El nostre grup estudia les enzims implicades en el transport d’àcids grassos en la mitocòndria, les carnitina-palmitoil transferases (CPT-I i II) i les enzims implicades en la via de cetogènesi (HMG-CoA sintasa I liasa).

La regulació d’aquests gens s’estudia mitjançant aproximacions moleculars que inclouen l’expressió in vivo e in vitro en sistemes heteròlegs de les formes salvatge I mutades. També, s’obtenen models 3D per aquestes proteïnes per homologia directa o remota, on s’interpreten els efectes de les mutacions.

També s’estudia la funció de la CPT-I en la regulació del àcids grassos i les possibles aplicacions en el tractament de la diabetis de tipus II. S’analitza l’efecte de la CPT-I en la secreció de insulina en les cèl•lules Beta del pàncreas i la incorporació diferent de glucosa en els miòcits. Al mateix temps, s’analitzen els mecanismes de la resistència a la insulina en el múscul i la implicació de CPT-I. .

En una altre línia, els processos de trans-splicing en mamífers, concretament l’habilitat del gen carnitina octanoil transferasa (COT) per produir transcrits amb exons repetits.

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

4. Molecular aspects of trans-splicing in mammals.

Dolors Cucurull

Professora Agregada

dserra@ub.edu

PUBLICACIONS

1. Estudi Molecular del gens del transport dels àcids grassos en la mitocòndria: Carnitina palmitoil transferasa I, Carnitina acetil transferasa. Models d'estructura 3D i funcionalitat.

• 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. Mecanismes moleculars de la carnitin-palmitoil transferasa en la secreció de insulina en les cèl·lules beta pancreàtiques i disminució de la resistència a la insulina en les cèl·lules musculars.

• 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. Cribatge mutacional de malalties metabòliques de la cetogènesi (deficiència en HMG-CoA sintasa i HMG-CoA liasa).

• 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. Aspectes moleculars del trans-splicing en mamífers.

• 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

Laboratori: Departament de Bioquimica i Biologia Molecular - Facultat de Farmàcia - Universitat de Barcelona

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