The role of transporters in cellular heme and porphyrin homeostasis.
Heme, a complex of iron and protoporphyrin IX (PPIX), senses and utilizes oxygen in nearly all living cells. It is an essential component of various hemoproteins, including those involved in oxygen transport and storage (hemoglobin, myoglobin), electron transfer, drug and steroid metabolism (cytochromes), and signal transduction (nitric oxide synthases, guanylate cyclases). The movement of heme into and within cells was thought to occur by diffusion. However, the chemical properties of heme make diffusion too slow to keep pace with biological processes, and accumulation of heme and its pre-cursor porphyrins in membranes can be deleterious. Due to pro-oxidant effects, heme may cause damage to DNA, proteins, the cytoskeleton and membrane lipids. The intracellular localization and concentrations of protoporphyrins and heme are tightly regulated, and elevated levels are linked to pathologic conditions (e.g., anemia, lead poisoning, thalassemias) associated with the formation of membrane lipid-damaging, reactive oxygen species. Until recently a mechanism to transport heme and protoporphyrins into organelles of mammalian cells had not been identified. In this review, we focus on the roles of the recently identified heme/porphyrin transport proteins heme carrier protein 1 (HCP1), FLVCR, Abcg2 and Abcb6 and discuss how these transporters contribute to intracellular heme and porphyrin homeostasis.
Krishnamurthy
Partha
P
Department of Pharmaceutical Sciences, MS 313, St. Jude Children's Research Hospital, 332. N. Lauderdale Avenue, Memphis, TN 38105, USA.
Xie
Tao
T
Schuetz
John D
JD
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D006418:Heme / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011166:Porphyrins / Q000502:physiology*; D058979:Proton-Coupled Folate Transporter; D011963:Receptors, GABA-A / Q000502:physiology; D011991:Receptors, Virus / Q000378:metabolism
C107991:ABCB6 protein, human; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; C492690:FLVCR1 protein, human; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D011166:Porphyrins; D058979:Proton-Coupled Folate Transporter; D011963:Receptors, GABA-A; D011991:Receptors, Virus; C505058:SLC46A1 protein, human; D006418:Heme