asins, G., Valencia, A. y Hegardt, F.G.
  Structural model of the catalytic core of carnitine palmitoyltransferase I and carnitine octanoyltransferase
  Journal of Biological Chemistry (2001) 276, 45001-45008. Abstract
• Morillas, M., Gómez-Puertas, P., Rubí, B., Clotet, J., Ariño, J., Valencia, A., Hegardt, F.G., Serra, D. y Asins, G.
  Structural model of a malonyl-CoA binding site of carnitine octanoyltransferase and carnitine palmitoyltransferase I. Mutational analysis of a malonyl-CoA affinity domain.
  Journal of Biological Chemistry (2002) 277, 11473-11480. Abstract
• Morillas, M., Gómez-Puertas, P., Bentebibel, A., Sellés, E., Casals, N., Valencia, A., Hegardt, F.G.,
  Asins, G. y Serra, D.
  Identification of conserved amino acid residues in rat liver carnitine palmitoyltransferase I critical for malonyl-CoA inhibition. Mutation of methionine 593 abolishes malonyl-CoA inhibition.
  Journal of Biological Chemistry (2003) 278, 9058-9063. Abstract

  

  2. Molecular mechanisms of carnitine palmitoil transferases I function in insulin secretion in pancreatic beta cells and depletion of insulin resistance in muscle cells

• Rubi B, Ishihara H, Hegardt FG, Wollheim CB, Maechler P.
  GAD65-mediated glutamate decarboxylation reduces glucose-stimulated insulin secretion in pancreatic beta cells.
  Journal of Biological Chemistry (2001) 276, 36391-36396. Abstract
• Rubí, B., Antinozzi, P.A., Herrero, L., Ishihara, H., Asins, G., Serra, D., Wollheim, C.B., Maechler, P. y Hegardt, F.G.
  Adenovirus-mediated overexpression of liver carnitine palmitoyltransferase I in INS1E cells. Effects on cell metabolism and insulin secretion
  Biochemical Journal (2002) 364, 219-226. Abstract

  
  3. Mutation screening of metabolic diseases of ketogenesis (deficiency in HMG-CoA synthase and HMG-CoA lyase).

• Buesa, C., Pie, J., Barceló, A., Casals, N., Mascaró, C., Casale, C.H., Haro, D., Duran, M., Smeitink, J.A.M & Hegardt, F.G.
  Aberrantly spliced mRNAs of the 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL) gene with a donor splice site point mutation produce hereditary HL deficiency
  Journal of Lipid Research (1996) 37, 2420-2432. Abstract
• Pié, P., Casals, N., Casale, C.H., Buesa, C., Mascaró, C., Barceló, A., Rolland, M. O., Zabot, M.T., Haro, D., Eyskens, F., Divry, P., & Hegardt, F.G.
  A nonsense mutation in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene produces exon skipping in two patients of different origin with HL deficiency
  Biochemical Journal (1997) 323, 329-335. Abstract
• Casals, N., Pié, J., Casale, C.H., Zapater, N., Ribes, A., Castro-Gago, M., Rodriguez-Segade, S., Wanders, R.J.A. y Hegardt, F.G.
  A two-base deletion in exon 6 of the 3-hydroxy-3-methylglutaryl coenzyme A lyase (HL) gene producing the skipping of exons 5 and 6 determines 3-hydroxy 3-methylglutaric aciduria
  Journal of Lipid Research. (1997) 38, 2303-2313. Abstract
• Casale, C.H., Casals, N., Pié, J., Zapater, N., Pérez-Cerdá, C., Merinero, B., Martínez-Pardo, M., García-Peñas, J.J., García-Gonzalez, J.M., Lama, R., Poll-The, B.T., Smeitink, J.A.M., Wanders, R.J.A., Ugarte, M., and Hegardt, F.G.
  A nonsense mutation in the exon 2 of the 3-hydroxy-3-methylglutaryl CoA lyase (HL) gene producing three mature mRNAs is the main cause of 3-hydroxy-3-methylglutaric aciduria in european mediterranean patients.
  Archives of Biochemistry and Biophysics (1998) 349, 129-137. Abstract
• Zapater, N., Pié, J., Lloberas, J., Rolland, M.O., Leroux, B., Vidailhet, M., Divry, P., Hegardt, F.G. y Casals, N.
  Two missense point mutations in different alleles in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene produce the 3-hydroxy-3-methylglutaric aciduria
  Archives of Biochemistry and Biophysics (1998) 358, 197-203. Abstract
• Hegardt, F.G.
  La aciduria 3-Hidroxi-3-metilglutàrica: Una malaltia molecular per deficiència de 3-Hidroxi-3-metilglutaril coenzim A liasa
  Treballs de la Societat Catalana de Biologia (1999) 49, 133-150.
• Aledo, R., Zschocke, J., Pié, J., Mir, C., Fiesel, S., Mayatepek, E., Hoffmann, G.F., Casals, N. y Hegardt, F.G.
  The genetic basis of mitochondrial HMG-CoA synthase deficiency
  Human Genetics (2001) 109, 19-23. Abstract
• Zschocke, J., Penzien, J.M., Bielen, R., Casals, N., Aledo, R., Pié, J., Hoffmann, G.F., Hegardt, F.G. y Mayatepek, E.
  The diagnosis of mitochondrial HMG-CoA synthase deficiency
  The Journal of Pediatrics (2002) 140, 778-780. Abstract
• Casals, N., Gómez-Puertas, P., Pié, J., Mir, C., Roca, R., Puisac, B., Aledo, R.,Clotet, J., Menao, S., Serra, D., Asins, G., Till, J., Elias-Jones, A.C., Cresto, J.C., Chamoles, N.A., Abdenur, J.E., Mayatepek, E., Besley, G., Valencia, A. y Hegardt, F.G.
  Structural TIM barrel model of 3-Hydroxy-3-methylglutaryl Coenzyme A lyase.
  Journal of Biological Chemistry (2003) 278, 29016-29023. Abstract

4. Molecular aspects of trans-splicing in mammals.

• Caudevilla, C., Serra, D., Miliar, A., Codony, C., Asins, G., Bach, M. y Hegardt F.G. Natural trans-splicing in the carnitine octanoyl transferase pre-mRNAs in rat liver.
  Proceedings of the National Academy of Sciences USA. (1998) 95, 12185-12190. Abstract
• Caudevilla, C., Serra, D., Miliar, A., Codony, C., Asins, G., Bach, M. y Hegardt, F.G. Processing of carnitine octanoiltransferase pre-mRNAs by cis- and transsplicing. Advances in Experimental Medicine and Biology (1999) 466, 95-102. Abstract
• Hegardt, F.G., Bach, M., Asins, G., Caudevilla, C., Morillas, M. Codony, C y Serra, D. Post-transcriptional regulation of rat carnitine octanoyltransferase
  Biochemical Society Transactions (2001) 29, 316-320. Abstract
• Codony, C., Guil, S., Caudevilla, C., Serra, D., Asins, G., Graessmann, A., Hegardt, F.G. y Bach-Elias, M. Modulation in vitro of H-ras oncogene expression by trans-splicing.
  Oncogene (2001) 20, 3683-3694. Abstract
• Caudevilla, C., Codony, C., Serra, D., Plasencia, G., Román, R., Graessmann, A, Asins, G., Bach-Elias, M. y Hegardt, F.G. Localization of an exonic splicing enhancer responsible for mammalian natural trans-splicing.
  Nucleic Acids Research (2001) 29, 3108-3115. Abstract

Laboratory: Departament of Biochemistry and Molecular Biology - School of Pharmacy- University of Barcelone

Tel: +34 - 93 402 45 22

Fax: +34 - 93 402 45 20

F.García Hegardt	fgarciaheg@ub.edu
Guillermina Asins Muñoz	gasins@ub.edu
Dolors Serra Cucurull	dserra@ub.edu