The role of ABCG2 and ABCB6 in porphyrin metabolism and cell survival.
The porphyrins (such as heme) are essential molecules within cells and have multiple roles in essential cellular processes such as: the mitochondrial electron transport chain, free-radical detoxification, and metabolism. The porphyrins need energy to traverse biological membranes. Our understanding of ABC transporters role in regulating intracellular porphyrin homeostasis is only now beginning to be understood. Two important contributors are members of the ABC transporter gene family: ABCB6 and ABCG2. ABCB6 is the first ABC transporter located in the outer mitochondrial membrane and oriented to facilitate porphyrin import. Consequently, ABCB6 can regulate and appropriately orchestrate porphyrin synthesis. This leads to an ability to regulate the amount of heme associated with heme requiring proteins. This ability can facilitate a cells protective response to an array of toxic insults. ABCG2 also binds and transports porphyrins, however its location at the plasma membrane provides a mechanism to remove excess porphyrins. Because ABCG2 is upregulated by hypoxia this provides a mechanism to export porphyrins, rebalance porphyrins and protect cells from porphyrin overaccumulation. Such a mechanism would be important to hypoxic cells which exhibit an increase in porphyrin synthesis under hypoxic conditions. Finally, we propose that these two transporters (ABCB6 and ABCG2) are coordinately regulated to modulate porphyrin concentrations under normal physiological and pathological conditions.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. pkrishnamurthy@kumc.edu
Partha
P
Krishnamurthy
John D
JD
Schuetz
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D017484:Dermatitis, Phototoxic / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011166:Porphyrins / Q000378:metabolism*
C107991:ABCB6 protein, human; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D011166:Porphyrins; D006418:Heme