Milestones in the Elucidation of Heme Biosynthesis

Heme (protoheme IX) is an essential cofactor in biology, serving diverse roles including, but not limited to, one-electron reactions, oxygen transport, catalysis, and signaling. The elucidation of its biosynthetic pathway represents one of the more remarkable scientific accomplishments of the past century. Early 19th-century chemists first isolated, named and characterized porphyrins, while their structural determination by Fischer in the 1920s earned a Nobel Prize. The mid-20th century ushered in isotopic tracer studies which revealed glycine and succinyl-CoA as the starting substrates for the pathway to heme. Identification of porphobilinogen (PBG) as an early pathway intermediate led to the identification of 5-aminolevulinic acid (ALA) as the first committed pathway precursor. Subsequent decades brought the recognition of porphyrinogens as true pathway intermediates, the sequence of decarboxylation and oxidation steps, the identification of the glutamate-based pathway to ALA in plants and most bacteria, the characterization of all pathway enzymes, the discovery of alternate bacterial pathways, and identification of multiprotein complexes. This review traces the historical progression of discoveries, highlighting both the breakthroughs and missteps that shape the current view of heme biosynthesis, and underscores the interplay of chemistry, physiology, and molecular biology in unraveling this ancient metabolic pathway.