الملخص
The catabolism of fungal 4-aminobutyrate (GABA) occurs via succinic semialdehyde (SSA). Succinic semialdehyde dehydrogenase (SSADH) from the acidogenic fungus Aspergillus niger was purified from GABA grown mycelia to the highest specific activity of 277 nmol min-1 mg-1, using phenyl Sepharose and DEAE Sephacel chromatography. The purified enzyme was specific for its substrates SSA and NAD+. The substrate inhibition observed with SSA was uncompetitive with respect to NAD+. While product inhibition by succinate was not observed, NADH inhibited the enzyme competitively with respect to NAD+ and noncompetitively with respect to SSA. Dead-end inhibition by AMP and p-hydroxybenzaldehyde (pHB) was analyzed. The pHB inhibition was competitive with SSA and uncompetitive with NAD+; AMP competed with NAD+. Consistent with the kinetic data, a sequential, ordered Bi Bi mechanism is proposed for this enzyme.
الموضوعات
Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Aspergillus niger/enzymology , Aspergillus niger/metabolism , Benzaldehydes/metabolism , Benzaldehydes/pharmacology , Binding, Competitive , Biocatalysis/drug effects , Fungal Proteins/isolation & purification , Fungal Proteins/metabolism , Kinetics , Mycelium/enzymology , Mycelium/metabolism , NAD/metabolism , NAD/pharmacology , Protein Binding , Substrate Specificity , Succinate-Semialdehyde Dehydrogenase/isolation & purification , Succinate-Semialdehyde Dehydrogenase/metabolism , gamma-Aminobutyric Acid/analogs & derivatives , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/pharmacologyالملخص
As plaquetas estão envolvidas em vários processos biológicos, desde o combate a agentes infecciosos até a coordenação do controle da permeabilidade vascular e angiogênese. Entretanto, o seu principal foco de ação consiste na modulação da cascata de coagulação. A intervenção coronariana percutânea é um procedimento com alto risco trombogênico, que induz a ativação plaquetária e de monócitos, devido à lesão direta do endotélio e pelo contato de estruturas trombogênicas com o sangue, levando ao aumento da atividade inflamatória, tanto no local do dano vascular coronariano como de forma sistêmica. Os receptores plaquetários P2Y12 desempenham papel central na amplificação da agregação induzida por todos os agonistas plaquetários, como a adenosina difosfato, o colágeno, tromboxano A2, adrenalina e serotonina. Por esse motivo, têm sido o principal alvo das drogas antiplaquetárias. Apesar de atuarem no mesmo receptor, características farmacocinéticas e farmacodinâmicas distintas conferem peculiaridades a cada agente.
Apart from their role in hemostasis and thrombosis, platelets are involved in many other biological processes such as wound healing and angiogenesis. Percutaneous coronary intervention is a highly thrombogenic procedure inducing platelets and monocytes activation through endothelial trauma and contact activation by intravascular devices. Platelet P2Y12 receptor activation by adenosine diphosphate facilitates non-ADP agonist-mediated platelet aggregation, dense granule secretion, procoagulant activity, and the phosphorylation of several intraplatelet proteins, making it an ideal drug target. However, not all compounds that target the P2Y12 receptor have similar efficacy and safety profiles. Despite targeting the same receptor, the unique pharmacologic properties of each of these P2Y12 receptor-directed compounds can lead to very different clinical effects.