Hepatic heme biosynthetic pathway and associated AHPs. Heme biosynthesis involves the conversion of glycine and succinyl CoA into heme via 8 enzymatic steps (enzymes are shown in italics). The first and rate-limiting enzyme, 5-aminolevulinic acid synthase 1 (ALAS1), uses pyridoxal 5-phosphate (or active vitamin B6) as a cofactor to condense glycine and succinyl CoA into 5-aminolevulinic acid (ALA). Two molecules of ALA are then condensed to form the monopyrrole porphobilinogen (PBG) through the action of the second enzyme, 5-aminolevulinic acid dehydratase. ALA and PBG are porphyrin precursors, and ALA in particular is believed to be neurotoxic. The third enzyme, hydroxymethylbilane synthase (HMBS), converts PBG to the linear tetrapyrrole, hydroxymethylbilane, which is then converted to the circular tetrapyrrole, uroporphyrinogen III, via uroporphyrinogen synthase. The subsequent 2 enzymatic reactions modify the side chains of the porphyrinogens, whereas the penultimate enzyme, protoporphyrinogen oxidase, oxidizes protoporphyrinogen IX to protoporphyrin IX. Finally, ferrochelatase inserts ferrous iron into protoporphyrin IX to form heme. In hepatocytes, heme synthesis is controlled by ALAS1 activity, which is regulated by the end-product, heme. Under heme-replete conditions, heme represses ALAS1 activity, whereas under heme-deficient conditions, this negative feedback inhibition is lost and heme synthesis is induced. The AHPs, shown in red, include 4 disorders that are caused by partial deficiencies of the corresponding heme biosynthetic enzymes.