Physiological signaling in the absence of amidated peptides

Iris Lindberg and Christopher C. Glembotski

PNAS October 1, 2019 116 (40) 19774-19776

Figure: Summary of the effects of PAM deletion in neurons or cardiac myocytes. Shown are (A) the topology of PAM, (B) the catalytic conversion of C-terminally glycine-extended peptides to amidated peptides by PAM in the brain, (C) the effects of PAM deletion in excitatory forebrain neurons on amidated peptide levels and behavior in mice, (D) the association of PAM and pro-ANP in the heart and the cosecretional cleavage of pro-ANP to bioactive ANP, and (E) the effects of PAM deletion in atrial myocytes on ANP levels and behavior. Heart and brain images courtesy of Alina Bilal (San Diego State University, San Diego, CA).

Peptidergic signaling is an ancient manner of intertissue communication in multicellular organisms. Even the early eukaryote Trichoplax, with its limited 6-tissue repertoire, uses peptides to communicate between its tissues (1). Humans use peptidergic communication not only to transfer signals between tissues, but also to employ peptide signals in brain and peripheral nerve tracts to efficiently transfer information regarding hunger, anxiety, and many other types of physiologic states (reviewed in ref. 2). In PNAS, a study by Powers et al. (3), “Identifying roles for peptidergic signaling in mice,” describes an approach to the study of peptidergic function that depends on a unique aspect of how signaling peptides are synthesized.

The manner in which signaling peptides are synthesized has remained remarkably constant over millions of years of eukaryotic evolution. Within the regulated secretory pathway (present in neurons and neuroendocrine cells), small peptides are typically excised from larger precursors by “eukaryotic subtilases” at sites marked by pairs of basic amino acids, typically Lys-Arg, followed by a series of enzymatic reactions. These reactions serve to trim, modify, and/or protect the termini of the excised peptides and are catalyzed by a variety of enzymes in addition to the subtilases. These include a specific carboxypeptidase, carboxypeptidase E, which removes terminal basic residues, and an amidating enzyme, which protects the carboxyl terminus of the trimmed peptide from degradation and often confers receptor-specific information.

This latter enzyme, peptidylglycine α-amidating monooxygenase (PAM) (Fig. 1A), represents a particularly fascinating molecular entity. Formed from 2 entirely different catalytic species, a monooxygenase and a lyase, in neuroendocrine cells such as neurons in the brain, this complex enzyme catalyzes a 2-step reaction that transforms a terminal glycine residue into an amide (Fig. 1B) (4). The importance of PAM is underscored by the fact that more than half of all known peptides are amidated, and for most of them the C-terminal amide is required for bioactivity (2, 5). In agreement with the idea that amidated peptides represent critical signaling molecules, organisms as simple as coral, Chlamydomonas, and Trichoplax use amidated peptides to accomplish complex functions.

See more: https://www.pnas.org/content/116/40/19774