XENIN 25

Gene, mRNA, and precursor

The human COPA gene is an approximately 54.7-kb long gene that maps to the 1p23.2. Human COPA mRNA codes for a 1233-aa long protein. ProXen, the 35-aa N-terminal region, is cleaved into a 25-aa mature Xen.

Receptors

The action of Xen is mediated by neurotensin receptor subtype 1 (NTSR1); however, several biological actions of Xen are independent of NTSR1. Xen activates ERK signaling in subpopulations of hypothalamic neurons.

Biological functions

Xen-25 exerts multiple physiological functions in peripheral and central tissues. Xen-25 stimulates exocrine pancreatic secretion and is involved in glucose homeostasis. In the GI tract, Xen-25 regulates gastric and intestinal motility. Xen-25 induces gall bladder contraction. In central tissues, the icv administration of Xen-25 suppresses food intake.

Description

A 25-aa peptide with six C-terminal aa in common with the amphibian octapeptide xenopsin was identified from the human gastric mucosa in 1992 and named xenin. Xen was identified in various mammals, including dogs, pigs, rats, guinea pigs, and rabbits, in 1995.

Clinical Use

A novel hybrid peptide, exendin-4/gastrin/Xen-8, was developed to improve the metabolic status in obese diabetic mice.21 In addition, Xen-8, a fragment of Xen-25, possesses the same biological functions as Xen-25. Thus, not only Xen-25, but also Xen-8 and the hybrid peptide are expected to exert beneficial metabolic effects in relation to new therapeutic approaches for diabetes and obesity.

Structure and conformation

Xen is highly conserved across species from insects to mammals. It is cleaved from the N-terminus of its precursor, coatomer protein α (COPA), by an aspartic protease, presumably cathepsin E. Xen has close structural similarities to neurotensin, and is a part of the neurotensin/xenopsin/xenin family along with neuromedin N and kinetensin/NRP. Xen consists of 25 aa, and the putative aa sequence of Xen based on the COPA gene database is evolutionarily conserved from yeast to mammals. The aa sequence of Xen is identical in the acorn worm, salmon, wild turkey, Chinese hamster, mouse, bull, rhesus macaque, and human. The bioactive C-terminal octapeptide of Xen, termed Xen-8, is a natural metabolite that circulates in the plasma.