Integrative structural and functional analysis of human malic enzyme 3: A potential therapeutic target for pancreatic cancer
Tsehai A.J. Grell,
Mark Mason,
Aaron A. Thompson,
Jose Carlos Gómez-Tamayo,
Daniel Riley,
Michelle V. Wagner,
Ruth Steele,
Rodrigo F. Ortiz-Meoz,
Jay Wadia,
Paul L. Shaffer,
Gary Tresadern,
Sujata Sharma,
Xiaodi Yu
Affiliations
Tsehai A.J. Grell
Structural and Protein Sciences, Janssen Research and Development, LLC, Spring House, Pennsylvania 19477, United States
Mark Mason
Structural and Protein Sciences, Janssen Research and Development, LLC, Spring House, Pennsylvania 19477, United States
Aaron A. Thompson
Structural and Protein Sciences, Janssen Research and Development, LLC, San Diego, California 92121, United States
Jose Carlos Gómez-Tamayo
Computational Chemistry, Janssen Research and Development, LLC, Beerse, B2340, Belgium
Daniel Riley
Lead Discovery and Molecular Pharmacology, Janssen Research and Development, LLC, Spring House, Pennsylvania 19477, United States
Michelle V. Wagner
Emerging Science Initiative, Janssen Research and Development, LLC, San Diego, California 92121, United States
Ruth Steele
Structural and Protein Sciences, Janssen Research and Development, LLC, Spring House, Pennsylvania 19477, United States
Rodrigo F. Ortiz-Meoz
Lead Discovery and Molecular Pharmacology, Janssen Research and Development, LLC, Spring House, Pennsylvania 19477, United States
Jay Wadia
Emerging Science Initiative, Janssen Research and Development, LLC, San Diego, California 92121, United States
Paul L. Shaffer
Structural and Protein Sciences, Janssen Research and Development, LLC, Spring House, Pennsylvania 19477, United States
Gary Tresadern
Computational Chemistry, Janssen Research and Development, LLC, Beerse, B2340, Belgium
Sujata Sharma
Structural and Protein Sciences, Janssen Research and Development, LLC, Spring House, Pennsylvania 19477, United States; Structural and Protein Sciences, Janssen Research and Development, LLC, San Diego, California 92121, United States; Corresponding author.
Xiaodi Yu
Structural and Protein Sciences, Janssen Research and Development, LLC, Spring House, Pennsylvania 19477, United States; Corresponding author.
Malic enzymes (ME1, ME2, and ME3) are involved in cellular energy regulation, redox homeostasis, and biosynthetic processes, through the production of pyruvate and reducing agent NAD(P)H. Recent studies have implicated the third and least well-characterized isoform, mitochondrial NADP+-dependent malic enzyme 3 (ME3), as a therapeutic target for pancreatic cancers. Here, we utilized an integrated structure approach to determine the structures of ME3 in various ligand-binding states at near-atomic resolutions. ME3 is captured in the open form existing as a stable tetramer and its dynamic Domain C is critical for activity. Catalytic assay results reveal that ME3 is a non-allosteric enzyme and does not require modulators for activity while structural analysis suggests that the inner stability of ME3 Domain A relative to ME2 disables allostery in ME3. With structural information available for all three malic enzymes, the foundation has been laid to understand the structural and biochemical differences of these enzymes and could aid in the development of specific malic enzyme small molecule drugs.