PreproPOMC

PreproPOMC, or preproopiomelanocortin, is the initial translation product of the POMC gene and serves as the secretory pathway–targeted precursor to a family of peptide hormones. It contains a signal peptide that directs it into the secretory pathway and a prohormone region that is subsequently processed into multiple active peptides.

In humans, the POMC gene is located on chromosome 2 and encodes a single polypeptide of about 267 amino acids, including a 26-residue signal peptide at the N-terminus. After signal peptide cleavage, the remaining 241 residues form the proopiomelanocortin precursor, which undergoes tissue-specific post-translational processing to yield several peptide products.

Processing and products: Endoproteolytic cleavage by prohormone convertases, notably PC1/3 and PC2, followed by carboxypeptidases, generates multiple peptides from POMC. The main derivatives include adrenocorticotropic hormone (ACTH, 1–39), beta-lipotropin, beta-endorphin, and alpha-melanocyte-stimulating hormone (alpha-MSH). The relative abundance of these products depends on the tissue type; corticotrophs predominantly produce ACTH, while melanotrophs and certain neurons produce MSH-related peptides and endorphins.

Function: The POMC-derived peptides act in diverse physiological pathways. ACTH stimulates cortisol production by the adrenal cortex; alpha-MSH regulates pigmentation and energy homeostasis via melanocortin receptors; beta-endorphin functions as an endogenous opioid with analgesic properties. The coordinated production of these peptides links stress response, metabolism, pain modulation, and pigmentation.

Clinical relevance: Mutations in POMC or defects in its processing enzymes can cause POMC deficiency syndromes characterized by early-onset obesity, adrenal insufficiency, and hypopigmentation, reflecting the loss of multiple POMC-derived peptides.