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Chem Biol ; 22(4): 492-503, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25910242

RESUMO

Coenzyme A (CoA) is an ubiquitous and essential cofactor, synthesized from the precursor pantothenate. Vitamin biosynthetic pathways are normally tightly regulated, including the pathway from pantothenate to CoA. However, no regulation of pantothenate biosynthesis has been identified. We have recently described an additional component in the pantothenate biosynthetic pathway, PanZ, which promotes the activation of the zymogen, PanD, to form aspartate α-decarboxylase (ADC) in a CoA-dependent manner. Here we report the structure of PanZ in complex with PanD, which reveals the structural basis for the CoA dependence of this interaction and activation. In addition, we show that PanZ acts as a CoA-dependent inhibitor of ADC catalysis. This inhibitory effect can effectively regulate the biosynthetic pathway to pantothenate, and thereby also regulate CoA biosynthesis. This represents a previously unobserved mode of metabolic regulation whereby a cofactor-utilizing protein negatively regulates the biosynthesis of the same cofactor.


Assuntos
Coenzima A/metabolismo , Glutamato Descarboxilase/metabolismo , Ácido Pantotênico/biossíntese , Sequência de Aminoácidos , Biocatálise , Coenzima A/química , Glutamato Descarboxilase/química , Glutamato Descarboxilase/genética , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Mutagênese , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Espalhamento a Baixo Ângulo , Alinhamento de Sequência , Difração de Raios X
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