RESUMO
Although dietary fatty acids can modulate metabolic and immune responses, the effects of palmitoleic acid (16:1n-7) remain unclear. Since this monounsaturated fatty acid is described as a lipokine, studies with cell culture and rodent models have suggested it enhances whole body insulin sensitivity, stimulates insulin secretion by ß cells, increases hepatic fatty acid oxidation, improves the blood lipid profile, and alters macrophage differentiation. However, human studies report elevated blood levels of palmitoleic acid in people with obesity and metabolic syndrome. These findings might be reflection of the level or activity of stearoyl-CoA desaturase-1, which synthesizes palmitoleate and is enhanced in liver and adipose tissue of obese patients. The aim of this review is to describe the immune-metabolic effects of palmitoleic acid observed in cell culture, animal models, and humans to answer the question of whether palmitoleic acid is a plausible nonpharmacological strategy to prevent, control, or ameliorate chronic metabolic and inflammatory disorders. Despite the beneficial effects observed in cell culture and in animal studies, there are insufficient human intervention studies to fully understand the physiological effects of palmitoleic acid. Therefore, more human-based research is needed to identify whether palmitoleic acid meets the promising therapeutic potential suggested by the preclinical research.
Assuntos
Ácidos Graxos Monoinsaturados/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Acetiltransferases/fisiologia , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Elongases de Ácidos Graxos , Humanos , Resistência à Insulina , Síndrome Metabólica/prevenção & controle , Obesidade/prevenção & controle , Estearoil-CoA Dessaturase/fisiologiaRESUMO
Many proteins are modified after their synthesis, by the addition of a lipid molecule to one or more cysteine residues, through a thioester bond. This modification is called S-acylation, and more commonly palmitoylation. This reaction is carried out by a family of enzymes, called palmitoyltransferases (PATs), characterized by the presence of a conserved 50- aminoacids domain called "Asp-His-His-Cys- Cysteine Rich Domain" (DHHC-CRD). There are 7 members of this family in the yeast Saccharomyces cerevisiae, and each of these proteins is thought to be responsible for the palmitoylation of a subset of substrates. Substrate specificity of PATs, however, is not yet fully understood. Several yeast PATs seem to have overlapping specificity, and it has been proposed that the machinery responsible for palmitoylating peripheral membrane proteins in mammalian cells, lacks specificity altogether.Here we investigate the specificity of transmembrane protein palmitoylation in S. cerevisiae, which is carried out predominantly by two PATs, Swf1 and Pfa4. We show that palmitoylation of transmembrane substrates requires dedicated PATs, since other yeast PATs are mostly unable to perform Swf1 or Pfa4 functions, even when overexpressed. Furthermore, we find that Swf1 is highly specific for its substrates, as it is unable to substitute for other PATs. To identify where Swf1 specificity lies, we carried out a bioinformatics survey to identify amino acids responsible for the determination of specificity or Specificity Determination Positions (SDPs) and showed experimentally, that mutation of the two best SDP candidates, A145 and K148, results in complete and partial loss of function, respectively. These residues are located within the conserved catalytic DHHC domain suggesting that it could also be involved in the determination of specificity. Finally, we show that modifying the position of the cysteines in Tlg1, a Swf1 substrate, results in lack of palmitoylation, as expected for a highly specific enzymatic reaction.
Assuntos
Acetiltransferases/metabolismo , Lipoilação/fisiologia , Proteínas de Membrana/metabolismo , Leveduras/metabolismo , Acetiltransferases/química , Acetiltransferases/genética , Acetiltransferases/fisiologia , Aciltransferases/química , Aciltransferases/genética , Aciltransferases/metabolismo , Aciltransferases/fisiologia , Sequência de Aminoácidos , Domínio Catalítico/genética , Domínio Catalítico/fisiologia , Lipoilação/genética , Proteínas de Membrana/química , Modelos Biológicos , Dados de Sequência Molecular , Estrutura Terciária de Proteína/fisiologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/fisiologia , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiologia , Homologia de Sequência de Aminoácidos , Especificidade por Substrato/genética , Leveduras/genéticaRESUMO
Roberts syndrome is an autosomal recessive disorder characterized by craniofacial anomalies, tetraphocomelia and loss of cohesion at heterochromatic regions of centromeres and the Y chromosome. We identified mutations in a new human gene, ESCO2, associated with Roberts syndrome in 15 kindreds. The ESCO2 protein product is a member of a conserved protein family that is required for the establishment of sister chromatid cohesion during S phase and has putative acetyltransferase activity.
Assuntos
Acetiltransferases/genética , Cromátides/fisiologia , Proteínas Cromossômicas não Histona/genética , Pareamento Cromossômico/fisiologia , Fenda Labial/genética , Fissura Palatina/genética , Ectromelia/genética , Proteínas Nucleares/genética , Proteínas de Saccharomyces cerevisiae/genética , Acetiltransferases/fisiologia , Proteínas Cromossômicas não Histona/metabolismo , Ectromelia/metabolismo , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Proteínas Nucleares/fisiologia , Linhagem , Proteínas de Saccharomyces cerevisiae/fisiologiaRESUMO
Over the last decade, great progress has been made in elucidating how the human genome operates in the chromatin context. This paper describes our work on two human acetyltransferases, PCAF and TIP60, and their interaction partners. This study provides new clues on the function of these enzymes. In a striking parallel with the general transcription factor TFIID, PCAF complex contains proteins that have histone-like domains. We speculate that these subunits can presumably form a nucleosome-like structure on DNA, which would allow PCAF to contribute to the maintenance of an active state of chromatin. On the other hand, TIP60 complex contains two eukaryotic homologs of bacterial RuvB helicase/ATPse, involved in recombination and repair. Accordingly, expression of a dominant negative mutant of TIP60 in living cells interferes with their ability to repair DNA damage, which points out, for the first time, a role for a histone acetyltransferase in a process other than transcription. We also have evidence implicating TIP60 in the apoptotic response to DNA damage.
Assuntos
Acetiltransferases/fisiologia , Proteínas/fisiologia , Proteínas de Saccharomyces cerevisiae , Fatores de Transcrição TFII/fisiologia , Acetilação , Acetiltransferases/análise , Cromatina/metabolismo , Histona Acetiltransferases , Humanos , Lisina Acetiltransferase 5 , Mapeamento de Peptídeos , Proteínas/análise , Especificidade por Substrato , Fatores de Transcrição TFII/análiseRESUMO
Over the last decade, great progress has been made in elucidating how the human genome operates in the chromatin context. This paper describes our work on two human acetyltransferases, PCAF and TIP60, and their interaction partners. This study provides new clues on the function of these enzymes. In a striking parallel with the general transcription factor TFIID, PCAF complex contains proteins that have histone-like domains. We speculate that these subunits can presumably form a nucleosome-like structure on DNA, which would allow PCAF to contribute to the maintenance of an active state of chromatin. On the other hand, TIP60 complex contains two eukaryotic homologs of bacterial RuvB helicase/ATPse, involved in recombination and repair. Accordingly, expression of a dominant negative mutant of TIP60 in living cells interferes with their ability to repair DNA damage, which points out, for the first time, a role for a histone acetyltransferase in a process other than transcription. We also have evidence implicating TIP60 in the apoptotic response to DNA damage.