Overview of cellular metabolism for heme synthesis during early and late erythropoiesis. A cartoon of a cell is shown where the plasma membrane is a heavy blue line, and the mitochondrial inner and outer membranes are red with intermembrane space in light pink. Plasma membrane transporters for glucose, glycine, and glutamine are orange; mitochondrial inner membrane transporters for glutamate, glycine, ALA, and pyruvate are green. The heme biosynthetic pathway is abbreviated as a dashed arrow, but is shown in its entirety in supplemental Figure 1. Heme, the end product, exits the mitochondrial matrix following its release from FECH, but the pathway for this is currently undetermined. The TCA cycle is in blue with the enzymes KDH and SCS see text) shown boxed in the figure. The site of inhibition by AOA is illustrated with a bold red X. Multiple glutamine transaminases exist within the cell, and all are inhibited by AOA. (A) Cellular metabolism for late erythropoiesis when large quantities of heme are necessary for hemoglobinization of the developing erythron. Inside the mitochondrion are shown the pathways of glutamate to ALA with KDH in complex with ALAS2 and the previously described heme metabolon (Heme Metab.)38 as a red pentagon. (B) Cellular metabolism during early erythropoiesis when heme for cellular functions is synthesized utilizing ALAS1. Under these conditions, the amounts of heme synthesized are relatively low, and the required succinyl-CoA can be provided by the TCA cycle.
