Peptidyl-glycine α-amidating monooxygenase

Majority of all biologically active peptides and peptide hormones undergo co- and post translational modifications, which is required for their full biological activities. Once active, peptide hormones function as signaling agents in paracrine and endocrine pathways in a large number of organisms. One such common post translational modification is a C-terminal α-amidation, which is achieved through the consecutive hydroxylase and lyase activities of a single bifunctional copper-dependent enzyme, peptidylglycine α-amidating monooxygenase (PAM) (Prigge et al., 2000).

In the first step, glycine-extended hormone intermediate is α-hydroxylated upon binding to the ascorbate reduced copper active site of the peptidylglycine α-hydroxylating monooxygenase (PHM). In the second step, zink-dependent peptidyl-α-hydroxyglycine-α-amidating lyase (PAL) finalize the prohormone activation by cleavage of glyoxylate from the peptidyl-α-hydroxyglycine (Prigge et al. 2004).

 

 

PAM is the only known enzyme to catalyze the formation of c‑terminally amidated bioactive peptide-hormones (Kumar, 2016) and it was found in variety of tissues, including brain, kidney, pituitary, gastrointestinal tract, neurons, blood plasma and reproductive tissues (Chen, Taylor, and Verchere 2018; Eipper, Mains, and Street 1988; Oldhaml et al. 1992; Schafer et al. 1992, Bolkenius and Ganzhorn 1998, Wand, Ney, Baylin, Eipper 1985). Already several decades ago the connection between the diverse human pathologies and the level of α-amidation has been made.

Thus, the increase of the PAM amidating activity could be directly linked to the presence or potential development of the medullary thyroid carcinoma, neuroendocrine and pancreatic endocrine tumors, insulin induced hypoglycemia, type 2 diabetes, multiple sclerosis, post-polio syndrome, diverse neural disfunction (Bousquet-Moore et al., 2010) and hypertension (Shimosawa et al., 2000) and many others. This vast abundancy of PAM in almost all cell types and its contribution to a vast spectrum of human pathologies, makes it a great potential biomarker to target disease diagnostics.