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.
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.
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.
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.
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.
