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Your search keyword '"Leonard PG"' showing total 2 results
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2 results on '"Leonard PG"'

1. Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase.

Author

Hicks KG, Cluntun AA, Schubert HL, Hackett SR, Berg JA, Leonard PG, Ajalla Aleixo MA, Zhou Y, Bott AJ, Salvatore SR, Chang F, Blevins A, Barta P, Tilley S, Leifer A, Guzman A, Arok A, Fogarty S, Winter JM, Ahn HC, Allen KN, Block S, Cardoso IA, Ding J, Dreveny I, Gasper WC, Ho Q, Matsuura A, Palladino MJ, Prajapati S, Sun P, Tittmann K, Tolan DR, Unterlass J, VanDemark AP, Vander Heiden MG, Webb BA, Yun CH, Zhao P, Wang B, Schopfer FJ, Hill CP, Nonato MC, Muller FL, Cox JE, and Rutter J

Subjects
Humans, Fatty Acids metabolism, Organ Specificity, Mass Spectrometry methods, Allosteric Regulation, Carbohydrate Metabolism, L-Lactate Dehydrogenase metabolism, Metabolome
Abstract

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.

Published
2023
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2. Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site.

Author

Liu Z, Li Y, Chen H, Lai HT, Wang P, Wu SY, Wold EA, Leonard PG, Joseph S, Hu H, Chiang CM, Brasier AR, Tian B, and Zhou J

Subjects
Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacokinetics, Binding Sites, Cell Cycle Proteins metabolism, Cell Line, Crystallography, X-Ray, Gene Expression drug effects, Humans, Interleukin-6 genetics, Interleukin-6 metabolism, Male, Mice, Inbred C57BL, Oxidoreductases Acting on CH-CH Group Donors genetics, Oxidoreductases Acting on CH-CH Group Donors metabolism, Phenylurea Compounds chemical synthesis, Phenylurea Compounds metabolism, Phenylurea Compounds pharmacokinetics, Protein Binding, Protein Domains, Rats, Transcription Factors metabolism, Mice, Anti-Inflammatory Agents pharmacology, Cell Cycle Proteins antagonists & inhibitors, Nuclear Proteins antagonists & inhibitors, Phenylurea Compounds pharmacology, Transcription Factors antagonists & inhibitors
Abstract

Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 ( 52 ) targeting a unique, previously unreported binding site, while exhibiting significant anti-inflammatory activities in vitro and in vivo . The X-ray crystal structural analysis of ZL0590 in complex with human BRD4 BD1 and the associated mutagenesis study illustrate a first-in-class nonacetylated lysine (KAc) binding site located at the helix αB and αC interface that contains important BRD4 residues (e.g., Glu151) not commonly shared among other family members and is spatially distinct from the classic KAc recognition pocket. This new finding facilitates further elucidation of the complex biology underpinning bromodomain specificity among BRD4 and its protein-protein interaction partners.

Published
2022
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