Publication: Validación de la enzima ICMT como una nueva diana terapéutica para el tratamiento del cáncer y la progeria
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2017-06-30
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Universidad Complutense de Madrid
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Abstract
La superfamilia de proteínas CAAX se caracteriza por la presencia del tetrapéptido CAAX en su extremo carboxilo terminal, en el que “C” representa una cisteína, “A” corresponde a un aminoácido alifático, y “X” se refiere a cualquier aminoácido. Varias proteínas CAAX se encuentran implicadas en numerosas patologías que incluyen el cáncer1 y la progeria.2 De hecho, las proteínas Ras, las cuales se incluyen dentro de la superfamilia de proteínas CAAX, representan una de las superfamilias de oncoproteínas más importantes, encontrándose sobreexpresadas en un 30% de los procesos tumorales.3,4 Con respecto a la progeria (o síndrome de progeria de Hutchinson-Guilford, HGPS), es la lámina A, otra proteína perteneciente a la familia CAAX, la principal responsable del desarrollo de los síntomas de esta enfermedad.5 Debido a la presencia del fragmento CAAX en el extremo carboxilo terminal de su estructura, estas proteínas requieren una serie de modificaciones post-traduccionales para alcanzar su forma biológicamente activa. Así, el procesamiento post-traduccional de Ras incluye la unión de un grupo farnesilo o geranilgeranilo a la cisteína del fragmento CAAX catalizada por las enzimas farnesiltransferasa (FTasa) o geranilgeraniltransferasa de tipo I (GGTasa I), respectivamente. A esta etapa de prenilación le sigue la proteólisis de los residuos AAX por la endoproteasa Ras converting enzyme 1 (Rce1) y la metilación final del grupo carboxilo expuesto por la enzima isoprenilcisteína carboximetiltransferasa (ICMT).6 Por otra parte, la prelámina A (precursora de lámina A) solo puede ser prenilada por la enzima FTasa, y no por GGTasa I, y la ruptura proteolítica puede ser mediada tanto por la enzima Rce1 como por la proteína zinc metalloprotease STE24 (ZMPSTE24). La carboximetilación es catalizada por la enzima ICMT y, adicionalmente, la prelámina A requiere una etapa final consistente en una segunda proteólisis regulada por la enzima ZMPSTE24...
The CAAX superfamiliy of proteins are characterized for the presence of the CAAX tetrapeptide at its carboxyl terminus, in which “C” represents a cysteine, “A” corresponds to an aliphatic aminoacid, and “X” refers to any aminoacid. Several CAAX proteins are implicated in numerous pathologies including cancer1 and progeria.2 In fact, Ras proteins, which are included in the CAAX superfamiliy of proteins, represent one of the most importat superfamily of oncoproteins and they are overexpressed in the 30% of all cancer processes.3,4 Regarding to progeria (or Hutchinson-Gilford progeria syndrome, HGPS), is lamin A, another CAAX protein, the main responsible for the onset of symptoms of the disease.5 Due to the presence of the CAAX motif in the carboxyl terminus of their structure, these proteins require a series of post-translational modifications to achive their biologically active form. Thus, the post-translational processing of Ras involves the attachment of a farnesyl or geranylgeranyl group to the CAAX cysteine by either farnesyltransferase (FTase) or geranylgeranyltransferase type I (GGTase I), respectively. This prenylation step is followed by proteolytic removal of the AAX residues by the endoprotease Ras converting enzyme 1 (Rce1), and final methylation of the newly exposed prenylcysteine by the enzyme isoprenylcysteine carboxyl methyltransferase (ICMT).6 On the other hand, prelamin A (precursor of lamin A) only can be prenylated by FTase, not by GGTase I, and the proteolytic step can be mediated for both Rce1 and zinc metalloprotease STE24 (ZMPSTE24) enzymes. Then, the carboxyl methylation is catalized by the enzyme ICMT and prelamin A requires an additional final step consisting in a second proteolysis regulated by the enzyme ZMPSTE24...
The CAAX superfamiliy of proteins are characterized for the presence of the CAAX tetrapeptide at its carboxyl terminus, in which “C” represents a cysteine, “A” corresponds to an aliphatic aminoacid, and “X” refers to any aminoacid. Several CAAX proteins are implicated in numerous pathologies including cancer1 and progeria.2 In fact, Ras proteins, which are included in the CAAX superfamiliy of proteins, represent one of the most importat superfamily of oncoproteins and they are overexpressed in the 30% of all cancer processes.3,4 Regarding to progeria (or Hutchinson-Gilford progeria syndrome, HGPS), is lamin A, another CAAX protein, the main responsible for the onset of symptoms of the disease.5 Due to the presence of the CAAX motif in the carboxyl terminus of their structure, these proteins require a series of post-translational modifications to achive their biologically active form. Thus, the post-translational processing of Ras involves the attachment of a farnesyl or geranylgeranyl group to the CAAX cysteine by either farnesyltransferase (FTase) or geranylgeranyltransferase type I (GGTase I), respectively. This prenylation step is followed by proteolytic removal of the AAX residues by the endoprotease Ras converting enzyme 1 (Rce1), and final methylation of the newly exposed prenylcysteine by the enzyme isoprenylcysteine carboxyl methyltransferase (ICMT).6 On the other hand, prelamin A (precursor of lamin A) only can be prenylated by FTase, not by GGTase I, and the proteolytic step can be mediated for both Rce1 and zinc metalloprotease STE24 (ZMPSTE24) enzymes. Then, the carboxyl methylation is catalized by the enzyme ICMT and prelamin A requires an additional final step consisting in a second proteolysis regulated by the enzyme ZMPSTE24...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica I, leída el 07-07-2016