Proenkephalin

Proenkephalin, also known as preproenkephalin, is a precursor protein that gives rise to enkephalin opioid peptides. In humans, it is encoded by the PENK gene and is expressed in various brain regions, including the striatum, cortex, hypothalamus, and brainstem, as well as in some peripheral tissues. The translated polypeptide contains several enkephalin sequences separated by basic amino acid pairs that serve as cleavage sites. Proteolytic processing by prohormone convertases and carboxypeptidases cleaves proenkephalin to generate multiple active opioid peptides, most notably Met-enkephalin and Leu-enkephalin, which are among the endogenous ligands for opioid receptors.

Enkephalin peptides derived from proenkephalin primarily bind to delta opioid receptors and, to a lesser extent, mu receptors, producing analgesia, modulation of nociception, and effects on mood, stress, and reward. Proenkephalin-derived peptides participate in pain inhibition, emotional regulation, and neuroendocrine signaling, and are released with other neurotransmitters in response to stress or noxious stimuli.

Regulation and clinical relevance: Altered PENK expression or enkephalin levels have been linked to pain sensitivity, opioid tolerance, mood disorders, and addiction-related processes in both preclinical and clinical contexts. The gene and its peptide products are studied as targets for analgesic therapies and as biomarkers for affective states.

Note: The term preproenkephalin reflects the presence of a signal peptide that directs the nascent polypeptide to the secretory pathway; after signal peptide removal, the proenkephalin protein is processed to active enkephalin peptides.