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TitleIntegrative structural and functional analysis of human malic enzyme 3: A potential therapeutic target for pancreatic cancer.
Journal, issue, pagesHeliyon, Vol. 8, Issue 12, Page e12392, Year 2022
Publish dateDec 19, 2022
AuthorsTsehai 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 /
PubMed AbstractMalic 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 ...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.
External linksHeliyon / PubMed:36590518 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.94 - 2.77 Å
Structure data

27936

8e76

EMDB-27936, PDB-8e76:
Cryo-EM structure of Apo form ME3
Method: EM (single particle) / Resolution: 2.51 Å

27937

8e78

EMDB-27937, PDB-8e78:
Cryo-EM structure of human ME3 in the presence of citrate
Method: EM (single particle) / Resolution: 2.77 Å

27945

8e8o

EMDB-27945, PDB-8e8o:
Cryo-EM structure of human ME3 in the presence of citrate
Method: EM (single particle) / Resolution: 2.77 Å

PDB-8eyn:
Crystal Structure of Human Mitochondrial NADP+ Malic Enzyme 3 in Apo Form
Method: X-RAY DIFFRACTION / Resolution: 1.94 Å

PDB-8eyo:
Crystal Structure of Human Mitochondrial NADP+ Malic Enzyme 3 with NADP bound
Method: X-RAY DIFFRACTION / Resolution: 2.49 Å

Chemicals

ChemComp-NAP:
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

ChemComp-CIT:
CITRIC ACID

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsHYDROLASE / ME1 / ME2 / ME3 / NAD(P)-dependent malic enzymes / Integrated structural techniques / crystal structures / cryo-EM structures / drug discovery / allosteric mechanism / OXIDOREDUCTASE / Malic Enzyme / Rossmann fold / NADP(+)-binding

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