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    Guoqing Du, PhD, John D. Schuetz, PhD, and Partha Krishnamurthy, PhD

    ABCB6 is key to production of heme in hemoglobin

    St. Jude researchers discover that ABCB6 proteins in the outer membrane of mitochondria are at the center of the cell’s network of biochemical reactions that control heme production

    Investigators at St. Jude Children's Research Hospital have discovered that a protein called ABCB6 plays a central role in production of a molecule that is key to the ability of red blood cells to carry oxygen, of liver cells to break down toxins, and of cells to extract energy from nutrients.

    The St. Jude investigators showed that ABCB6 is lodged within the outer membrane mitochondria—the tiny sacs that are the energy powerhouses in cells—and that it ferries into mitochondria a type of molecule called a porphryin—a molecule essential for life. A report on these results appears in the advanced online publication of Nature.

    Inside the mitochondrion, porphyrins are converted to heme. Heme is the oxygen-carrying part of the red blood cell molecule called hemoglobin, as well as a critical part of certain liver enzymes that break down toxins, and so-called “respiratory chain” enzymes in mitochondria that use oxygen to produce energy-rich molecules. 

    The discovery of the location and function of ABCB6 solved the long-standing riddle of how porphyrins get into mitchondria so they can be used to make heme, said John Schuetz, PhD, a member of St. Jude Pharmaceutical Sciences.

    The team found that the increase in ABCB6 in mitochondrial membranes caused the cells to make more porphyrin, the building block of heme. “Any disruption of this relationship can cause serious problems in the cell by altering levels of heme or porphyrins,” Schuetz said. 

    One such group of diseases are the porphyrias, which are caused by a buildup of porphyrins. Cutaneous porphyria causes the skin to blister and swell in sunlight; and acute porphoryia triggers pain paralysis, cramping and personality changes or mental disorders. Also, people with porphyria can suffer sudden, acute attacks if they take certain tranquilizers and other drugs that interfere with this system. “So our work contributes to the overall picture of how disruption of the biochemical pathway of heme production can cause a variety of serious diseases, such as porphyria,” Schuetz said.

    Other authors include co-first authors Partha Krishnamurthy and Guoqing Du, Yu Fukuda, Daxi Sun, Janardhan Sampath, Kelly Mercer, Junfeng Wang, Beatriz Sosa-Pineda and Gopal Murti, all of St. Jude.

    This work was supported in part by the National Institutes of Health and ALSAC.

    November 2006