PCSK1

PCSK1, or proprotein convertase subtilisin/kexin type 1, is a member of the proprotein convertase family of subtilisin-like serine endopeptidases. It encodes the enzyme proprotein convertase 1 (PC1/3), which activates a range of peptide hormones and neuropeptides by proteolytic cleavage of their inactive pro-forms within the secretory pathway.

In humans, the PCSK1 gene is expressed predominantly in neuroendocrine tissues, including the pancreas, pituitary, hypothalamus, and certain brain regions, as well as enteroendocrine cells. PC1/3 is activated by autocatalytic processing in the secretory pathway and then cleaves peptide precursors at basic residues, generating mature hormones and neuropeptides.

Physiological substrates include proinsulin (to insulin and C-peptide), proglucagon (to glucagon and GLP-1 fragments), and POMC-derived peptides such as ACTH and alpha-melanocyte-stimulating hormone. Through such processing, PC1/3 participates in regulation of appetite, energy balance, glucose homeostasis, and endocrine signaling.

Deficiency of PCSK1 due to biallelic mutations results in PCSK1 deficiency, a rare neuroendocrine obesity syndrome. Affected individuals often present with severe early-onset obesity, hypogonadism or other pituitary hormonal deficiencies, growth retardation, and impaired glucose regulation. The condition underscores PC1/3’s role in processing multiple hormones and neuropeptides.

Genetic variation in PCSK1 has been associated with obesity and metabolic traits in population studies, though effects are typically modest and context-dependent. PCSK1 and related proprotein convertases are subjects of ongoing research for their roles in metabolism and endocrine disorders.