Thoughts on interactions between PGRMC1 and diverse attested and potential hydrophobic ligands

Progesterone Receptor Membrane Component 1 (PGRMC1) is located in many different subcellular locations with many different attested and probably location-specific functions. PGRMC1 was recently identified in the mitochondrial outer membrane where it interacts with ferrochelatase, the last enzyme in the heme synthetic pathway. It has been proposed that PGRMC1 may act as a chaperone to shuttle newly synthesized heme from the mitochondrion to cytochrome P450 (cyP450) enzymes. Here we consider potential roles that PGRMC1 may play in transferring heme, and other small hydrophobic ligands such as cholesterol and steroids, between the hydrophobic compartment of the membrane lipid bilayer interior to aqueous proteins, and perhaps to the membranes of other organelles. We review the synthesis and roles of especially PGRMC1- and cyP450-bound heme, the sources and transport of cholesterol, the involvement of PGRMC1 in cholesterol regulation, and the production of the first progestogen pregnenolone from cholesterol. We also show by clustering by inferred models of evolution (CLIME) analysis that PGRMC1 and related proteins exhibit co-evolution with a series of cyP450 enzymes, as well as a group of mitochondrial proteins lacking in several parasitic protist groups. The blood fluke Schistosoma mansoni also lacks a PGRMC1 homolog as well as cyP450 s involved in cholesterol synthesis, suggesting co-evolution of the combined loss of PGRMC1-like and sterologenic cyP450 proteins by distinct uni- and multi-cellular parasites. Altogether, PGRMC1 is implicated with important roles in sterol synthesis and energy regulation that are dispensable in certain parasites. Some novel hypothetical models for PGRMC1 function are proposed to direct future investigative research.