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

G Fenalti; R Law; A M Buckle; C Langendorf; K Tuck; C Rosado; N Faux; K Mahmood; C Hampe; J P Banga; M Wilce; J Schmidberger; J Rossjohn; O El-Kabbani; R N Pike; A I Smith; I Mackay; M Rowley; J C Whisstock

doi:10.1038/nsmb1228

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

G Fenalti, R Law, A M Buckle, C Langendorf, K Tuck, C Rosado, N Faux, K Mahmood, C Hampe, J P Banga, M Wilce, J Schmidberger, J Rossjohn, O El-Kabbani, R N Pike, A I Smith, I Mackay, M Rowley, J C Whisstock

Diabetes

Research output: Contribution to journal › Article › peer-review

193 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 language	English
Pages (from-to)	280 - 286
Number of pages	7
Journal	NATURE STRUCTURAL AND MOLECULAR BIOLOGY
Volume	14
Issue number	4
DOIs	https://doi.org/10.1038/nsmb1228
Publication status	Published - Apr 2007

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Fenalti, G., Law, R., Buckle, A. M., Langendorf, C., Tuck, K., Rosado, C., Faux, N., Mahmood, K., Hampe, C., Banga, J. P., Wilce, M., Schmidberger, J., Rossjohn, J., El-Kabbani, O., Pike, R. N., Smith, A. I., Mackay, I., Rowley, M., & Whisstock, J. C. (2007). GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop. NATURE STRUCTURAL AND MOLECULAR BIOLOGY, 14(4), 280 - 286. https://doi.org/10.1038/nsmb1228

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title = "GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop",

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.",

author = "G Fenalti and R Law and Buckle, {A M} and C Langendorf and K Tuck and C Rosado and N Faux and K Mahmood and C Hampe and Banga, {J P} and M Wilce and J Schmidberger and J Rossjohn and O El-Kabbani and Pike, {R N} and Smith, {A I} and I Mackay and M Rowley and Whisstock, {J C}",

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Fenalti, G, Law, R, Buckle, AM, Langendorf, C, Tuck, K, Rosado, C, Faux, N, Mahmood, K, Hampe, C, Banga, JP, Wilce, M, Schmidberger, J, Rossjohn, J, El-Kabbani, O, Pike, RN, Smith, AI, Mackay, I, Rowley, M & Whisstock, JC 2007, 'GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop', NATURE STRUCTURAL AND MOLECULAR BIOLOGY, vol. 14, no. 4, pp. 280 - 286. https://doi.org/10.1038/nsmb1228

TY - JOUR

T1 - GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop

AU - Fenalti, G

AU - Law, R

AU - Buckle, A M

AU - Langendorf, C

AU - Tuck, K

AU - Rosado, C

AU - Faux, N

AU - Mahmood, K

AU - Hampe, C

AU - Banga, J P

AU - Wilce, M

AU - Schmidberger, J

AU - Rossjohn, J

AU - El-Kabbani, O

AU - Pike, R N

AU - Smith, A I

AU - Mackay, I

AU - Rowley, M

AU - Whisstock, J C

PY - 2007/4

Y1 - 2007/4

N2 - 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.

AB - 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.

U2 - 10.1038/nsmb1228

DO - 10.1038/nsmb1228

M3 - Article

VL - 14

SP - 280

EP - 286

JO - NATURE STRUCTURAL AND MOLECULAR BIOLOGY

JF - NATURE STRUCTURAL AND MOLECULAR BIOLOGY

IS - 4

ER -

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

Abstract

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