GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop

Gustavo Fenalti, Ruby H P Law, Ashley Maurice Buckle, Christopher Langendorf, Kellie Louise Tuck, Carlos Joaquim Rosado, Noel Garry Faux, Khalid Mahmood, Christiane S Hampe, J Paul Banga, Matthew Charles James Wilce, Jason Schmidberger, Jamie Rossjohn, Ossama El-Kabbani, Robert Neil Pike, Alexander Ian Smith, Ian R Mackay, Merrill Joy Rowley, James Whisstock

Research output: Contribution to journalArticleResearchpeer-review

140 Citations (Scopus)

Abstract

Gamma-aminobutyric acid ( GABA) is synthesized by two isoforms of the pyridoxal 5 -phosphate-dependent enzyme glutamic acid decarboxylase (GAD65 and GAD67). GAD67 is constitutively active and is responsible for basal GABA production. In contrast, GAD65, an autoantigen in type I diabetes, is transiently activated in response to the demand for extra GABA in neurotransmission, and cycles between an active holo form and an inactive apo form. We have determined the crystal structures of N-terminal truncations of both GAD isoforms. The structure of GAD67 shows a tethered loop covering the active site, providing a catalytic environment that sustains GABA production. In contrast, the same catalytic loop is inherently mobile in GAD65. Kinetic studies suggest that mobility in the catalytic loop promotes a side reaction that results in cofactor release and GAD65 autoinactivation. These data reveal the molecular basis for regulation of GABA homeostasis.
Original languageEnglish
Pages (from-to)280 - 286
Number of pages7
JournalNature Structural & Molecular Biology
Volume14
Issue number4
Publication statusPublished - 2007

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