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Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase

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Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase. / Alphey, Magnus Stephen; Fisher, Gemma; Ge, Ying; Gould, Eoin Rory; Guerreiro Machado, Teresa Filipa; Liu, Huanting; Florence, Gordon John; Naismith, James Henderson; da Silva, Rafael G.

In: ACS Catalysis, Vol. 8, No. 6, 11.05.2018, p. 5601-5610.

Research output: Contribution to journalArticle

Harvard

Alphey, MS, Fisher, G, Ge, Y, Gould, ER, Guerreiro Machado, TF, Liu, H, Florence, GJ, Naismith, JH & da Silva, RG 2018, 'Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase', ACS Catalysis, vol. 8, no. 6, pp. 5601-5610. https://doi.org/10.1021/acscatal.8b00867

APA

Alphey, M. S., Fisher, G., Ge, Y., Gould, E. R., Guerreiro Machado, T. F., Liu, H., ... da Silva, R. G. (2018). Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase. ACS Catalysis, 8(6), 5601-5610. https://doi.org/10.1021/acscatal.8b00867

Vancouver

Alphey MS, Fisher G, Ge Y, Gould ER, Guerreiro Machado TF, Liu H et al. Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase. ACS Catalysis. 2018 May 11;8(6):5601-5610. https://doi.org/10.1021/acscatal.8b00867

Author

Alphey, Magnus Stephen ; Fisher, Gemma ; Ge, Ying ; Gould, Eoin Rory ; Guerreiro Machado, Teresa Filipa ; Liu, Huanting ; Florence, Gordon John ; Naismith, James Henderson ; da Silva, Rafael G. / Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase. In: ACS Catalysis. 2018 ; Vol. 8, No. 6. pp. 5601-5610.

Bibtex - Download

@article{f9da9fe0cacd4f2cad684ef3402e9d16,
title = "Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase",
abstract = "Allosteric modulation of catalysis is a common regulatory strategy of flux-controlling biosynthetic enzymes. The enzyme ATP phosphoribosyltransferase (ATPPRT) catalyzes the first reaction in histidine biosynthesis, the magnesium-dependent condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generate N1-(5-phospho-β-d-ribosyl)-ATP (PRATP) and pyrophosphate (PPi). ATPPRT is allosterically inhibited by the final product of the pathway, histidine. Hetero-octameric ATPPRT consists of four catalytic subunits (HisGS) and four regulatory subunits (HisZ) engaged in intricate catalytic regulation. HisZ enhances HisGS catalysis in the absence of histidine while mediating allosteric inhibition in its presence. Here we report HisGS structures for the apoenzyme and complexes with substrates (PRPP, PRPP-ATP, PRPP-ADP), product (PRATP), and inhibitor (AMP), along with ATPPRT holoenzyme structures in complexes with substrates (PRPP, PRPP-ATP, PRPP-ADP) and product (PRATP). These 10 crystal structures provide an atomic view of the catalytic cycle and allosteric activation of Psychrobacter arcticus ATPPRT. In both ternary complexes with PRPP-ATP, the adenine ring is found in an anticatalytic orientation, rotated 180° from the catalytic rotamer. Arg32 interacts with phosphate groups of ATP and PRPP, bringing the substrates in proximity for catalysis. The negative charge repulsion is further attenuated by a magnesium ion sandwiched between the α- and β-phosphate groups of both substrates. HisZ binding to form the hetero-octamer brings HisGS subunits closer together in a tighter dimer in the Michaelis complex, which poises Arg56 from the adjacent HisGS molecule for cross-subunit stabilization of the PPi leaving group at the transition state. The more electrostatically preorganized active site of the holoenzyme likely minimizes the reorganization energy required to accommodate the transition state. This provides a structural basis for allosteric activation in which chemistry is accelerated by facilitating leaving group departure.",
keywords = "Allostery, ATP phosphoribosyltransferase, Catalytic activation, HisG, Histidine, Biosynthesis, HisZ, Psychrophilic",
author = "Alphey, {Magnus Stephen} and Gemma Fisher and Ying Ge and Gould, {Eoin Rory} and {Guerreiro Machado}, {Teresa Filipa} and Huanting Liu and Florence, {Gordon John} and Naismith, {James Henderson} and {da Silva}, {Rafael G}",
note = "This work was supported by the University of St Andrews, a Leverhulme Trust grant (RL - 2012 - 025) to G.J.F, the Engineering and Physical Sciences Research Council (EPSRC) [grant number EP/L016419/1] via a CRITICAT Centre for Doctoral Training studentship to TFGM, and the Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BB/M010996/1] via an EASTBIO Doctoral Training Partnership studentship to GF.",
year = "2018",
month = "5",
day = "11",
doi = "10.1021/acscatal.8b00867",
language = "English",
volume = "8",
pages = "5601--5610",
journal = "ACS Catalysis",
issn = "2155-5435",
publisher = "American Chemical Society (ACS)",
number = "6",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Catalytic and anticatalytic snapshots of a short-form ATP phosphoribosyltransferase

AU - Alphey, Magnus Stephen

AU - Fisher, Gemma

AU - Ge, Ying

AU - Gould, Eoin Rory

AU - Guerreiro Machado, Teresa Filipa

AU - Liu, Huanting

AU - Florence, Gordon John

AU - Naismith, James Henderson

AU - da Silva, Rafael G

N1 - This work was supported by the University of St Andrews, a Leverhulme Trust grant (RL - 2012 - 025) to G.J.F, the Engineering and Physical Sciences Research Council (EPSRC) [grant number EP/L016419/1] via a CRITICAT Centre for Doctoral Training studentship to TFGM, and the Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BB/M010996/1] via an EASTBIO Doctoral Training Partnership studentship to GF.

PY - 2018/5/11

Y1 - 2018/5/11

N2 - Allosteric modulation of catalysis is a common regulatory strategy of flux-controlling biosynthetic enzymes. The enzyme ATP phosphoribosyltransferase (ATPPRT) catalyzes the first reaction in histidine biosynthesis, the magnesium-dependent condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generate N1-(5-phospho-β-d-ribosyl)-ATP (PRATP) and pyrophosphate (PPi). ATPPRT is allosterically inhibited by the final product of the pathway, histidine. Hetero-octameric ATPPRT consists of four catalytic subunits (HisGS) and four regulatory subunits (HisZ) engaged in intricate catalytic regulation. HisZ enhances HisGS catalysis in the absence of histidine while mediating allosteric inhibition in its presence. Here we report HisGS structures for the apoenzyme and complexes with substrates (PRPP, PRPP-ATP, PRPP-ADP), product (PRATP), and inhibitor (AMP), along with ATPPRT holoenzyme structures in complexes with substrates (PRPP, PRPP-ATP, PRPP-ADP) and product (PRATP). These 10 crystal structures provide an atomic view of the catalytic cycle and allosteric activation of Psychrobacter arcticus ATPPRT. In both ternary complexes with PRPP-ATP, the adenine ring is found in an anticatalytic orientation, rotated 180° from the catalytic rotamer. Arg32 interacts with phosphate groups of ATP and PRPP, bringing the substrates in proximity for catalysis. The negative charge repulsion is further attenuated by a magnesium ion sandwiched between the α- and β-phosphate groups of both substrates. HisZ binding to form the hetero-octamer brings HisGS subunits closer together in a tighter dimer in the Michaelis complex, which poises Arg56 from the adjacent HisGS molecule for cross-subunit stabilization of the PPi leaving group at the transition state. The more electrostatically preorganized active site of the holoenzyme likely minimizes the reorganization energy required to accommodate the transition state. This provides a structural basis for allosteric activation in which chemistry is accelerated by facilitating leaving group departure.

AB - Allosteric modulation of catalysis is a common regulatory strategy of flux-controlling biosynthetic enzymes. The enzyme ATP phosphoribosyltransferase (ATPPRT) catalyzes the first reaction in histidine biosynthesis, the magnesium-dependent condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generate N1-(5-phospho-β-d-ribosyl)-ATP (PRATP) and pyrophosphate (PPi). ATPPRT is allosterically inhibited by the final product of the pathway, histidine. Hetero-octameric ATPPRT consists of four catalytic subunits (HisGS) and four regulatory subunits (HisZ) engaged in intricate catalytic regulation. HisZ enhances HisGS catalysis in the absence of histidine while mediating allosteric inhibition in its presence. Here we report HisGS structures for the apoenzyme and complexes with substrates (PRPP, PRPP-ATP, PRPP-ADP), product (PRATP), and inhibitor (AMP), along with ATPPRT holoenzyme structures in complexes with substrates (PRPP, PRPP-ATP, PRPP-ADP) and product (PRATP). These 10 crystal structures provide an atomic view of the catalytic cycle and allosteric activation of Psychrobacter arcticus ATPPRT. In both ternary complexes with PRPP-ATP, the adenine ring is found in an anticatalytic orientation, rotated 180° from the catalytic rotamer. Arg32 interacts with phosphate groups of ATP and PRPP, bringing the substrates in proximity for catalysis. The negative charge repulsion is further attenuated by a magnesium ion sandwiched between the α- and β-phosphate groups of both substrates. HisZ binding to form the hetero-octamer brings HisGS subunits closer together in a tighter dimer in the Michaelis complex, which poises Arg56 from the adjacent HisGS molecule for cross-subunit stabilization of the PPi leaving group at the transition state. The more electrostatically preorganized active site of the holoenzyme likely minimizes the reorganization energy required to accommodate the transition state. This provides a structural basis for allosteric activation in which chemistry is accelerated by facilitating leaving group departure.

KW - Allostery

KW - ATP phosphoribosyltransferase

KW - Catalytic activation

KW - HisG

KW - Histidine

KW - Biosynthesis

KW - HisZ

KW - Psychrophilic

U2 - 10.1021/acscatal.8b00867

DO - 10.1021/acscatal.8b00867

M3 - Article

VL - 8

SP - 5601

EP - 5610

JO - ACS Catalysis

JF - ACS Catalysis

SN - 2155-5435

IS - 6

ER -

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