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Linda A. Fothergill-Gilmore
University of Edinburgh
130Publications
23H-index
2,023Citations
Publications 130
Newest
#1W. Zhong (Singapore–MIT alliance)H-Index: 2
#2Jingjing Guo (NAU: Nanjing Agricultural University)
Last.Peter C. Dedon (MIT: Massachusetts Institute of Technology)H-Index: 48
view all 14 authors...
Abstract In response to the stress of infection, Mycobacterium tuberculosis (Mtb) reprograms its metabolism to accommodate nutrient and energetic demands in a changing environment. Pyruvate kinase (PYK) is an essential glycolytic enzyme in the phosphoenolpyruvate–pyruvate–oxaloacetate node that is a central switch point for carbon flux distribution. Here we show that the competitive binding of pentose monophosphate inhibitors or the activator glucose 6-phosphate (G6P) to MtbPYK tightly regulates...
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#1Meng Yuan (Edin.: University of Edinburgh)H-Index: 3
#2Iain W. McNae (Edin.: University of Edinburgh)H-Index: 21
Last.Malcolm D. Walkinshaw (Edin.: University of Edinburgh)H-Index: 50
view all 9 authors...
We have tested the effect of all 20 proteinogenic amino acids on the activity of the M2 isoenzyme of pyruvate kinase (M2PYK) and show that, within physiologically relevant concentrations, phenylalanine, alanine, tryptophan, methionine, valine, and proline act as inhibitors, while histidine and serine act as activators. Size exclusion chromatography has been used to show that all amino acids, whether activators or inhibitors, stabilise the tetrameric form of M2PYK. In the absence of amino-acid li...
9 CitationsSource
#1W. Zhong (Singapore–MIT alliance)H-Index: 2
#2Liang Cui (Singapore–MIT alliance)H-Index: 3
Last.Peter C. Dedon (MIT: Massachusetts Institute of Technology)H-Index: 48
view all 12 authors...
Pyruvate kinase (PYK) is an essential glycolytic enzyme that controls glycolytic flux and is critical for ATP production in all organisms, with tight regulation by multiple metabolites. Yet the allosteric mechanisms governing PYK activity in bacterial pathogens are poorly understood. Here we report biochemical, structural and metabolomic evidence that Mycobacterium tuberculosis (Mtb) PYK uses AMP and glucose-6-phosphate (G6P) as synergistic allosteric activators that function as a molecular “OR ...
11 CitationsSource
#1Meng YuanH-Index: 3
#2Montserrat G. Vásquez-Valdivieso (Edin.: University of Edinburgh)H-Index: 2
Last.Malcolm D. WalkinshawH-Index: 50
view all 6 authors...
Abstract The gluconeogenic enzyme fructose-1,6-bisphosphatase has been proposed as a potential drug target against Leishmania parasites that cause up to 20,000–30,000 deaths annually. A comparison of three crystal structures of Leishmania major fructose-1,6-bisphosphatase ( Lm FBPase) along with enzyme kinetic data show how AMP acts as an allosteric inhibitor and provides insight into its metal-dependent reaction mechanism. The crystal structure of the apoenzyme form of Lm FBPase is a homotetram...
2 CitationsSource
#1Meng YuanH-Index: 3
Last.Malcolm D. WalkinshawH-Index: 50
view all 6 authors...
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#1Meng YuanH-Index: 3
Last.Malcolm D. WalkinshawH-Index: 50
view all 6 authors...
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Last.Houston
view all 4 authors...
Background & Hypothesis: The parasitic protozoa from the order Trypanosomatida relies exclusively on glycolysis for its survival in the mammalian hosts. As a corollary, the enzymes in this pathway have been recognised as chemotherapeutic targets. Phosphoglycerate mutase (iPGAM), which is the seventh enzyme in the pathway, is of particular interest because it possesses no structural and biochemical relationship with the corresponding enzyme in human. This enzyme has also been validated as an attr...
#1Hugh P. MorganH-Index: 17
#2W. ZhongH-Index: 4
Last.Malcolm D. WalkinshawH-Index: 50
view all 6 authors...
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#1W. ZhongH-Index: 4
#2Hugh P. MorganH-Index: 17
Last.Malcolm D. WalkinshawH-Index: 50
view all 6 authors...
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#1Hugh P. Morgan (Edin.: University of Edinburgh)H-Index: 17
#2W. Zhong (Edin.: University of Edinburgh)H-Index: 4
Last.Malcolm D. Walkinshaw (Edin.: University of Edinburgh)H-Index: 50
view all 6 authors...
The transition between the inactive T-state (apoenzyme) and active R-state (effector bound enzyme) of Trypanosoma cruzi pyruvate kinase (PYK) is accompanied by a symmetrical 8° rigid body rocking motion of the A- and C-domain cores in each of the four subunits, coupled with the formation of additional salt bridges across two of the four subunit interfaces. These salt bridges provide increased tetramer stability correlated with an enhanced specificity constant (kcat/S0.5). A detailed kinetic and ...
8 CitationsSource
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