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J Biol Chem. 2018 Sep 14;293(37):14557-14568. doi: 10.1074/jbc.RA118.004169. Epub 2018 Jul 16.

Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells.

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From the Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio 44195.
the School of Chemistry and Biochemistry and Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332.
the Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Balidiri Reixac 10-12, Barcelona 08028, Spain, and.
the Laboratory of Clinical Biochemistry and Metabolism, Center of Pediatrics, Medical Center, University of Freiburg, D-79106 Freiburg, Germany.
From the Department of Inflammation and Immunity, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio 44195,


Cellular heme is thought to be distributed between a pool of sequestered heme that is tightly bound within hemeproteins and a labile heme pool required for signaling and transfer into proteins. A heme chaperone that can hold and allocate labile heme within cells has long been proposed but never been identified. Here, we show that the glycolytic protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) fulfills this role by acting as an essential repository and allocator of bioavailable heme to downstream protein targets. We identified a conserved histidine in GAPDH that is needed for its robust heme binding both in vitro and in mammalian cells. Substitution of this histidine, and the consequent decreases in GAPDH heme binding, antagonized heme delivery to both cytosolic and nuclear hemeprotein targets, including inducible nitric-oxide synthase (iNOS) in murine macrophages and the nuclear transcription factor Hap1 in yeast, even though this GAPDH variant caused cellular levels of labile heme to rise dramatically. We conclude that by virtue of its heme-binding property, GAPDH binds and chaperones labile heme to create a heme pool that is bioavailable to downstream proteins. Our finding solves a fundamental question in cell biology and provides a new foundation for exploring heme homeostasis in health and disease.


GAPDH; heme; heme chaperone; heme toxicity; heme trafficking; hemostasis; intracellular trafficking; iron; kinetics; porphyrin; tetrapyrroles

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