POMC is synthesized in brain, pituitary gland, and skin cells. It is transported into the secretory pathway and processed by several enzymes into a variety of active peptides, depending on the cells in which it is synthesized. In hypothalamic neurons, POMC processing to produce α-MSH is particularly important. The POMC precursor is first cut by proconvertase 1 (PC1) to release ACTH_1–39, which is then cut by proconvertase 2 (PC2) to produce α-MSH_1–17. Carboxypeptidase E (CPE) removes the basic amino acids (Lys-Lys-Arg) from the C terminus, and peptidyl α-amidating monooxygenase (PAM) converts the C-terminal glycine to an amide (NH₂). The N terminus of α-MSH_1–13 is acetylated by N-acetyltransferase (NAT) to produce mature, functional α-MSH_1–13. After release from synaptic vesicles, α-MSH_1–13 is inactivated (to α-MSH_1–12) by the action of PRCP, the subject of the Wallingford et al. (8) study in this issue of the JCI.